Phrenic Nerve Stimulation Increases Brain Connectivity in Deeply Sedated Mechanically Ventilated Moderate ARDS Patients

Phrenic afferent input excites C 1-C 2 spinal neurons in rats

Phrenic nerve stimulation is often considered to be difficult and unreliable. The time taken for the phrenic nerves to be located and adequately stimulated was measured in 110 subjects, aged 21-89 years, 26 of whom had diaphragmatic weakness; and phrenic nerve conduction time was recorded in 76 of these individuals. Each phrenic nerve was stimulated transcutaneously in the neck with square wave impulses 0.1 ms in duration at 1 Hz and 80-160 volts while diaphragmatic muscle action potentials were recorded with surface electrodes. The time taken to locate either phrenic nerve ranged from two seconds to 22 minutes (median 10s). Both nerves were located in 83 of the 84 control subjects (99%) and in 21 of the 26 patients with diaphragmatic weakness (81%). Mean (SD) phrenic nerve conduction time in the control subjects was 6.94 (0.77) ms on the right and 6.61 (0.77) ms on the left. A weak relationship was found between conduction time and the subjects' age and height. Four out of 24 patients with diaphragmatic weakness had a prolonged phrenic nerve conduction time. Transcutaneous stimulation of the phrenic nerves was not a time consuming procedure, and it was well tolerated, reproducible, and successful in 95% of subjects.

Sophisticated techniques for electrical stimulation of excitable tissue to treat neuromuscular disorders rationally have been developed over the past 3 decades. A historical review shows that electricity has been applied to the phrenic nerves to activate the diaphragm for some 200 years. Of the contemporary methods for stimulating the phrenic nerve in cases of ventilatory insufficiency, the authors prefer stimulation of the phrenic nerve in the thorax using a platinum ribbon electrode placed behind the nerve and an attached subcutaneously implanted radiofrequency (RF) receiver inductively coupled to an external RF transmitter. Instructions are given for implanting the electrode-receiver assembly, emphasizing atraumatic handling of the phrenic nerve and strict aseptic techniques. Diaphragm pacing is conducted with low frequency electrical stimulation at a slow repetition (respiratory) rate to condition the diaphragm muscle against fatigue and maintain it fatigue-free. Candidates for diaphragm pacing are those with ventilatory insufficiency due to malfunction of the respiratory control center or interruption of the upper motor neurons of the phrenic nerve. In the Yale series, there were 77 patients treated by diaphragm pacing; 63 (82%) started before 1981 and thus were available for follow-up for at least 5 years; 33 (52%) were paced for 5 to 10 years, and 15 (24%) were paced for 10 to 16. Long term stimulation of the phrenic nerves to pace the diaphragm is an effective method of ventilatory support in selected cases.

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.

Diaphragm pacing with electrical stimulation of the phrenic nerve is an established treatment for central hypoventilation syndrome. The device, however, is not readily available, at least, in Japan. We applied the spinal cord stimulator for pain control to phrenic nerve stimulation. The purpose of this study is to evaluate the efficacy and feasibility of phrenic pacing with the compromise method. We implanted a spinal cord stimulator in five patients with chronic central hypoventilation. The stimulation electrode was placed along the phrenic nerve in the neck, and the device was implanted in the anterior chest. We used the cyclic mode, and set the parameters at 1 second ramp up, 2 seconds on, 3 seconds off. The pulse width and the frequency were set at 150 microsec and 21 Hz respectively. The amplitude was adjusted to obtain sufficient tidal volume and to maintain PaCO2 at around 40 mmHg. During the follow-up period from 3 to 34 months (mean 23), stable and sufficient ventilation were observed in all patients without complications. Although longer follow-up is necessary, diaphragm pacing with the spinal cord stimulator is feasible for treatment of central hypoventilation syndrome.

