Diaphragm Pacing

The history of pacing the diaphragm is not new. The earliest record of phrenic stimulation for the treatment of asphyxia was reported in 1783. In the mid-1850s, French neurologists also proposed such an idea, but it was Hugo Wilhelm von Ziemssen who performed the first diaphragmatic pacing on a young female patient who had asphyxiated on charcoal vapor. Several decades later, Duchenne also commended the benefits of diaphragmatic stimulation. Diaphragmatic stimulation did not gain any momentum because of the crude nature of surgery and lack of appropriate anesthesia. The technique was revived about a century later by Sarnoff and colleagues at Harvard, where they paced the phrenic nerve in dogs. Later, they applied the technique to a young child with complete respiratory paralysis following an intracranial aneurysm rupture. However, the true beginnings of diaphragmatic pacing started in the 1860s and 70s. The father of modern diaphragm pacing is Dr William W L Glenn from Yale University, who showed that the technique was not only practical but could be used clinically for the treatment for several medical disorders. With advances in technology, more refined and flexible electrodes were developed, and the thoracoscopic method of implantation became practical.[1, 2, 3, 4, 5]

There are 3 commercially available devices that can stimulate the diaphragm—namely, the Synapse Biomedical NeuRx; the Mark IV Breathing Pacemaker, made by Avery Biomedical Devices; and the Atrotech OY's Atrostim PNS. The Avery and the Synapse devices are available in the United States, and the Atrotech device is available only in Europe. The Synapse NeuRx DPS received FDA approval in 2011 for humanitarian use in patients 21 years or older with amyotrophic lateral sclerosis (ALS), and the cost may not be reimbursed by Medicaid or Medicare services. The Avery  Mark IV Breathing Pacemaker received full premarket approval by the FDA in 1987 and is reimbursed by Medicaid and Medicare services. A key difference between the two is that the Mark IV Breathing Pacemaker stimulates the phrenic nerve and the NeuRx DPS stimulates the diaphragm.[6, 7]

Currently, several clinical centers offer diaphragm pacing for selected patients.[1, 2, 8, 9, 3, 4]

All currently available systems involve an external transmitter and an implanted receiver, but fully implantable diaphragmatic pacing systems are being developed. The current pacing systems are more affordable and easier to place than the earlier systems.[5, 10]

Diaphragmatic pacing should be considered in the following patients: 

• Those with apnea from a central cause (the CNS lesion must be higher than C2,C3 because the phrenic nerve originates from the anterior horns of C3-5.
• Patients with amyotrophic lateral sclerosis and polio
• Patients with upper cervical spine injury
• Patients with basilar meningitis or brainstem infarction
• Patients with central sleep apnea

Diaphragm pacing is performed to provide ventilatory support in 2 main clinical scenarios:

• Central alveolar ventilation, or what is better known as sleep apnea

• High spinal cord paralysis in which the drive for respiration is still present but the injury to the spinal cord prevents stimulation from the phrenic nerves

These 2 conditions account for most cases of diaphragm pacing.[11, 12, 13]

Another, albeit rare, use of diaphragm pacing is to treat patients with intractable hiccups.[14] The remaining group of patients in whom diaphragm pacing has been used consists of those with severe COPD. In these individuals, the hypoxic stimulation is diminished by administration of any amount of oxygen.[15]

Diaphragm pacing is contraindicated for patients in whom the phrenic nerve is not functional. Such patients include those with severe traumatic injury to the nerve, those with nerve tumors, and most of those with neuropathies. In addition, diaphragm pacing is contraindicated for patients with conditions in which the diaphragm itself is not functional.

Compared with positive-pressure ventilation, diaphragm pacing has a number of advantages. One major advantage is that it allows a greater degree of independence. With diaphragm pacing, the patient is no longer isolated in a room, attached to a mechanical ventilator with an uncomfortable tube down the upper airways. Patients with central hypoventilation may be able to ambulate, go to work, travel, and perform most daily living activities. Portable diaphragmatic pacemakers are available that can be used for ambulatory monitoring of heart rate and rhythm.

