How to implant a phrenic nerve stimulator for treatment of central sleep apnea?

Abstract Background Central sleep apnea (CSA) is a breathing disorder caused by the intermittent absence of central respiratory drive. Transvenous phrenic nerve stimulation is a new therapeutic option, recently approved by the FDA , for the treatment of CSA. Objective To describe the technique used to implant the transvenous phrenic nerve stimulation system (the remedē System, Respicardia, Inc). Methods The remedē System is placed in the pectoral region, typically on the right side. A single stimulation lead is placed in either the left pericardiophrenic vein (PPV) or the right brachiocephalic vein (RBC). A sensing lead is placed into the azygous vein to detect respiration. Results In the remedē System Pivotal trial, 147 of 151 (97%) patients were successfully implanted with the system. Sixty‐two percent of stimulation leads were placed in the PPV and 35% in the RBC. Mean procedure time was 2.7 ± 0.8 hours and 94% of patients were free from implant‐related serious adverse events through 6 months. Conclusion In patients with CSA, transvenous phrenic nerve stimulation is an effective and safe therapy with an implant procedure similar to that of cardiac implantable electronic devices.


| BACKGROUND
Central sleep apnea (CSA) is a breathing disorder characterized by periods of apnea or absence of airflow caused by absent central respiratory drive because of increased sensitivity to the partial pressure of CO 2 . 1 CSA commonly presents as Cheyne-Stokes breathing, characterized by cycles of deep, rapid, crescendo decrescendo breathing (hyperpnea), followed by slower, shallower breathing (hypopnea), or no breathing without respiratory effort from the diaphragm (apnea). 1 Etiologies of CSA include cardiovascular disease, stroke, chronic use of opioids, renal disease, and idiopathic causes. The prevalence of CSA in atrial fibrillation and heart failure is as high as 30% and 40%, respectively. 2,3 Moreover, a well-established relationship exists between Cheyne-Stokes respirations and increased mortality in patients with heart failure. [4][5][6] In addition to increased mortality, the recurring hypoxemia and neurohormonal activation associated with CSA lead to systemic and pulmonary hypertension, arrhythmias, and increased cardiovascular burden. 5,6 To date, treatment options for CSA have been limited, especially in patients with heart failure and reduced left ventricular function where mask-based therapies may, in fact, lead to an increase in mortality (SERVE-HF). 7,8 The remedē System is a novel implantable technology that is FDA-approved to treat moderate to severe CSA in adult patients. 9 The remedē System is comprised of an implantable pulse generator (IPG), a stimulation lead for unilateral phrenic nerve stimulation, an optional sensing lead to detect respirations and a programmer. The IPG is a programmable device that provides an electrical stimulus to the left or right phrenic nerve and monitors the patient's respiration using transthoracic impedance. Stimulation of the left or right phrenic nerve causes the diaphragm to contract, thereby developing negative intrathoracic pressure and restoring regular breathing pattern. 10 Because of the lack of therapeutic options available for patients with CSA and the morbidity associated with the disease, phrenic nerve stimulation is an important treatment, especially for patients with concomitant heart failure. The remedē System Pivotal Trial demonstrated significant improvements in the number of sleep apnea events, sleep architecture, hypoxia, and arousals (all P < 0.001). The safety profile demonstrated a 91% freedom from adverse events associated with the implant procedure, the remedē System, or delivered therapy through the 12-month visit. Further, the study showed significant improvements in patient's quality of life as measured by the Epworth Sleepiness Scale and Patient Global Assessment. 9 Recently, improvements were seen at 12 months in ejection fraction, Minnesota Living with Heart Failure Questionnaire, and a trend towards increased time to first heart failure hospitalization. 11 This article describes the implant techniques and experience of this important new therapeutic modality for the treatment of CSA.

| Venous access
The implant procedure is performed in the electrophysiology laboratory under conscious sedation as the patient and physician must communicate during stimulation lead placement testing. Patient preparation and antibiotics are similar to cardiac implantable electronic device (CIED) implants. 12 The remedē System guide catheter (Respiguide, Respicardia, Inc) and stimulation leads are designed primarily for right-sided access, however, the system can be implanted on the patient's left side. Venous access is obtained by means of the right axillary, cephalic, or subclavian vein. Two long access wires (150 cm) are advanced into the inferior vena cava. The procedures and techniques used to deploy the lead into the PPV are described below.

