Stimulation for Inspiration

Abstract

Mechanical ventilation (MV), although lifesaving, has significant morbidity, mortality, and health care costs. One of the primary causes of prolonged MV is diaphragm control abnormalities causing disuse atrophy. Diaphragm pacing (DP) allows diaphragm contraction leading to improved ventilation that can significantly overcome the adverse effects of positive pressure ventilation. DP has a role in replacing ventilators in spinal cord injury and delaying or decreasing ventilators in numerous other conditions.

Keywords

Diaphragm, Diaphragm pacing, Diaphragm stimulation, Mechanical ventilation, Phrenic nerve pacing

Outline
Background 1347
Current Experience 1348
Future Trends 1353
Conclusion 1354
Conflict of Interest Disclosure [CR]
References 1354

Conflict of Interest Disclosure

Dr. Raymond Onders, University Hospitals of Cleveland and Case Western Reserve University School of Medicine have intellectual property rights involved with the diaphragm pacing system and equity in Synapse Biomedical who manufactures the device.

Background

The diaphragm is the primary muscle of respiration responsible for approximately 80% of inspiratory lung volume during automatic breathing. The diaphragm is innervated by the right and left phrenic nerves which originate with the phrenic lower motor neurons (LMN) in the spinal column at the cervical levels 3–5. These cervical phrenic motor neurons can be controlled involuntarily by upper motor neurons (UMN) in the respiratory control center in the brainstem or by the cerebral cortex UMN. There are numerous etiologies that can affect this system that will cause contraction abnormalities of the diaphragm resulting in respiratory compromise ranging from mild shortness of breath to the need for invasive mechanical ventilation (MV). The pre-Bötzinger complex, part of the ventral respiratory group (VRG), is responsible for respiratory drive and is the only drive during sleep. Loss of pre-Bötzinger complex neurons may affect respiratory rate and lead to central apneas. Congenital Central Hypoventilation Syndrome (CCHS or Ondine’s Curse) is an isolated genetic loss of this center leading to the need for MV during sleep.

MV has been the primary therapy for respiratory failure and a fundamental treatment in intensive care units (ICUs) where it is usually a time-limited therapy that when withdrawn, has no untoward sequelae. When the diaphragm is not contracting there is a decrease in ventilation that adversely affects normal respiratory physiology that can lead to hypercarbia from decreased minute ventilation or hypoxia from increased dead space. Research in animals and humans has shown that short exposure to MV leads to decreases in protein synthesis and increased proteolysis, which is histopathologically manifested as diaphragm muscle atrophy, with up to 50% of the diaphragm muscle atrophying and conversion to the nonfunctional, fast-twitch, type-IIb muscle fibers in less than 1 day ( ). The severity of this muscle atrophy increases with increased time of MV exposure. This condition is called ventilator-induced diaphragm dysfunction (VIDD).

This chapter will outline options where electrical stimulation is used to overcome loss of control of the diaphragm and maintain normal diaphragm physiology. The chapter will also identify how the implanted diaphragm electrodes can monitor the electromyography of the diaphragm which in turn provides evidence that diaphragm stimulation has had positive therapeutic effects in respiratory neuroplasticity.

Current Experience

Electrical activation of the diaphragm muscle, by way of phrenic nerve stimulation (PNS) or through direct diaphragm pacing (DP) at the motor point have been developed to provide stimulation of the diaphragm to improve ventilation in a number of diseases. The concept of PNS to provide ventilatory support dates back to the 18th century. In the 1940s, a group first demonstrated that ventilation could be maintained with percutaneous electrodes in patients with poliomyelitis ( ). In the 1960s, significant technological advances were made that led to the development of traditional PNS systems (Avery Mark IV Breathing Pacemaker System, Avery Biomedical Devices, Commack, NY, United States). They developed an implantable electrode/receiver system which could be activated by radiofrequency waves generated by a power source external to the body. These investigators also accumulated significant clinical experience which defined patient evaluation methods, surgical techniques, and safe parameters of stimulation which resulted in diaphragm conditioning via stimulation of the phrenic nerve ( ).

In the 1980s, the group at Case Western Reserve University in Cleveland showed the diaphragm could be directly stimulated at the motor point to provide ventilation ( ). In the late 1990s the device had been refined for the initial human studies at University Hospitals Case Medical Center and subsequent standard laparoscopic implantation for spinal cord injured (SCI) patients in the 2000s ( ). Because muscle motor-point electrodes can be removed and used for short periods of time, Onders and colleagues began investigating its use in other groups of patients including patients with motor neuron disease or amyotrophic lateral sclerosis (ALS) and for temporary use in the intensive care unit.

To be effective in recruiting diaphragm muscle and provide ventilatory support, the phrenic nerve must be able to provide conduction pathways through the muscle. Therefore, the LMN in the spinal cord and the phrenic nerve must be intact to avoid muscle dennervation and to stimulate the muscle at acceptable levels. A thorough assessment of phrenic nerve function should be performed in all patients contemplating phrenic nerve or diaphragm motor point pacing. Unfortunately, many patients with SCI have sustained injury to the phrenic motor neurons in the spinal cord and/or phrenic rootlets. If phrenic nerve function is absent or significantly reduced, phrenic nerve or DP should not be undertaken. Phrenic nerve function should be assessed both by measurements of phrenic nerve conduction times and/or by fluoroscopic evaluation of diaphragm movement during phrenic nerve stimulation as has been described ( ).

