Cryotherapy is an ancient and vibrant ablative treatment technique. Cryogenic substances and cryogenic instruments are applied to cause the target tissue cells to necrotize and fall off for the purpose of treating the disease. Cryotherapy currently includes both contact and non-contact modalities. Contact cryotherapy mainly refers to the traditional sense of cryoablation (freeze-thaw) and modern sense of cryorecanalization (cryotomy), while non-contact cryotherapy mainly refers to low-pressure spray cryotherapy (spray cryotherapy). Cryotherapy has been widely used to treat specific lung diseases, especially benign and malignant lesions in the airway lumen, using rigid bronchoscopy and/or bendable bronchoscopy as the interventional medium, which is a relatively safe, effective and easy to master treatment technique.
I. The working principle and basic equipment of cryotherapy technology
1, the principle and mechanism of cryotherapy: the molecular movement in the cell is closely related to the temperature. When the temperature decreases, the molecular movement slows down and eventually stops. Therefore, cryotherapy determines the factors of cell death: freezing duration, thawing time, the minimum temperature reached, freezing rate and the number of freezing – thawing, etc.. The cryoprobe refrigeration is based on the Joule-Thomson principle. When the liquid refrigerant is rapidly released from the high-pressure storage cylinder, the gas changes from a high-pressure state to a low-pressure state, and the rapidly expanding gas absorbs the thermal energy of the surrounding environment and converts it into the kinetic energy required for expansion, thus rapidly creating a low temperature at the front of the cryoprobe.
(1) The mechanism of freezing damage to cells: mainly includes ① the extrusion of crystals outside the cell and deformation of the cell (ice extrusion effect). (2) The crystals inside the cell to the cell membrane damage effect. ③Cell dehydration leading to cell disintegration. ④Thawing after freezing, especially slow natural melting, causes small ice crystals inside the cell to accumulate into large ice crystals, which can also contribute to cell destruction and death.
(2) Freeze-thaw and freeze-cut tissue mechanisms: mainly ① Freeze-thaw: freezing can form a clear demarcation between frozen and non-frozen tissue. The presence of microcirculation determines the effect of cryotherapy on the tissue. During the freezing process, thrombosis of microvessels within a 5 mm radius of the freezing probe leads to ischemia and infarction of the tissue, and Larson et al. reported that two distinct zones can be formed during cryoablation, namely the central cell necrosis zone and the surrounding cell damage zone. The central necrotic zone will be enlarged by the second freezing, therefore, the effect of single freezing treatment alone is not obvious during cryoablation. Moreover, ischemic necrosis of tissues appears only after 7-15 days of cryoablation, so the efficacy of freeze-thaw therapy is delayed and is not applicable to the treatment of relieving acute central airway obstruction. ② Cryotomy is performed on the basis of freeze-thawing. The crystalline ice formed at a low temperature of 0℃～-30℃ has a strong binding force, which can produce adhesion if the freezing probe is in contact with the tissue, and this adhesion force varies with the temperature, which is the basis of cryotomy. Plus there is a clear demarcation line between the frozen area and the surrounding area, which can easily remove the adhesion to the tumor tissues around the probe, except that a new type of cryoprobe needs to be used in the implementation of cryosection. Compared to conventional cryoprobes, the new probe has a larger surface area, which allows for greater freezing efficiency and freezing of larger tissues. The tip of the probe is also more securely attached to the central gas channel, allowing the new probe to withstand greater pulling forces. Therefore, the application of cryosection technology can promptly reduce or eliminate the symptoms of acute airway lumen obstruction.
2.Cryotherapy equipment and devices
(1) Freezing agent: At present, there are three main types of freezing agents used for bronchoscopic cryotherapy: carbon dioxide, nitrous oxide and liquid nitrogen. At room temperature, carbon dioxide will produce crystals after being released from the high-pressure storage cylinder, and these crystals will have some influence on the operation of the probe, but because of its safety and low price, it is more commonly used in China. Nitrous oxide released from the high-pressure storage cylinder can make the tip of the frozen probe reach -89℃ in a few seconds, and no crystals are formed, so it is most commonly used. Liquid nitrogen can make the lowest temperature of the probe tip can reach -196 ℃, commonly used in spray freezing treatment.