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

Background and Aim:Cryoballoon ablation is an effective technique for treating Atrial Fibrillation (AF). Its application in the pulmonary vein antrum poses a potential risk of phrenic nerve damage due to its anatomic proximity. Manual protocols are implemented during the ablation procedure to mitigate this risk, although these may be susceptible to subjectivity and variations. In this work, we propose an online system capable of automatically detecting the phrenic nerve integrity during the cryoablation procedure for AF in the pulmonary veins. The system performs digital processing of the ECG signals recorded during the ablation process, detects and segments the ECG signals, and uses a machine learning classifier to infer the risk of damage. Methods:The used dataset consisted of monitoring system signals obtained from the cryoablation procedures of ten AF patients from Virgen de la Arrixaca University Clinical Hospital in Murcia, Spain. The first stage involves signal processing of the ECG leads, using noise filtering and delineation to unmask any residual cellular potential during phrenic nerve stimulation. A comparative analysis was conducted where the electrocatheter was placed near the phrenic nerve to stimulate it and when the electrocatheter was intentionally displaced, resulting in the phrenic nerve not being stimulated despite an electrical pulse being applied. The detection stage used a linear support vector classifier for both scenarios. Results:It was possible to automatically classify the level of muscle activity from the phrenic nerve with high accuracy in this known-solution dataset. An online system was created capable of performing and synchronizing all the described stages to manage the signal extracted from the monitoring system. Conclusion:The system presented here can be a valuable tool for clinical practice, enabling the identification of specific pacing pulses when phrenic nerve involvement occurs, eventually and probably minimizing the use of manual protocols subject to interpretation biases.

When lung volume in animals is passively increased beyond total lung capacity (TLC; transrespiratory pressure = +30 cmH(2)O), stimulation of the phrenic nerves causes a rise, rather than a fall, in pleural pressure. It has been suggested that this was the result of inward displacement of the lower ribs, but the mechanism is uncertain. In the present study, radiopaque markers were attached to muscle bundles in the midcostal region of the diaphragm and to the tenth rib pair in five dogs, and computed tomography was used to measure the displacement, length, and configuration of the muscle and the displacement of the lower ribs during relaxation at seven different lung volumes up to +60 cmH(2)O transrespiratory pressure and during phrenic nerve stimulation at the same lung volumes. The data showed that 1) during phrenic nerve stimulation at 60 cmH(2)O, airway opening pressure increased by 1.5 ± 0.7 cmH(2)O; 2) the dome of the diaphragm and the lower ribs were essentially stationary during such stimulation, but the muscle fibers still shortened significantly; 3) with passive inflation beyond TLC, an area with a cranial concavity appeared at the periphery of the costal portion of the diaphragm, forming a groove along the ventral third of the rib cage; and 4) this area decreased markedly in size or disappeared during phrenic stimulation. It is concluded that the lung-deflating action of the isolated diaphragm beyond TLC is primarily related to the invaginations in the muscle caused by the acute margins of the lower lung lobes. These findings also suggest that the inspiratory inward displacement of the lower ribs commonly observed in patients with emphysema (Hoover's sign) requires not only a marked hyperinflation but also a large fall in pleural pressure.

Left ventricular pacing with long pulse duration can avoid phrenic nerve stimulation

Introduction Central sleep apnea is highly common in heart failure (HF) patients and often appears as Cheyne-Stokes-respiration (CSR). Presence of CSR in HF has been clearly shown to connote worse prognosis and HF patients with CSR experience increased mortality. Since widely used adaptive servoventilation is now contraindicated in HF with reduced ejection fraction alternative approaches for CSR treatment are needed. Unilateral phrenic nerve stimulation (PNS) is a novel technique to treat CSR and has recently been demonstrated to be safe and effective in HF patients, resulting in its market approval. While PNS has been shown to sufficiently treat CSR nothing is known in regard to functional characteristics in PNS treated HF patients. Therefore, this study investigated standardized six-minute walk test (6MWT) before and during PNS treatment in HF patients assessing functional impact of PNS on HF. Methods We prospectively enrolled 25 HF patients that have been implanted with novel PNS, mean age 67.05±11.22 years, 88% male, showing effective PNS CSR treatment. Adjacent to determine PNS effectiveness on CSR treatment standardized 6MWT was conducted before, at 6 months and at 12 months after PNS implantation. Results 25 (100%) patients had CSR, introduced PNS significantly suppressed respiratory events from 118.33±96.35 before to 34.65±51.41 after PNS therapy onset (p=0.001). Regarding functional improvements 6MWT improved from initial 369.5±163.56 meters before PNS implantation to 410±169.71 meters after 12 months. Hereby, total walking distance increased by 49.5% ± 100.8% (p=0.035). Conclusion PNS treatment is not only a novel technique to allow CSR treatment in HF, but for the first time, we provide comprehensible data illustrating functional improvements in HF in 6MWT, implying significant enhancements in daily physical capability of HF CSR patients treated with PN.

