Wu Huiming, Zhao Jianjun

[The Third Clinical Medical College of Harbin Medical University]

Abstract

Since 2015, irreversible electroporation has been introduced and approved for clinical use in China. So far, some largescale centers and their experts in China have accumulated rich experience in the application of this technology. However, as a new technology, there are still many blind spots and misunderstandings in its technical promotion and clinical application. Therefore, this paper mainly discusses the basic principles and advantages of irreversible electroporation in the treatment of liver cancer, preoperative case screening, intraoperative operative points, postoperative management, efficacy evaluation, safety and complications, technical disadvantages and limitations, and makes a prospect for the future of irreversible Electroporation.

IRE Fundamentals and Advantages

Fundamental Principle：IRE is a novel therapeutic modality based on the principle of electroporation or electro-permeabilization, which is based on changing the electrochemical potential of the cell membrane by altering the electric field to polarize the lipid bilayer of the cell membrane, destabilizing it and creating nanoscale defects. These defects, called "nanopores" or "conductive pores", assist molecules to penetrate the cell membrane and eventually enter the target cell. Depending on the intensity of the pulse stimulation, the nanopores formed can be temporary (reversible electroporation). During clinical treatment, clinicians insert multiple probes in parallel around the tumor to form a capacitor-like structure between the tumor cells and the electrodes on either side of the tumor. By applying high-frequency electrical pulses instantaneously, the electric field of the target area is changed to induce the production of IRE in the target area.

Technical advantages：Since the principle of tumor cell removal by IRE is carried out by inducing apoptosis, this technique overcomes the thermal sedimentation effect of thermal ablation techniques such as radiofrequency ablation, and because it does not rely on high temperature when killing tumor cells, it does not produce coagulative necrosis during treatment and does not cause damage to the above-mentioned areas during the treatment of tumors located in the adjacent important ductal structures as well as the heart, diaphragm, and pancreas. It does not cause damage to these areas during the treatment of tumors located in the adjacent important ductal structures as well as the heart, diaphragm and pancreas. In clinical studies, this technique has also demonstrated the advantages of short operation time, precise localization, and activation of the body's immune system. Therefore, the indications for IRE treatment are broader than for other surgical procedures.

Intraoperative Anesthesia Management 

Assessment：Patients should be evaluated preoperatively prior to IRE to determine if they have arrhythmias or severe aortic valve insufficiency, coronary artery disease, or other factors that can produce adverse outcomes due to intraoperative blood pressure fluctuations. The patient is also evaluated preoperatively according to the American Society of Anesthesiologists (ASA) anesthesia risk classification criteria.

Pre-anesthesia preparation：Because of the need for complete muscle relaxation when treating patients with the IRE technique, patients are more susceptible to arrhythmias and elevated blood pressure during the procedure. Preoperative equipment should be prepared to measure muscle relaxation, heart rate, depth of anesthesia and body temperature.

Muscle relaxation testing：The IRE procedure can only be performed safely if the patient's muscle nerves are completely blocked. This is due to the fact that the probes used intraoperatively do not have a fixation device and therefore any type of intraoperative organ movement needs to be avoided in order to ensure a safe procedure. Since four probes are typically required intraoperatively for effective ablation, any moderate to severe retroperitoneal or diaphragmatic excitation can cause the target organ to move 3.0 to 5.0 cm, which may result in potential needle injury. Therefore, in order to perform the procedure safely and minimize injury, the surgeon needs to completely anesthetize the patient during the procedure and test for deep muscle relaxation. During clinical procedures, electrical pulses can cause slight muscle contractions in the treated area during the procedure, even after confirming that the patient is completely pharmacologically neuromuscularly blocked (TOF=0). These contractions may be due to the leakage current of the electrical pulses causing a regional electromagnetic field, which leads to muscle depolarization, which is not prevented by non-depolarizing neuromuscular blocking agents. Also, because there is no skeletal muscle distribution within the liver tissue, intraoperative overdose of muscle relaxants does not result in further improvement of probe tremor, but rather prolongs the patient's postoperative muscle recovery time. 

Respiratory testing：Clinicians should closely monitor changes in the patient's PETCO2 during mechanical ventilation and keep the patient's PETCO2 in the range of 35-45 mmHg, and perform blood gas analysis on the patient when necessary to prevent intraoperative hypercapnia.

Fluid management：IRE is a minimally invasive surgery and the intraoperative bleeding of patients is low. During clinical treatment, it is found that the intraoperative bleeding of patients is generally only 5~12ml, so the clinician can follow the 4-2-1 principle that the first 10kg of normal physiological requirement is at the rate of 4ml/(kg-h), the second 10kg at the rate of 2ml/(kg-h), and later at the rate of 1ml/(kg-h). The clinician should maintain the patient's urine volume above 0.5ml/(kg-h) during the operation.  

