Phrenic nerve neurotization utilizing the spinal accessory nerve: technical note with potential application in patients with high cervical quadriplegia

Introduction  High cervical quadriplegia is associated with high morbidity and mortality. Artificial respiration in these patients carries significant long-term risks such as infection, atelectasis, and respiratory failure. As phrenic nerve pacing has been proven to free many of these patients from ventilatory dependency, we hypothesized that neurotization of the phrenic nerve with the spinal accessory nerve (SAN) may offer one potential alternative to phrenic nerve stimulation via pacing and may be more efficacious and longer lasting without the complications of an implantable device. Materials and methods  Ten cadavers (20 sides) underwent exposure of the cervical phrenic nerve and the SAN in the posterior cervical triangle. The SAN was split into anterior and posterior halves and the anterior half transposed to the ipsilateral phrenic nerve as it crossed the anterior scalene muscle. Results  The mean distance between the cervical phrenic nerve and the SAN in the posterior cervical triangle was 2.5 cm proximally, 4 cm at a midpoint, and 6 cm distally. The range for these measurements was 2 to 4 cm, 3.5 to 5 cm, and 4 to 8.5 cm, respectively. The mean excess length of SAN available after transposition to the more anteromedially placed phrenic nerve was 5 cm (range 4 to 6.5 cm). The mean diameter of these regional parts of the spinal accessory and phrenic nerves was 2 and 2.5 mm, respectively. No statistically significant difference was found for measurements between sides. Conclusions  To our knowledge, using the SAN for neurotization to the phrenic nerve for potential use in patients with spinal cord injury has not been previously explored. Following clinical trials, these data may provide a mechanism for self stimulation of the diaphragm and obviate phrenic nerve pacing in patients with high cervical quadriplegia. Our study found that such a maneuver is technically feasible in the cadaver.     

Phrenic nerve stimulation: The Australian experience

Phrenic nerve stimulation is a technique whereby a nerve stimulator provides electrical stimulation of the phrenic nerve to cause diaphragmatic contraction. The most common indications for this procedure are central alveolar hypoventilation and high quadriplegia. This paper reviews the available data on the 19 patients treated with phrenic nerve stimulation in Australia to date. Of the 19 patients, 14 required pacing due to quadriplegia, one had congenital central hypoventilation syndrome and one had brainstem encephalitis. Information was unavailable for the remaining three patients. Currently, 11 of the pacers are known to be actively implanted, with the total pacing duration ranging from 1 to 21 years (mean 13 years). Eight of the 19 patients had revision surgeries. Four of these were to replace the original I-107 system (which had a 3–5-year life expectancy) with the current I-110 system, which is expected to perform electrically for the patient’s lifetime. Three patients had revisions due to mechanical failure. The remaining patients’ notes were incomplete. These data suggest that phrenic nerve stimulation can be used instead of mechanical ventilators for long-term ongoing respiratory support.     

Paroxysmal apnea and vasomotor instability following medullary infarction

BACKGROUND: Central hypoventilation and paroxysmal hypertension are uncommon complications of medullary infarction. To our knowledge, the combination of these autonomic complications of medullary stroke has not previously been reported. OBJECTIVE: To describe a patient who experienced life-threatening paroxysmal attacks of central apnea and vasomotor instability 3 months after medullary infarction, a combination of symptoms that is unusual. PATIENT, METHODS, AND RESULTS: Following a right lateral medullary infarction, an otherwise stable 70-year-old woman developed recurrent episodes of apnea (PCO2), > 100 mm Hg), blood pressure instability (systolic blood pressure, > 200 to < 100 mm Hg), and mental status changes (from agitation to coma) within hours of removal from mechanical ventilation. These attacks occurred repeatedly after removal from mechanical ventilation and were prevented by diaphragm pacing with a phrenic nerve pacemaker and nocturnal mechanical ventilation via a tracheostomy. CONCLUSIONS: A syndrome of life-threatening central hypoventilation and vasomotor instability can occur after medullary infarction. Placement of a phrenic nerve pacemaker can prevent these complications, without the functional limitations imposed by continuous mechanical ventilation.     