Another major advantage is that diaphragm pacing affords the patient the ability to speak, which is impossible with an endotracheal tube in place. Once diaphragm pacing has been performed, the tracheostomy stoma can be plugged and speech resumed. Speech capability made possible by diaphragm pacing is particularly important to patients who are quadriplegic and on a ventilator.[16, 17, 18, 19]  In addition, diaphragm pacing does not result in tracheal injury, tracheomalacia, tracheal stenosis, subglottic stenosis, tracheoesophageal fistula, or tracheitis.

Furthermore, the extremely irritating copious secretions seen during mechanical ventilation are avoided. Patients on a ventilator are always at risk for death. The tubing may become kinked, coiled, obstructed, or even disconnected, and the tracheostomy site may become plugged.[20]

Studies have shown that diaphragm pacing is effective and helps support ventilation in specific patient populations. Diaphragmatic pacing can provide independence from a mechanical ventilator and can help patients communicate and have a better quality of life. However, long-term studies are still needed; the majority of studies published are retrospective studies or case reports.[21, 22]  Some studies have reported that patients can be paced for up to 20 years without much negative sequelae; however, the data have been difficult to interpret because of heterogeneity of methodology for follow-up. It should also be mentioned that a trial involving the NeuTx DPS system pacer for patients with ALS was halted and there is concern that this device may actually be causing harm.[4, 5, 13, 17, 18, 19, 23, 24, 25, 26, 27, 28, 29, 30]

Unlike stimulation of the heart, stimulation of the diaphragm is a long process that requires training of the muscle. A single stimulus usually is not sufficient to produce a contraction: a series of stimuli (ie, a pulse train) is needed to produce a summed contraction. Key aspects of pulse-train stimulation that must be coordinated include the number of pulse trains delivered per minute (rate) and their duration, as well as pulse amplitude, width, interval, and frequency. The muscle contractions usually last only for the duration of the pulse train.

Research has shown that pulse-train stimulation of the diaphragm for weeks to months can result in an orderly sequence of positive ultrastructural and biochemical changes. The muscles slowly develop increased blood supply; enzyme efficiency improves; and mitochondrial capacity for oxidative phosphorylation is enhanced. These changes reflect the transformation of fast glycolytic and slow oxidative muscle fibers to entirely slow fibers, which allows the oxidative muscle fibers to perform sustained mechanical work for prolonged periods.

This conditioning is essential to prevent fatigue in skeletal muscle. Although with normal respiration the diaphragm is at work every second, 24 hours a day, the pattern of recruitment of individual nerve fascicles and motor units (usually hundreds of fibers) is such that not all motor units are active during an individual breathing cycle; this pattern allows the fatigued muscles to recover. With pulse-train stimulation of the diaphragm, it is likely that most nerve fibers and muscle groups are stimulated strongly during each breath.

These adaptive changes are required for successful acceptance of pulse-train stimulation. However, it should be remembered that in individuals with quadriplegia, the diaphragm may have atrophied from disuse during mechanical ventilation, in which case it must be gradually restored to a functional state, which may not be possible in some patients.[1, 2, 8]

Both the Synapse Biomedical NeuRx DPS RA/4 and the Avery Biomedical Mark IV Breathing Pacemaker devices are FDA approved and available for use in the United States. The key difference between the two is that the Mark IV Breathing Pacemaker simulates the phrenic nerve and the NeuRx DPS stimulates the diaphragm. In addition, the NeuRx DPS is only available for humanitarian use in patients with ALS, and the cost may not be reimbursed by Medicaid or Medicare services, whereas the Avery Biomedical Mark IV device received full premarket approval by the FDA and is reimbursed by Medicaid and Medicare services.[6, 7]

Regarding the equipment, the internal electrode of the device is attached to a small receiver, and the external transmitter box connects to an antenna that is anchored on the skin surface, just above the implanted receiver. The transmitter is battery operated and has adjustments for respiratory rate, pulse-train duration, pulse duration, amplitude of current, and pulse frequency. In the majority of patients, the surgeon or pulmonologist will only adjust the respiration rate of current amplitude.

