Interventional Bronchoscopy: Cryotherapy

General description of procedure, equipment, technique

Cryotherapy

Initially defined in 1995 and subsequently described in European Respiratory Society (ERS) and American Thoracic Society (ATS) guidelines, interventional pulmonology is “the art and science of medicine as related to the performance of diagnostic and invasive therapeutic procedures that require additional training and expertise beyond that required in a standard pulmonary medicine training program.” Clinical entities encompassed within the discipline include complex airway management, benign and malignant central airway obstruction, pleural diseases, and pulmonary vascular procedures.

Diagnostic and therapeutic procedures pertaining to these areas include rigid bronchoscopy, transbronchial needle aspiration, autofluorescence bronchoscopy, endobronchial ultrasound, transthoracic needle aspiration and biopsy, laser bronchoscopy, endobronchial electrosurgery, argon-plasma coagulation, cryotherapy, airway stent insertion, balloon bronchoplasty and dilatation techniques, endobronchial radiation (brachytherapy), photodynamic therapy, percutaneous dilatational tracheotomy, transtracheal oxygen catheter insertion, medical thoracoscopy, and image-guided thoracic interventions. This presentation focuses on cryotherapy.

Cryotherapy deals with the destruction of tissue through the cytotoxic effects of freezing. Documents from 3500 BC described the use of cold as treatment for swelling and war wounds, and Hippocrates noted the use of cold to treat orthopedic injuries. The Joule-Thomson effect, which describes the cooling of a gas or liquid when forced through a valve from a high-pressure to a low-pressure region, is the basis for cryoprobe therapy.

Damage induced by freezing occurs at several levels, including the molecular, cellular, and structural levels, as well as at the level of whole tissues. The effect of freeze injury is influenced by many factors, and survival of cells is dependent on the cooling rate, the thawing rate, the lowest temperature achieved, and whether repeated freezing-thawing cycles occur. Certain tissues (e.g., skin, mucous membranes, and granulation tissue) are cryosensitive, while others (e.g., fat, cartilage, and fibrous or connective tissue) are cryoresistant. Tissue cryosensitivity depends on cellular water content, so tumor cells may be more sensitive than normal cells.

Currently two techniques of cryotherapy are available for the airway. The more traditional “standard” method uses nitrous oxide (N₂O) and an enclosed cyroprobe with a metal tip for heat transfer. The vapor haze of N₂O occurs at the metal tip of the cryoprobe, where it expands from a high pressure to atmospheric pressure (the Joule-Thomson effect). This expansion lowers the temperature, producing droplets of liquid and reaching equilibrium at – 89^oC atmospheric pressure. Cryoprobe devices can be rigid, semi-rigid, or flexible and can be used with appropriate bronchoscopes.

A newer developing method of cryotherapy is termed metered cryospray (MCS). For this technique, liquid nitrogen (LN₂) is used as a cryogen. A cold-resistant catheter is placed into the airway via flexible or rigid bronchoscopy and LN₂ is released, undergoes rapid expansion and instantly vaporizes causing intense cooling of tissues in-line with the vapor stream. The egress of the gas is through the natural airway that is open to the atmosphere. Very rapid freeze-thaw cycles are obtained with MCS.

Whether using probe cryotherapy or MCS, the physics of heat transfer and tissue effects occur in similar fashions. Upon vaporization, heat is removed at a constant temperature (heat of vaporization). Several studies have shown that the core temperature needed for lesion destruction is between -20^o C and -40^o C. Freezing to -40^o C or below at the rapid rate of -100^o C per minute will cause more than 90 percent of cells to die.

Monitoring of tissue freezing remains a problem. The empirical method relies on the experience of the operator, who relies on the change in color or consistency of the frozen tissue and the length of freezing procedure. In clinical studies that use rigid, semi-rigid, or flexible cryoprobes, each freeze-thaw cycle is about 30 seconds. The thaw phase is almost immediate when using rigid probes that have a system of reheating; however, when flexible probes are used, thawing is achieved by equilibration with body temperature, thus increasing freeze-thaw cycle times. For cryospray, small studies suggest that freeze times of 5 seconds of frost formation on the tissue is followed by visually monitored thawing. As many as 5 cycles may be used to achieve the desired effect.

Indications and patient selection

Cryotherapy is indicated for tracheobronchial obstruction, and ablation of unwanted or abnormal tissue. Patient selection criteria are similar to those used for laser therapy, APC, or electrocautery, except when there is an urgency to treat. At this time, specific indications for MCS over cryoprobe techniques are not known. However, cryoprobes may be used for extraction of foreign bodies, blood clots, and mucus plugs.

