Anthony F. DiMarco

Background/Objective: A significant fraction of patients with cervical spinal cord injury suffer from respiratory muscle paralysis and dependence on chronic mechanical ventilation. In selected patients, diaphragm pacing (DP) through electrical stimulation of the phrenic nerves provides an alternative to mechanical ventilation with significant advantages in life quality. Methods: A case report of an individual who successfully underwent DP using intramuscular diaphragm electrodes. A brief review of the state of the art of DP including the clinical benefits of DP, patient selection and evaluation, description of equipment, methods of transition from mechanical ventilation to DP, potential complications and side effects, long-term outcome, and potential future developments in this field is included. Results: Several available DP systems are available, including conventional ones in which electrodes are positioned directly on the phrenic nerves through thoracotomy and less invasive systems in which electrodes are placed within the diaphragm through laparoscopy. For patients with only unilateral phrenic nerve function, a combined intercostal and unilateral diaphragm pacing system is under development. Conclusions: In patients with ventilator-dependent tetraplegia, there are alternative methods of ventilatory support, which offer substantial benefits compared to mechanical ventilation.

In patients with diaphragm paralysis, ventilation to the basal lung zones is reduced, whereas in patients with paralysis of the rib cage muscles, ventilation to the upper lung zones in reduced. Inspiration produced by either rib cage muscle or diaphragm contraction alone, therefore, may result in mismatching of ventilation and perfusion and in gas-exchange impairment. To test this hypothesis, we assessed gas exchange in 11 anesthetized dogs during ventilation produced by either diaphragm or intercostal muscle contraction alone. Diaphragm activation was achieved by phrenic nerve stimulation. Intercostal muscle activation was accomplished by electrical stimulation by using electrodes positioned epidurally at the T₂ spinal cord level. Stimulation parameters were adjusted to provide a constant tidal volume and inspiratory flow rate. During diaphragm (D) and intercostal muscle breathing (IC), mean arterial Po₂ was 97.1 ± 2.1 and 88.1 ± 2.7 Torr, respectively ( P < 0.01). Arterial Pco₂ was lower during D than during IC (32.6 ± 1.4 and 36.6 ± 1.8 Torr, respectively; P < 0.05). During IC, oxygen consumption was also higher than that during D (0.13 ± 0.01 and 0.09 ± 0.01 l/min, respectively; P < 0.05). The alveolar-arterial oxygen difference was 11.3 ± 1.9 and 7.7 ± 1.0 Torr ( P < 0.01) during IC and D, respectively. These results indicate that diaphragm breathing is significantly more efficient than intercostal muscle breathing. However, despite marked differences in the pattern of inspiratory muscle contraction, the distribution of ventilation remains well matched to pulmonary perfusion resulting in preservation of normal gas exchange.

In patients with ventilator-dependent tetraplegia, phrenic nerve pacing (PNP) provides significant clinical advantages compared with mechanical ventilation. This technique however generally requires a thoracotomy with its associated risks and in-patient hospital stay and carries some risk of phrenic nerve injury. We have developed a method by which the phrenic nerves can be activated via intramuscular diaphragm electrodes. In one patient with ventilator-dependent tetraplegia, two intramuscular diaphragm electrodes were implanted into each hemidiaphragm near the phrenic nerve motor points via laparoscopic surgery. The motor points were identified employing a previously devised mapping technique. Because inspired volumes were suboptimal on the right, a second laparoscopic procedure was necessary to position electrodes near the anterior and posterior branches of the right phrenic nerve. During bilateral stimulation, inspired volume was 580 ml. After a reconditioning program of progressively increasing diaphragm pacing, maximum inspired volumes on the left and right hemidiaphragms increased significantly. Maximum combined bilateral stimulation was 1120 ml. Importantly, the patient has been able to comfortably tolerate full-time pacing. If confirmed in additional patients, PNP with intramuscular diaphragm electrodes via laparoscopic surgery may provide a less invasive and less costly alternative to conventional PNP.

Lower thoracic spinal cord stimulation (SCS) may be a useful method to restore an effective cough mechanism. In dogs, two groups of studies were performed to evaluate the mechanism of the expiratory muscle activation during stimulation at the T₉-T₁₀ level, which results in the greatest changes in airway pressure. In one group, expiratory muscle activation was monitored by evoked muscle compound action potentials (CAPs) from the internal intercostal muscles in the 10th, 11th, and 12th interspaces and from portions of the external oblique innervated by the L₁ and L₂ motor roots. SCS, applied with single shocks, resulted in short-latency CAPs at T₁₀ but not at more caudal levels. SCS resulted in long-latency CAPs at each of the more caudal caudal recording sites. Bilateral dorsal column sectioning, just below the T₁₁ spinal cord level, did not affect the short-latency CAPs but abolished the long-latency CAPs and also resulted in a fall in airway pressure generation. In the second group, sequential spinal root sectioning was performed to assess their individual mechanical contribution to pressure generation. Section of the ventral roots from T₈ through T₁₀ resulted in negligible changes, whereas section of more caudal roots resulted in a progressive reduction in pressure generation. We conclude that 1) SCS at the T₉-T₁₀ level results in direct activation of spinal cord roots within two to three segments of the stimulating electrode and activation of more distal roots via spinal cord pathways, and 2) pathway activation of motor roots makes a substantial contribution to pressure generation.