Before the performing the procedure, it is essential to check the viability of the phrenic nerve. This can be done by stimulating the phrenic nerve in the neck and assessing diaphragmatic movements either with ultrasound or fluoroscopy. If there is weak diaphragmatic response to phrenic nerve stimulation or if there is unilateral movements, the procedure may not be indicated.

The surgical procedure for inserting the diaphragmatic pacemaker is not complicated. To stimulate the phrenic nerve, one may place the electrode in the neck or in the chest. With the neck approach, a small supraclavicular incision is made just above the clavicle. The sternocleidomastoid muscle is retracted and the phrenic nerve is identified as it courses between the middle and anterior scalene muscles. The identification of the nerve can be confirmed with a nerve simulator and use of intraoperative fluoroscopy. Stimulation of the phrenic nerve in the chest is done via a thoracoscopic approach. In the right chest cavity, the phrenic nerve can be found coursing just posterior to the esophagus; in the left chest, it is located lateral to the pericardium. The mediastinal pleura is incised parallel to the phrenic nerve, but a few millimeters of tissue are left on either side of the nerve. This incision is made both anterior and posterior to the nerve.

The diaphragm may also be stimulated directly with electrodes if necessary. Before implanting electrodes in the diaphragm, motor mapping is done and a grid map algorithm is created. Once the points of maximal contraction are identified, the electrodes are implanted into these sites and again hooked to an external stimulator. Laparoscopy is often used to implant  electrodes bilateraly on the diaphragm.[1, 2, 8, 9]

Excellent contractions of the diaphragm with pacing should be confirmed with imaging, and the threshold should be in the range of 1-2 mA. Failure to pace or the presence of a high threshold should lead to reassessment to detect reasons for lack of optimal functioning, such as improper connections, wire injury, lead dislodgment, or interposition of excess tissues between the electrode and the nerve.

The current is set on the basis of fluoroscopic testing. In most cases, a standardized method is developed to assess the optimum diaphragmatic excursion, and this system is followed each time. Maximal voluntary descent of the diaphragm during inspiration is determined for each patient. The amount of current required to generate this descent is assessed, and the current is kept at the minimum setting that produces the desired result.[1, 2, 8]

Prophylactic antibiotics should be given preoperatively to prevent infection.

Unlike cardiac pacemakers, diaphragmatic pacemakers cannot be used immediately. Pacing is usually not started for 2-3 weeks after implantation is complete. Early pacing usually leads to development of pleural effusions, most likely from the breakage of lung and chest wall adhesions that bleed. A program of gradual conditioning is started to allow the diaphragm to regain its muscle strength and bulk. The adaptive process should be slow and gradual. The rest period is gradually and progressively shortened until full-time pacing is achieved.

Careful assessment of lung function and arterial blood gases to look for fatigue may be advisable. At the same time, the frequency of stimuli in the pulse train is decreased progressively to minimize fatigue of the diaphragm and allow longer pacing periods. Concurrently, the respiratory rate is gradually decreased to the lowest number that provides adequate ventilation. To ensure that the adequacy of ventilation is maintained in the sitting position, a frim abdominal binder is used for quadriplegics. In addition, the respiratory rate is increased gradually until the patient appears comfortable and not hypoxic.[1, 2]

Other monitoring measures that are frequently employed include pulse oximetry, pulmonary function testing, and periodic arterial blood gas measurement. In addition, there is no substitute for a thorough physical examination. These patients need hourly monitoring during the initial phase of conditioning until pacing is advanced and tolerated. Noninvasive oxygen monitoring is routinely performed, and carbon dioxide is also monitored to ensure adequate ventilation.