(2) The control device mainly includes the freezing host and control panel, foot switch. At present, the main products for domestic applications for the German ERBE company and Beijing Kulan company’s cryotherapy instrument. (3) freezing probe: divided into bendable freezing probe and hard freezing probe. They are used for bendable bronchoscopy and rigid bronchoscopy for interventional diagnosis and treatment, respectively. Used for freeze-cutting and freeze-checking for the new freezing probe, this probe is 78 cm long and 2.3-2.4 mm in diameter, different from the freeze-thawing probe, the new probe has a larger surface area, so that it can play a greater freezing effectiveness and freeze a larger tissue. The tip of the probe is also more securely attached to the central gas channel and can withstand greater pulling forces. The handle is reinforced with the probe to avoid excessive bending, the connector is independently designed to have a longer sterilization life, and the surface of the probe is made of hydrophilic material with anti-bending protection of the probe.
Operation method
Cryotherapy uses rigid bronchoscope and bendable bronchoscope as intervention tools. The choice is made according to the patient’s condition and the available equipment and personnel proficiency. In comparison, because cryotherapy is safe and less irritating to patients, it is more common to perform interventions under local anesthesia or general anesthesia through bendable bronchoscopes, and because the minimum diameter of the cryoprobe is 1.9 mm, bendable bronchoscopes with a working orifice of 2 mm or more can be selected. However, a larger diameter cryoprobe can be selected for rigid bronchoscopy with obvious effect and short treatment time, but it must be performed under general anesthesia.
1. Preoperative preparation: Routine reading of chest X-ray and chest CT to understand and be familiar with the site, extent, length and range of intraluminal lesions, and direct enhancement chest CT if necessary to clarify the relationship between lesions and blood vessels to determine freeze-thaw or cryotomy. Fully assess the general condition of the patient and the risk of treatment.
2.According to the patient’s condition and anesthesia mode, establish intravenous access and routinely monitor the patient’s ECG, respiration, blood pressure and finger pulse oxygen saturation intraoperatively and dynamically.
3.Operate according to the bronchoscopy routine. After identifying the lesion, aspirate the surface secretion and blood accumulation of the lesion, and routinely spray 1~2ml of 0.005% epinephrine dilution to reduce the oozing and bleeding situation.
The metal end of the freezing probe must be at least 5 mm away from the distal end of the bronchoscope, and the tip of the probe or the side wall of the probe can be used to freeze the lesion, and the metal end of the probe should be placed on the lesion or deep inside the lesion as far as possible to produce the maximum freezing effect.
5, the foot freezing switch lasts for about 30 s, there is an ice ball formed at the tip of the freezing probe, the tissue is white and dehydrated, allowing 30 s to 60 s of freezing, usually an experienced operator can decide the best freezing time based on the color change. Release the freezing switch and allow it to unthaw on its own, completing 1 freeze-thaw cycle for about 1 min to 3 min.
6. One week after the freeze-thaw treatment, bronchoscopy was performed. On the one hand, the effect of freeze-thaw treatment is evaluated, on the other hand, the necrotic tissue after freeze-thaw is cleaned up, and the cleaning can be done by applying bronchoscopic suction, biopsy forceps or foreign body forceps, and if necessary, freeze-mucosal removal is given for cleaning, and further freeze-thaw treatment is performed for residual lesions.
7, during cryotomy, the front end of the probe is inserted 1 cm to 2 cm inside the lesion, and then the pedal is stepped down to freeze, and the freezing time varies from 3 s to 20 s. Most of the freezing process is done under visualization to prevent frostbite to the normal airway wall. After the formation of crystals around the probe, pulling the freezing probe and bronchoscope can cut the frozen lesion tissue directly, and after removing the bronchoscope and freezing probe from the airway together, the cut tissue can be thawed by putting it in saline, and the target tissue in the airway can be cleaned by repeating the above operation.