Cardiac resynchronization therapy is an established therapy for heart failure, improving quality of life and prognosis. Despite advances in technique, available leads and delivery systems, trans-venous left ventricular (LV) lead positioning remains dependent on the patient's underlying venous anatomy. The left phrenic nerve courses over the surface of the pericardium laterally and may be stimulated by the LV pacing lead, causing uncomfortable diaphragmatic twitch. This paper describes a video-assisted thoracoscopic (VATS) procedure to correct phrenic nerve stimulation secondary to cardiac resynchronization therapy. Most current ways of avoiding phrenic stimulation involve either electronic reprogramming to distance the phrenic nerve from the stimulation circuit or repositioning the lead. We describe a case where the phrenic nerve was surgically insulated from the stimulating current by insinuating a patch of bovine pericardium between the epicardium and native pericardium of the heart thus completely resolving previously intolerable and incessant diaphragmatic twitch. The procedure was performed under general anaesthesia with single-lung ventilation and minimal use of neuromuscular blocking agents. Surgical patch insulation of the phrenic nerve was performed using minimally invasive VATS surgery, as a short-stay procedure, with no complications. No diaphragmatic twitch occurred post-surgery and the patient continued to gain symptomatic benefit from cardiac synchronization therapy (New York Heart Association Class III to II), enabling return to work. In cases where the trans-venous position of a LV lead is limited by troublesome phrenic nerve stimulation, thoracoscopic surgical patch insulation of the phrenic nerve could be considered to allow beneficial cardiac resynchronization therapy.

BackgroundIn critically ill patients, deep sedation and mechanical ventilation suppress the brain-diaphragm-lung axis and are associated with cognitive issues in survivors.MethodsThis exploratory crossover design study investigates whether phrenic nerve stimulation can enhance brain activity and connectivity in six deeply sedated, mechanically ventilated patients with acute respiratory distress syndrome.ResultsOur findings indicate that adding phrenic stimulation on top of invasive mechanical ventilation in deeply sedated, critically ill, moderate acute respiratory distress syndrome patients increases cortical activity, connectivity, and synchronization in the frontal-temporal-parietal cortices.ConclusionsAdding phrenic stimulation on top of invasive mechanical ventilation in deeply sedated, critically ill, moderate acute respiratory distress syndrome patients increases cortical activity, connectivity, and synchronization. The observed changes resemble those during diaphragmatic breathing in awake humans. These results suggest that phrenic nerve stimulation has the potential to restore the brain-diaphragm-lung crosstalk when it has been shut down or impaired by mechanical ventilation and sedation. Further research should evaluate the clinical significance of these results.

Suitability of the Pericardiophrenic Veins for Phrenic Nerve Stimulation: An Anatomic Study

Objective To investigate the application of quadripolar left ventricular lead in cardiac resynchronization therapy (CRT). Methods Twenty patients implanted CRT/cardiac resynchronization therapy defibrillator (CRT-D) with quadripolar left ventricular lead were matched 1∶1 with regard to left ventricular end diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and the etiology of cardiomyopathy to a retrospective cohort of 20 patients who implanted CRT with bipolar lead.The position of left ventricular lead, duration of procedure, fluoroscopy time, phrenic nerve stimulation (PNS), left ventricular-right ventricular (LV-RV) conduction time, left ventricular pacing threshold, LVEDD and LVEF at 12-month follow-up were compared between the two groups. Results The procedure duration and the time of fluoroscopy in quadripolar group were shorter than these in biopolar group (102.85±12.01) min vs. (114.70±19.36) min, P<0.05; (16.90±2.13) min vs.(22.5±3.57) min, P<0.05], and incidence of PNS was lower(0 vs.25%, P<0.05). The rates of the target vein located in lateral position(90%vs.65%, P<0.05) and the non apical region (100% vs.85%, P<0.05) in quadripolar group were higher than those in bipolar group.There was longer LV-RV conduction time in quadripolar group than that in bipolar group (30.95 ms vs.26.00 ms, P<0.05). There were no significant differences in the LVEF, LVEDD, the rates of lead dislocation and rehospitalization between two groups, but the left ventricular pacing threshold in quadripolar group was lower than that in bipolar group [(1.20±0.55) V/0.4 ms vs.(2.35±0.96) V/0.4 ms, P<0.05]. Conclusion Quadripolar left ventricular lead is worthy of popularization and application, which can simplify the procedure and increase the success rate of left ventricular lead implantation. Key words: Quadripolar left ventricular lead; Cardiac resynchronization therapy; Phrenic nerve stimulation

Wide-area antral pulmonary vein and posterior wall isolation by way of segmental nonocclusive applications using a novel radiofrequency ablation balloon