Contraindications

There are no contraindications that are specific to cryotherapy. However, for MCS, an inability to open the airway or lesions too distally located within the bronchial tree to allow for rapid gas egress would be a contraindication.

Details of how the procedure is performed

The flexible cryoprobe is passed through the working channel of the bronchoscope, the tip of which is placed in the proximity of the tumor. Activation of the cryoprobe using a foot pedal elicits ice ball formation on the tip of the probe within thirty seconds. Two to three freeze-thaw cycles, each lasting one minute (30 second freeze followed by a 30 second thaw), are applied to the same or adjacent area. The tissues are frozen at -30° to -40°C.

The tip of the probe may be applied perpendicularly or tangentially, or it may be driven into the tumor mass. The metallic tip of the cryoprobe is placed on the tumor or pushed into it so that it produces circumferential freezing of maximal volume. Two to three freeze-thaw cycles are carried out at each site. The probe is then moved 5-6 mm, and another three cycles of cryotherapy are carried out in the new area. The hemostatic effect of freezing is often sufficient to stop hemoptysis when it is present at patient presentation.

For MCS, the tip of the catheter is placed in direct line with the target tissue. The ventilation system is opened to allow for gas egress and reduce the chance of barotrauma, and then gas is released at a constant flow rate. The tissue is observed and 5 seconds of frost formation on the tissue is monitored. The gas flow is then stopped and the tissue is allowed to thaw. Five cycles of freeze-thaw are performed in this fashion. The tissue is rapidly cooled to below -100°C.

Interpretation of results

Not applicable.

Performance characteristics of the procedure

Not applicable.

Outcomes

In a report describing eighty-one cryotherapy sessions performed in thirty-three consecutive patients with dyspnea, hemoptysis, cough, or stridor, most experienced improvement in symptoms. Another report of six hundred patients treated with cryotherapy found that 78 percent noticed a subjective improvement in symptoms, with reduction in cough (64%), dyspnea (66%), hemoptysis (65%), or stridor (70%).

Other studies have described cessation of hemoptysis in 80 percent of treated patients and reduction in dyspnea in 50 percent. Similar findings in a smaller series using fiberoptic bronchoscopy or by improvement of pulmonary function was seen in 58 percent of patients, and these changes in lung function correlated with symptoms.

Cryotherapy has been shown to be useful in recanalization of airways with endobronchial tumors, and success rates as high as 91 percent have been reported. Cryotherapy has also been helpful in procuring larger transbronchial biopsy specimens.

Recently, there has been renewed interest in cryotherapy for treatment of early stages of airway cancer. In one study of thirty-six patients with a total of forty-four lesions (“in situ” or microinvasive tumors of the upper airways or bronchial tree), complete clinical and histological control of the tumor was achieved in 88.8 percent with a mean follow-up of thirty-two months. The mean survival of this population was thirty months.

Benign lesions have been treated with cryotherapy with good results, particularly for granulomatous tissue, which is highly sensitive to the effects of cold. Cryotherapy may yield good results in management of carcinoids, cylindromas, and laryngotracheal papillomas when resectional surgery is not an option.

Cryotherapy has been used with success in the extraction of foreign bodies, mostly in the removal of friable biological matter, such as pills, peanuts, teeth, and chicken bones. The technique has also proved helpful in the removal blood clots, mucus plugs, and tissue slough.

MCS is relatively new with less data than traditional cryotherapy. In a treat and resect trial, MCS was found to cause tissue damage to approximately 1.5 mm but with no underlying connective tissue damage. In a portion of the studies that involved a delayed resection, complete or near complete healing of the mucosa was observed with persistent reduction in mucous glands and smooth muscle.

Outcomes from a multi-institutional registry have been published on cryospray. In this registry there were 21 intra-operative events in 80 patients undergoing 114 procedures. These data include two intra-operative deaths attributed to bradycardia, and three pneumothoracies. Recent changes in the indications for use recommends application of MCS at a distance of 2 cm from the lesion and to mitigate risk of gas under pressure being administered to the disrupted vascular tumor bed. However, the technique was relatively successful in achieving an improved caliber of the airway. More recent studies, such as one noted above, have not had the same complication rate, presumably because of a change in technology and experience with the procedure.

Alternative and/or additional procedures to consider

Alternatives to cryotherapy include ND:YAG laser, APC, and electrocautery.

Complications and their management

Bleeding, when it occurs, must be stopped. Early data suggests the risk of bleeding is less than other modalities.

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