| Implantation of the stimulation lead
To visualize the PPV, the 7 French (Fr) guide catheter is delivered over an access wire into the superior vena cava (SVC). Using the guide catheter and the access wire, the guide catheter is advanced into the LBC (Video S1), and the tip is positioned at the junction of the left subclavian and LBC veins ( Figure 1A). With the guide catheter and inner catheter oriented towards the floor of the LBC, a nonselective contrast injection is performed to identify venous branches ( Figure 1B

| Implantation of the sensing lead
Once the stimulation lead is deployed, the sensing lead is implanted into the azygos vein or one of its lateral branches. The sensing lead can be any 6 Fr bipolar lead with a passive fixation bias, based on implanting physician preference. The sensing lead detects respiration by means of transthoracic impedance. The sensing lead is an optional lead. There was no difference in therapy effectiveness or safety outcomes in patients with or without dedicated sensing lead during the pivotal trial. One benefit of a dedicated sensing lead is that remedē System diagnostic software tools may display information with higher respiratory signal quality, which may reduce the number of patient visits needed during therapy titration.
Using the second venous access wire, a 9 Fr coronary sinus (CS) right guide catheter is delivered into the SVC to a level midway between the tracheal carina and junction of the brachiocephalic veins.
In the anterior-posterior (AP) projection, the tip of the guide catheter is Once the guide catheter is advanced to a depth midway between the diaphragm and azygos vein ostium, the 0.035" wire is removed and a venogram is performed to confirm cannulation of the azygos vein and to  Figure 4B; Videos S12 & S13). The inner catheter can be used for a selective contrast injection to confirm the course and caliber of the branch vein. (Figure 5A; Video S14).
Subsequently, the 9 Fr guide catheter is advanced up to or into the branch in preparation for delivery of the sensing lead. The inner catheter is then removed and the sensing lead is back loaded onto the 0.014" wire and advanced into the side branch, positioning the electrodes 7 to 10 cm lateral to the spine ( Figure 5B; Video S15). No electrical testing of the sensing lead is needed. Using the 0.014" coronary wire to stabilize the lead, the guide catheter is removed using a slitter and standard coronary sinus catheter removal techniques. The sensing lead is stabilized using the ligature sleeve.  Figure 6A; Video S17).

| Device activation and operation
After a 1-month period allowed for healing and lead maturation, patients undergo therapy initiation. Therapy is programmed to automatically begin when the patient is in a sleeping position, at rest during their normal sleep hours, and after lead impedance is measured. Individualized device settings, including therapy start/stop times and programmed stimulation parameters, are determined by in-office testing, interviewing the patient regarding sleep habits and, when necessary, monitoring patient response to overnight stimulation.  During implantation, ERS in the ipsilateral shoulder or neck with or without diaphragmatic contraction was detected in 11 of 151 (7%) patients during implantation. All were resolved with repositioning of the lead during the procedure or through the use of alternate electrodes at the time of therapy initiation.

| Alternate approach
The average overall procedure time (skin to skin) was 2.7 ± 0.8 hours from the first incision to final suture. Implanters with seven or more cases   10 contraction enables the resumption of a normal breathing pattern and stabilization of blood carbon dioxide levels. 16 By stabilizing carbon dioxide, phrenic nerve stimulation prevents apneic events and the subsequent periods of rapid breathing. Sensing of this respiration pattern is accomplished by programming a sensing vector using either the stimulation lead or sensing lead. The vector is determined at therapy initiation at which time various sensing vectors are evaluated.
Compared to the surgical implantation of a cuff electrode, the transvenous approach eliminates the risk of damage to the nerve, cuffrelated neural compression, and impairment of blood flow that can lead to degeneration and demyelination of axons. Furthermore, the transvenous approach offers the patient a rapid and comfortable recovery. The mean procedure time of 2.7 hours and the improvement in procedure time with growing experience commensurate with that previously reported. 17 The practicality and safety of implanting the remedē system permits the delivery of the only therapy that to date has been proven in a randomized controlled trial to ameliorate CSA and mitigate its harmful consequences. 8

| CONCLUSION
Phrenic nerve stimulation is a safe and novel means for the treatment of CSA. The transvenous implantation technique of the remedē System is very similar to CIED procedures utilizing instruments and techniques familiar to electrophysiologists. The ability to implant the remedē System enables the only therapy shown to meaningfully improve CSA and its detrimental clinical sequelae.