Heart rate detection：It is well known that strong currents have the potential to cause arrhythmias in patients, including ventricular tachycardia and even ventricular fibrillation. Due to the working principle of the IRE technique, the electric field it generates may interfere with the cardiac electrical activity. To prevent arrhythmias in patients intraoperatively, the operator must synchronize the frequency of the applied electrical impulses with the patient's heart rate. The reason for this is that the delivery of electrical impulse stimulation during absolute cardiac undershoot does not induce action potentials, so an electrocardiogram (ECG) should be used during the procedure and the patient's electrical activity should be closely monitored. It is important to note that IRE is contraindicated in patients with preexisting arrhythmias because of the poor reliability of R-wave detection in such patients, although there is no literature to support this, but accurate R-wave detection is also relied upon for other surgical applications, such as electrical cardioversion for atrial fibrillation. the reliability of R-wave detection in patients with arrhythmias requires further discussion. It has been documented that ECG signal loss can occur during surgery, and therefore the gain should be reduced and leads placed perpendicular to the electrodes during the procedure, which will improve the synchronization of the surgical device. 

Analgesia and hypertension management：During surgery, although the patient is in a state of complete muscle relaxation and deep anesthesia, there is still a rapid increase in blood pressure. Robert et al. found that remifentanil improved the efficiency of patient management of neuromuscular blockade and reduced blood pressure. In addition, this regimen reduced the overall operative time for IRE by 30 min (median time 12-40 min) compared to fentanyl, the most commonly used intraoperative analgesic, and significantly reduced the postoperative tracheal extubation time, with a median time of 8 min (range 3-19 min). When treating elderly patients with IRE, it is important to note that these patients have weak cardiovascular autonomic nervous system regulation and often have reduced ventricular diastolic function, requiring physicians to prevent hypotension in these patients after ablation.

Body temperature detection：Clinically, when IRE is applied to treat tumors, the temperature is lower than 50℃, which has the characteristics of short treatment time and no heat deposition effect, and will not cause significant increase of patient's body temperature when radiofrequency ablation and other techniques are used to treat liver tumors. In the process of clinical practice by measuring the nasopharyngeal temperature of patients, it was found that the body temperature during ablation generally decreased by 0.3~0.6℃ compared with that at the end of ablation, and the body temperature of patients were all lower than 36℃. Therefore, clinicians need to conduct routine body temperature detection on patients in the process of such procedures and take certain heat preservation measures such as increasing the temperature of operating room when necessary. Also, during clinical operations, there is a certain increase in temperature located in the ablation center area, which requires clinicians to carefully consider the impact of the increased temperature in the ablation center on the patient during IRE treatment and to support the use of pulse delivery protocols and devices to mitigate the degree of thermal effects.

Management of the recovery period from anesthesia：As the procedure for IRE requires the patient to be fully anesthetized to maintain the patient in a state of deep muscle relaxation i.e. to maintain a TOF of 0. When the procedure is completed, the patient needs to be admitted to the monitoring or recovery room to await full recovery of the patient's postoperative muscle relaxation and the clinician may give the patient appropriate sedative medication during this time. The clinician should remove the tracheal tube after the patient's tidal volume, consciousness and other indicators have reached the standard extubation indications under the guidance of the muscle relaxation monitor. At the same time, the clinician should conduct a visual analogue scale (VAS) to quantify the patient's pain after the operation and take necessary analgesic measures according to the patient's score.

Outlook

IRE, as an emerging ablation technique, is a safe and effective treatment, but at the same time there are still many uncharted areas to be explored. Firstly, although patients experience an accelerated heart rate during the procedure, whether the frequency of electrical stimulation can be appropriately accelerated to shorten the procedure time after the patient's heart rate is accelerated intraoperatively. Secondly, whether treatment of large and medium-sized liver tumors can be performed by inducing reversible electroablation with the aid of anti-tumor drugs. Finally, if the preoperative puncture biopsy results in mixed hepatocellular carcinoma or cholangiocarcinoma, whether it is necessary to clear the lymph nodes in the hilar region; if so, how to choose the relevant procedure. In addition, whether IRE is equivalent to surgical resection or conventional ablation when the tumor is ≤3 cm in diameter needs to be further investigated. It is worth noting that several studies have shown that the future direction of IRE technology is to be combined with immunotherapy. It is believed that with the continuous clinical trials in China and abroad, the efficacy and safety of IRE technology will be further improved for the benefit of more patients.

Currently, a multi-center clinical registration trial of the Steep Pulse Therapeutic Apparatus (Nanoknife) for the ablation treatment of pancreatic malignant tumors is underway in several hospitals across the country. For more information, please leave a message in the background or contact the following person by phone.

Contact person:Manage Zuo from Alpmed

Tel:022-23788188 Ext 7206