8, low-pressure spray freezing in addition to the above steps, because liquid nitrogen sprayed into the target tissue when there is liquid into gas, the volume increases 700 times, so to spray freezing treatment at the upper end of the stenosis rather than perpendicular to the stenosis, and to ensure that a large amount of gas can be effectively released in a short period of time to avoid air pressure injury. Make sure to disconnect from the ventilator when spraying cryotherapy to allow for effective gas release. Each spraying is more than 5 seconds, 4 cycles that is to complete a treatment process, the total treatment time of about 30 min.
Third, the indications and clinical application of cryotherapy
1, the indications for cryotherapy
(1) Palliative treatment and resection of malignant tumors in the trachea and bronchial cavity. (2) Effective treatment of mucosal and submucosal carcinoma in situ and superficial carcinoma in the lumen of trachea and bronchus. (3) Radical treatment of benign tracheal and bronchial lesions. (4) Removal of foreign bodies in the trachea and bronchial lumen. (5) Removal of mucus plug, blood clot and granulation tissue in the trachea and bronchial lumen. (6) Hemoptysis caused by visible benign or malignant lesions. (7) Adjuvant therapy for chemotherapy and radiation treatment of malignant tumors.
2.The advantages of cryotherapy
(1) Easy to control the depth, thus the risk of perforation is small. (2) No damage to cartilage and connective tissue, thus high safety of cryotherapy in the airway cavity. (3) Since there is no high-frequency electrocautery effect, it can be used for the treatment of patients with pacemakers. (4) Cryotherapy is a low-temperature treatment, so there is no risk of misfire. (5) It is inexpensive, easy to master, and convenient to carry out widely. (6) It does not damage the stent and can be used for the elimination treatment of benign and malignant tissue hyperplasia in the airway stent.
3.Efficacy evaluation
(1) Cryotherapy for malignant tumors in trachea and bronchial cavity
Symptomatic, inoperable malignant tumors in the trachea and bronchial lumen are the main indications for cryotherapy. Lee et al. analyzed a total of 2353 patients in 16 relatively complete studies and showed significant improvement in respiratory symptoms, lung function and quality of life. The overall efficiency of treatment was 80%, and the incidence of complications ranged from 0 to 11.1% and were all within manageable limits. So far, studies have shown that bronchoscopic cryotherapy for malignant tumors in the trachea and bronchial lumen is safe and effective. Yu Xiaoying et al. performed cryotherapy on 56 cases of endotracheal malignant tumors with an efficiency of 96.4% and no significant complications occurred. Feng Huasong et al. performed freeze-thawing and freeze-cutting treatment on 30 cases of intraluminal malignant tumors in the trachea and bronchial lumen, and their efficiency rate was 91.7% without obvious complications. The symptoms of obstructive pneumonia and pulmonary atelectasis were significantly controlled after cryotherapy (66.7%). Compared with laser and electrocautery treatment, cryotherapy has the advantages of low cost, easy protection, and less prone to airway wall perforation and intraluminal burning.
Cryosurgery can effectively treat malignant tumors in the trachea and bronchial lumen. Cryosurgery was first reported by Hetzel et al. in 2004 because of the use of a new cryoprobe, which overcame the disadvantages of the slow effect of freeze-thaw therapy and was effective in achieving immediate recanalization of the airway lumen and complete removal of obstruction in the bronchial lumen. This prospective study was conducted in 60 patients. Of these patients, 23 had complete obstruction of the bronchial lumen and the other 37 patients had severe obstruction of the lumen. After a single cryotomy, complete recanalization of the tracheal lumen was achieved immediately in 37 patients (61%) and partial recanalization was achieved in 13 patients (22%). Although residual tumor tissue obstructed the airway, a 6 mm diameter tracheoscope was able to pass through the stenosis easily, achieving an overall success rate of 83%.
The treatment of tracheal and bronchial luminal malignancies with low-pressure spray freezing is just beginning. The results showed that the depth of impact on the airway was only 1.5 mm, and there was no significant impact on the airway cartilage and connective tissue, indicating that spray freezing is safe for treating lesions in the airway lumen. It is believed that with large-scale clinical research, low-pressure spray freezing will become a new option for treating malignant tumors in the airway lumen.