A Preliminary Feasibility Study of Different Implantable Pulse Generators Technologies for Diaphragm Pacing System

Diaphragm pacing stimulation (DPS) for ventilator‐dependent patients provides several advantages over conventional techniques such as phrenic nerve pacing or mechanical ventilator support. To date, the only existing system for DPS uses lead electrodes, percutaneously attached to an external pulse generator (PG). However, for a widespread use of this technique it would be more appropriate to eliminate the need for percutaneous wire and use a totally implantable system. The aim of this study was to determine if it were feasible to replace the external PG by an implantable system. We present here the results of a preliminary study of two different PG, currently used in other electrical stimulation (ES) clinical applications, which could be used as implantable DPS systems. One radio‐frequency‐powered PG, one rechargeable battery‐powered PG, and the current external PG were tested. Each was attached to the externalized part of the wires, connected to the diaphragm and tidal volume (TV) was measured in one ventilator‐dependent patient who has been using the current percutaneous stimulator for 3 years. Results indicated that both implantable PGs could achieve equivalent ventilatory requirements to the current external stimulator. No significant differences were observed between the three PG systems when stimulating the electrodes as used in the patient's own chronically attached PG system. We found that TV increased with increases in charge and frequency as expected when stimulating the patient's electrodes individually and in combination with each PG system. These results are a significant step toward developing a totally implantable DPS system for the ventilator‐dependant patients. Further clinical tests to demonstrate the safety and efficacy of a fully implanted DPS system are warranted.     

Neuronal progenitor transplantation and respiratory outcomes following upper cervical spinal cord injury in adult rats

Despite extensive gray matter loss following spinal cord injury (SCI), little attention has been given to neuronal replacement strategies and their effects on specific functional circuits in the injured spinal cord. In the present study, we assessed breathing behavior and phrenic nerve electrophysiological activity following transplantation of microdissected dorsal or ventral pieces of rat fetal spinal cord tissue (FSC_D or FSC_V, respectively) into acute, cervical (C2) spinal hemisections. Transneuronal tracing demonstrated connectivity between donor neurons from both sources and the host phrenic circuitry. Phrenic nerve recordings revealed differential effects of dorsally vs. ventrally derived neural progenitors on ipsilateral phrenic nerve recovery and activity. These initial results suggest that local gray matter repair can influence motoneuron function in targeted circuits following spinal cord injury and that outcomes will be dependent on the properties and phenotypic fates of the donor cells employed.     

Phrenic nerve conduction studies in spinal cord injury: Applications for diaphragmatic pacing

The diaphragm pacing system (DPS) is a minimally invasive alternative to mechanical ventilation in patients with quadriplegia due to cervical myelopathy primarily caused by high cervical spinal cord injury. We evaluated 36 patients, 29 of whom had traumatic spinal cord injury, two who had a history of remote meningitis and demyelinating disease, and five who had cervical myelopathies of unknown etiology. Phrenic nerve conduction studies were performed with simultaneous fluoroscopic observation of diaphragm excursion to assess diaphragm viability. In the preoperative evaluation, diaphragm compound muscle action potentials (CMAPs) were recorded only when the diaphragm moved on fluoroscopy with ipsilateral stimulation. Twenty‐six patients who were determined to have a viable diaphragm underwent DPS. Following DPS the primary outcome was the time (hours per day) that patients were able to pace and stay off the ventilator. Of 26 implanted patients, 96% (25 patients) were able to pace and tolerate being off the ventilator for more than 4 h per day. This study demonstrates that the presence of a diaphragm CMAP is associated with diaphragm movement observed by fluoroscopy in cervical myelopathy. In addition, DPS can help patients with cervical spinal cord injury to breathe unassisted by a ventilator. Muscle Nerve 38: 1546–1552, 2008     

高颈段脊髓电刺激促醒颅脑创伤昏迷一例并文献复习

目的 研究高颈段脊髓电刺激对颅脑创伤昏迷的促醒作用.方法 观察1例重型颅脑创伤患者高颈段脊髓电刺激术后清醒时间、脑电图、诱发电位及脑血流的变化.结果 患者术后2个月逐渐清醒,脑电图逐渐转为正常α节律,诱发电位潜伏期延长逐渐改善,脑血流明显增加.结论 高颈段脊髓电刺激可能通过增加脑血流、恢复正常的神经电生理活动促醒颅脑创伤昏迷患者.

Abstract：

Objective To study the awoking effect of high cervical spinal cord stimulation on comatose patients with traumatic brain injury.Methods Recovery time,electroencephalogram(EEG),evoked patentials,cerebral blood perfusion after cervical spinal cord stimulation in a comatose patient were investigated.Results The patient emerged form conla at 2 months after spinal cord stimulation treatment.EEG gradually turned into a normal(rhythm,evoked potentials latency improved,and cerebral blood perfusion increased significantly.Conclusions High cervical spinal cord stimulation exerts its beneficial effects to comatose patients with traumatic brain injury by increasing cerebral blood perfusion and restoring normal cerebral electrical activity.     