Approximately 5% of spinal cord-injured individuals suffer from respiratory muscle paralysis and require chronic mechanical ventilation. Unfortunately, this form of life support is associated with a number of undesirable side effects and discomforts. The only available alternative to mechanical ventilation is diaphragm pacing via bilateral phrenic nerve stimulation. This technique can provide patients with marked improvements in life quality and offers significant advantages compared to mechanical ventilation. Many patients, however, do not have bilateral phrenic function or are not willing to accept the risks inherent with phrenic nerve pacing and therefore are not candidates for this technique. Two alternative methods to ventilate patients with ventilator-dependent tetraplegia are reviewed in this paper. In patients with only a single functional phrenic nerve who are therefore not candidates for phrenic nerve pacing, combined intercostal muscle and unilateral phrenic nerve stimulation has recently been shown to maintain ventilatory support. In patients with bilateral phrenic nerve function, on-going studies suggest that intramuscular diaphragm pacing may be a useful alternative to direct phrenic nerve pacing. With the electrodes placed into the diaphragm laparoscopically, this method allows for the diaphragm to be activated without manipulation of the phrenic nerve, need for thoracotomy, or hospitalization. Both techniques provide benefits similar to that derived from bilateral phrenic nerve pacing and hold promise as alternative methods of ventilatory support in selected populations groups.

Previous studies have suggested that the optimum length for force generation of the parasternal intercostal (PS) muscles is well above functional residual capacity (FRC). We further explored this issue by examining the pressure-generating capacity of the PS muscles as a function of lung volume in anaesthetized dogs. Upper thoracic spinal cord stimulation (SCS) was used to electrically activate the PS muscles. Changes in airway pressure and parasternal resting length (LR) during airway occlusion were monitored over a wide range of lung volumes during SCS. To assess the effects of parasternal contraction alone, SCS was performed following phrenicotomy and section of the external intercostal, levator costae and triangularis sterni muscles. With increasing lung volume, there were progressive decrements in the capacity of the PS muscles to produce changes in airway pressure. The relationship between PS pressure generation and lung volume was similar to a previous comparable assessment of the external intercostal muscles. The PS muscles shortened during passive inflation and also shortened further (by > 20 % of LR) during SCS. Total shortening (passive plus active) increased progressively with increasing lung volume. Our results indicate that the capacity of the PS muscles to produce changes in airway pressure (a) falls progressively with increasing lung volume and (b) is similar to that of the external intercostal muscles. We speculate that the fall in PS pressure-generating capacity is related, in part, to progressive reductions in end-inspiratory length.

Recent reports have demonstrated that superoxide is released by the contracting diaphragm. Moreover, extracellular scavengers of superoxide (i.e., exogenously administered superoxide dismutase) reduce diaphragm fatigue rate, arguing that superoxide released from contracting muscles may have functionally significant effects. The mechanism by which free radical formation and release occurs has not, however, been determined, and all past studies of this phenomenon have been conducted at a single muscle length (the length of maximum force generation, Lo) and at a single level of carbon dioxide. The purpose of the present study was twofold: (1) to examine the effect of blockade of two free radical-generating pathways (i.e., to block cyclooxygenase with indomethacin and xanthine oxidase with oxypurinol) on superoxide release by the contracting diaphragm, and (2) to examine the effect of altering muscle length, carbon dioxide levels, and stimulation frequency on superoxide release during contraction. Studies were performed using an isolated, arterially perfused, rat diaphragm preparation in which superoxide release was assessed in real time by measuring arteriovenous cytochrome c reduction gradients across this muscle. We found that superoxide release during contraction was: (1) not altered by indomethacin administration, (2) partially reduced by oxypurinol administration, (3) reduced by decreasing muscle length, (4) reduced by increasing carbon dioxide concentrations, and (5) reduced by decreasing stimulation frequency. The first two findings indicate that xanthine oxidase pathways contribute to free radical formation under these circumstances but cyclooxygenase does not. The last three findings suggest that these common physiologic alterations have significant effects on free radical release by contracting muscle.

Lower thoracic spinal cord stimulation (SCS) results in the generation of large positive airway pressures (Paw) and may be a useful method of restoring cough in patients with spinal cord injury. The purpose of the present study was to assess the mechanical contribution of individual respiratory muscles to pressure generation during SCS. In anesthetized dogs, SCS was applied at different spinal cord levels by using a 15-lead multicontact electrode before and after sequential ablation of the external and internal obliques, transversus abdominis (TA), rectus abdominis, and internal intercostal muscles. Paw was monitored after tracheal occlusion. SCS at the T₉ spinal cord level resulted in maximal changes in Paw (60 ± 3 cmH₂O). Section of the oblique muscles resulted in a fall in Paw to 29 ± 2 cmH₂O. After subsequent section of the rectus abdominis and TA, Paw fell to 25 ± 2 and 12 ± 1 cmH₂O respectively. There was a small remaining Paw (4 ± 1 cmH₂O) after section of the internal intercostal nerves. Stimulation with a two-electrode lead system (T₉ + T₁₃) resulted in significantly greater pressure generation compared with a single-electrode lead due to increased contributions from the obliques and transversus muscles. In a separate group of animals, Paw generation was monitored after section of the abdominal muscles and again after section of the external intercostal and levator costae muscles. These studies demonstrated that inspiratory intercostal muscle stimulation resulted in only a small opposing inspiratory action (≤3 cmH₂O). We conclude that, during SCS, 1) contraction of the obliques and TA muscles makes the largest contribution to changes in Paw, and 2) stimulation with a two-electrode lead system results in more complete abdominal muscle activation and enhanced mechanical actions of the obliques and transversus muscles.