Unfortunately, the present method of detecting an intact phrenic nerve is plagued by technical difficulties and inherent false positive and false negative results. In a recent report the “gold standard” phrenic nerve study had 50% false negative or false positive test results when compared to direct surgical stimulation of the diaphragm ( ). The ultimate test is direct surgical stimulation of the diaphragm muscle which can easily be done with the laparoscopic DP technique. Most patients are willing to undergo an outpatient diagnostic laparoscopy to see if they can be removed from the adverse effects of a ventilator. If the diaphragm is stimulable during the diagnostic laparoscopy, then the DP system is implanted.

Presently, two additional PNS systems besides the Avery Mark IV Breathing System are available worldwide with a number of features in common. Electrodes are implanted on the phrenic nerves and attached to an internal stimulator that is powered by an external controller through the skin via a radiofrequency link. Low levels of electrical current pass through these electrodes exciting the nerve, which leads to contraction of the diaphragm muscle.

The Astrostim (Atrotech, Tampere, Finland) system differs from the Avery system in the electrode technology. The electrode is made of two identical strips of Teflon fabric with two platinum buttons mounted onto each strip. This four-pole arrangement divides the nerve into four stimulation compartments, each of which is designed to activate a quadrant of the phrenic nerve. During a single stimulation sequence, which consists of four current combinations, one pole in turn acts as a cathode and one pole, on the opposite side, as an anode. Consequently, there are four excitation compartments around the nerve. Theoretically this stimulation pattern is intended to more closely mimic natural activation of the nerve and should enhance the transformation of muscle fibers into slow-twitch fatigue-resistant fibers, thus improving endurance characteristics of the diaphragm and shortening the conditioning process.

The “Vienna phrenic pacemaker” (Medimplant, Vienna, Austria) system is also unique in terms of electrode design, involving multiple electrode contacts with the nerve. A microsurgical technique is required to suture four electrode leads to the epineurium of each phrenic nerve. The nerve tissue between each electrode lead provides different stimulation compartments. As many as 16 different electrode combinations can be adjusted individually for each nerve, although only one electrode combination is stimulated during any given inspiration. As with the Atrotech device, only a portion of the nerve is stimulated at any given time, allowing more time for recovery. This form of stimulation, referred to as carousel stimulation, is also thought to reduce the incidence of fatigue when compared to the unipolar design. Neither this system nor the Astrostim system is available in the United States.

Surgical implantation of the PNS can be done via either a cervical or thoracic approach. Cervical electrode placement, while less invasive surgically, is controversial for several reasons. Cervical phrenic nerve stimulation may result in incomplete diaphragm activation due to the occurrence of an accessory branch from a lower segment of the cervical spinal cord which joins the main trunk of the phrenic nerve in the lower neck region or thorax. Moreover, other nerves in close vicinity to the phrenic nerve may be activated, resulting in pain or undesirable movement. Finally, neck movement may place significant mechanical stress on the nerve/electrode system increasing the risk of injury to the nerve and connection failure. Thoracic placement is now more routinely done thoracoscopically, which decreases the morbidity.

A potential complication of PNS placement is iatrogenic injury to the phrenic nerve and subsequent pacemaker failure. It is critical that the phrenic nerves are carefully manipulated to avoid stretching or tension on the nerve during surgery. To prevent ischemic injury, the network of blood vessels within the perineurium must be preserved. The greatest technical challenge comes from thoracoscopically placing the electrode nerve cuffs in position below the nerve and sutured into place while allowing some “slack” to avoid traction tension on the nerve itself.

The electrode wires are connected to two implanted radiofrequency receivers, which are usually positioned superficially over the anterior chest wall. Two antennas are positioned over each radio receiver and connected to an external radio transmitter. Threshold current values of each electrode should be determined by gradually increasing stimulus amplitude until a diaphragm twitch is observed or palpated. When values are increased above this level, a smooth forceful diaphragm contraction should occur. If threshold values are high, the electrode leads may need to be repositioned.

The present DP system which has been used in over 1800 patients (NeuRx RA/4 System, Synapse Biomedical, Oberlin, Ohio, United States) is a distinct method over phrenic nerve pacing and originally developed to provide negative pressure ventilation and replace MV in high-level tetraplegics. The surgical procedure will be described in depth in another chapter, but in brief, it involves minimally invasive laparoscopic surgery that implants two electrodes in each hemi-diaphragm at the mapped phrenic motor points where maximal diaphragm contraction can occur ( Fig. 112.1 ). These electrode from each hemi-diaphragm are tunneled subcutaneously to a common exit site in the chest. A single external stimulator is connected to the leads at the percutaneous exit site, which delivers the stimulus pulses and provides respiratory timing ( Fig. 112.2 ). Electrode evaluation is performed by adjusting individual stimulus parameters (pulse amplitude, width, rate, and frequency) for each electrode so that a comfortable level of stimulation can be identified for the diaphragm conditioning sessions. The DP external pulse generator will be programmed to provide a tidal volume that provides 15% above the basal needs (5–7 cc/Kg) and that the patient can easily tolerate. The settings will always be below 25 in amplitude, below 20 in frequency, and below 200 in pulse width. Essentially, DP electrically stimulates intact lower motor units in the diaphragm causing diaphragm contraction for ventilation and rehabilitation of the diaphragm. DP overcomes atrophy of the diaphragm and converts the diaphragm to slow-twitch muscle fiber type.