If, at any time during the conditioning phase, tidal volume falls or carbon dioxide tension starts to rise, diaphragmatic fatigue should be suspected. In such cases, the patient should be allowed to rest on a mechanical ventilator for a minimum of 12 hours or, if that is not feasible, at least overnight. The next day, pacing should resume at a shorter duration.

Patients with central alveolar hypoventilation usually need to be paced at night. The daytime break often gives the diaphragm enough time to recover from fatigue.[8, 9]

Close monitoring is required during the initial conditioning period. Even after discharge, monitoring continues to be necessary because the system is still prone to errors and fatigue. Patient factors that influence pacing include hormonal changes, infection, fever, and stress, as well as any other factors that place additional stress on the diaphragm and thereby lead to extra ventilatory requirements. It is important to remember that when mechanical ventilation is started in these patients, it can lead to disuse of the diaphragm.[1]

A permanent tracheostomy is highly recommended as a safety measure for all patients who undergo diaphragm pacing. Diaphragm pacing is known to be associated with intermittent upper airway obstruction resulting from strong diaphragmatic contractions that are not synchronized with the muscles of the upper airway. At night, all patients are told to leave the tracheostomy stoma open. Thus, if periodic dysfunction occurs at night, the tracheostomy offers secure access to the airways for the institution of positive-pressure ventilation. Once full-time ventilation is achieved, the stoma can be closed with a button instead of a tracheostomy tube. The stoma button not only is acceptable cosmetically but also allows normal speech and reduces tracheal irritation and injury.[1, 2, 5, 29]

Some surgeons prefer the cervical approach because it avoids the morbidity associated with a thoracic procedure. Many of these patients have marginal pulmonary function as well as other comorbidities. The disadvantage of the cervical approach is that in a small number of patients, the current amplitude required to stimulate the phrenic nerve may also stimulate adjacent nerves in the area. For example, it has been reported that some people with cervical phrenic nerve pacers can develop stimulation of the brachial plexus, which may cause involuntary movements of the upper arm.

The benefit of the thoracic approach is that stimulation of the brachial plexus is avoided. Furthermore, there is evidence that an accessory branch of the phrenic nerve reconnects to the main trunk in the chest and that this results in good diaphragmatic stimulation. For patients who are critically ill or not able to tolerate a thoracotomy, a thoracoscopic approach is recommended.

In patients who have a paralyzed diaphragm or those who have not utilized the diaphragm for 6 or more months, conditioning of the diaphragm is required. There is no universal approach for diaphragmatic conditioning that is effective in all patients, with the duration varying from patient to patient.

In general, the following steps are undertaken to condition the diaphragm:

• Gradually increase the duration of diaphragm pacing each day or week. Allow for rest at night, when the patient is on a mechanical ventilator.
• During pacing, monitor the patient's arterial blood gas and pulse oximetry to assess for oxygenation and ventilation.
• Avoid hypercapnia; if it occurs, increase the ventilatory rate.
• The manufacturer of each device provides guidelines on the conditioning process, and their recommendations should be followed.

Complications

Complications of diaphragmatic pacing may occur from the surgical procedure or may be pacing related. They include the following:

• Skin infection after surgery

• Lung complications after a thoracic procedure (eg, atelectasis, pneumonia, pain)

• Dislodgement of electrode

• Transmission of electrical impulses to the brachial plexus, with involuntary arm movements

• Hardware malfunction

The goals of pharmacotherapy are to prevent infections and complications and to reduce morbidity.

Class Summary

Prophylactic antibiotics should be administered preoperatively to prevent infection.

Cefazolin

Cefazolin is a first-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth.

Vancomycin

Vancomycin is a potent antibiotic directed against gram-positive organisms and is active against Enterococcus species. Vancomycin is indicated for patients who cannot receive penicillins and cephalosporins.

Arterial blood gases are vital to assess the oxygenation and ventilation of the patient being paced.