(2) Cryotherapy for benign tumors and benign lesions in the lumen of trachea and bronchus
Since cryotherapy is less likely to cause scar formation compared with thermal therapy, it has good application value for benign lesions of airway such as inflammation, trauma, granulomatous stenosis and hyperplasia caused by tracheal intubation, and also has certain efficacy for some benign tumors such as papilloma and malignant tumor. Among various benign lesions, the newborn granulation tissue is the most sensitive to the effect of freezing, such as the treatment of bronchial tuberculosis, especially the ulcerated necrotic type and granulomatous proliferative type of bronchial tuberculosis, the efficiency of luminal stenosis improvement can be as high as 100%, and also has good effect on the ablation treatment of granulation tissue hyperplasia lesions in the anastomosis after lung transplantation, airway stent and the granulation tissue at its two ends. The removal of proliferative granulation tissue in the airway lumen by cryosurgery is fast and effective, and Frank et al. have reported the immediate recanalization of the airway lumen by removing lipomas, mucus plug, tracheal foreign body, granulation tissue and carcinosarcoma in the bronchus by cryosurgery.
Some progress has been made in the study of spray freezing for benign airway stenosis. 35 patients with benign airway stenosis were treated by Fernando et al. using a combination of low-pressure spray freezing and balloon dilation techniques. Among them, 18 cases of subglottic stenosis, 9 cases of tracheal stenosis and 8 cases of bronchial stenosis were treated with a total of 63 low-pressure spray cryotherapy sessions, each with 3-4 spray cryotherapy cycles, and the symptom improvement rate was 84.9%, while the degree of airway stenosis improved significantly compared with that before treatment, with fewer complications. This was mainly due to the failure to effectively release the expanded gas when spraying cryotherapy close to the stenosis.
4. Complications of cryotherapy and treatment
(1) Bleeding: Whether it is freeze-thawing or freeze-cutting, the main complication is bleeding, but it generally occurs less often. For a small amount of bleeding, it does not need to be treated because of its own coagulation function. For a small amount of bleeding, bronchoscopic suction is given or ice saline is applied for flushing to stop the bleeding, and if the bleeding is slightly more, 0.005 % epinephrine dilution can be used for infiltration to stop the bleeding. In patients with significant bleeding, APC can be applied to stop the bleeding. There have been no reports of hemodynamic disturbances due to bleeding as a result of cryotherapy.
(2) Mediastinal emphysema and pneumothorax: rarely occur. If the mediastinal emphysema is serious, suprasternal fossa incision and drainage is feasible. If severe pneumothorax cannot be improved by oxygenation and other treatments, closed drainage of the chest cavity can be given.
(3) Others: Atrial fibrillation, bronchospasm, fever, etc. have been reported, which are mostly transient and can sometimes recover on their own without special treatment.
5.Cautions for cryotherapy
(1) Cryotherapy mainly removes benign or malignant lesions in the airway lumen, so cryotherapy cannot remove the invisible tissue and is not effective for extraluminal pressure lesions.
(2) When freeze-thaw treatment is performed on target tissues, at least three rapid freezing-slow thawing cycles should be performed on the same site for maximum freezing effect because the effect of one freezing treatment is not obvious. Freeze-thaw treatment requires one week for tissue detachment, so it is not suitable for the treatment of lesions that will lead to respiratory failure and need to be removed immediately. Also, the possibility of asphyxia due to edema of the surrounding tissues after freeze-thaw treatment should be considered. Cryotomy treatment is relatively rapid, but it should still be used with caution and not as a preferred technique for asphyxiating endotracheal lesions.
(3) When spraying cryotherapy, the rapid expansion of gas in a short period of time should be taken into account, so the effective channels for gas release should be unobstructed to avoid complications.
(4) Cryotherapy is only a treatment technique in the airway lumen, and combined application with other treatment methods will play a more obvious therapeutic effect.
IV. Conclusion
Cryotherapy is a safe, effective, inexpensive and relatively easy to master technology, mainly used for the treatment of benign and malignant lesions in the airway lumen. For malignant lesions in the airway cavity, cryotherapy can effectively improve clinical symptoms, improve the quality and prolong the survival time of patients. Cryotherapy has an extremely important role in the treatment of benign lesions because it is less likely to cause scarring. It is more effective when combined with other interventional therapies.