High-Level Cervical Spinal Cord Stimulation Used to Treat Intractable Pain Arising from Transverse Myelitis Caused by Schistosomiasis

The efficacy of spinal cord stimulation (SCS) for treatment of various chronic painful conditions is well established. Very few reports have documented the use of SCS for treatment of chronic pain after spinal cord injury. We present a case showing a good outcome after such treatment, and suggest that high cervical stimulation may be efficacious. A 53-year-old male underwent SCS on the C1-3 level for treatment of intractable neuropathic pain below the T3 level, and in the upper extremities, arising from spinal cord injury resulting from transverse myelitis caused by schistosomiasis. High cervical SCS significantly improved the pain in the upper extremities and at the T3-T10 dermatome level. The patient continues to report excellent pain relief 9 months later. The present case suggests that high cervical stimulation may improve chronic pain in the upper extremities and the T3-T10 dermatome level arising from spinal cord injury.     

Breathing Induced by Abdominal Muscle Stimulation in Individuals Without Spontaneous Ventilation

The purpose of the study was to determine if functional electrical stimulation of abdominal muscles (FESAM) could maintain pulmonary ventilation at acceptable levels in individuals with spinal cord injury (SCI) who are unable to breathe spontaneously. This is the first published investigation of this technique in this subject population. This case series study included three individuals with SCI; two were on mechanical ventilation (MV), and one used mechanical ventilation and also had an implanted phrenic nerve stimulator (PNS). Using surface electrodes, stimulation was applied to the rectus abdominis and lateral group of abdominal muscles. Repetitive trains of pulses produced a breathing frequency of 20 breaths/min. The longest periods of breathing using only FESAM‐supported ventilation for the three subjects were 30, 40, and 210 s, respectively. Airflow at the mouth and volumes were measured with a pneumotachograph and/or optoelectronic plethysmography. Oxygenation was monitored with a pulse oximeter. The tidal volumes generated exclusively by FESAM were sufficient to maintain adequate oxygenation during the periods of stimulation. When oxygenation measured with pulse oximetry dropped to 92% saturation, FESAM was discontinued, and MV or PNS was resumed. This is the first report of achieving successful ventilation in individuals with SCI who have zero tidal volume using FESAM. These preliminary results indicate the clinical potential of FESAM as an additional tool in the armamentarium of supported ventilation.     

Effects of chronic systemic theophylline injections on recovery of hemidiaphragmatic function after cervical spinal cord injury in adult rats

Based on a previous demonstration that acutely administered theophylline induces respiratory-related recovery in an animal model of spinal cord injury, the influence of chronically administered theophylline on maintaining recovery was assessed. The absence of respiratory-related activity in the left phrenic nerve and hemidiaphragm of rats subjected to an ipsilateral C2 spinal cord hemisection was confirmed electrophysiologically 24 h after injury. Theophylline was then injected i.p. for 3–30 consecutive days. Recovery of respiratory-related activity was observed in the majority (29 out of 32) of the experimental animals. We conclude that theophylline not only induces, but also maintains recovery for prolonged periods after cervical spinal cord injury.     

Spinal Cord Injury Induced by a Cervical Spinal Cord Stimulator

Objective: The use of cervical spinal cord stimulators for the treatment of refractory neck and upper extremity pain is widely accepted and growing in use as a treatment modality. This case highlights a previously unreported potential complication of spinal cord stimulators. Methods: Analysis of a patient with a cervical spinal cord stimulator presenting with a spinal cord injury. Patient was followed from presentation in the emergency room until 1‐year follow‐up in the office. Results: The patient in this case presented after a fall and sustained a cervical spinal cord injury induced by the electrodes of her spinal cord stimulator working as a space occupying mass. Conclusion: As more patients are undergoing implantation of spinal cord stimulators we must be aware of the long‐term risks that can be encountered.     

The crossed phrenic phenomenon

The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficien-cy constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in these patients. In seeking to enhance our capacity to treat specifically the respiratory dysfunction follow-ing spinal cord injury, investigators have studied the "crossed phrenic phenomenon", wherein contraction of a hemidiaphragm paralyzed by a complete hemisection of the ipsilateral cervical spinal cord above the phrenic nucleus can be induced by respiratory stressors and recovers spontaneously over time. Strength-ening of latent contralateral projections to the phrenic nucleus and sprouting of new descending axons have been proposed as mechanisms contributing to the observed recovery. We have recently demonstrat-ed recovery of spontaneous crossed phrenic activity occurring over minutes to hours in C1-hemisected unanesthetized decerebrate rats. The specific neurochemical and molecular pathways underlying crossed phrenic activity following injury require further clarification. A thorough understanding of these is nec-essary in order to develop targeted therapies for respiratory neurorehabilitation following spinal trauma. Animal studies provide preliminary evidence for the utility of neuropharmacological manipulation of sero-tonergic and adenosinergic pathways, nerve grafts, olfactory ensheathing cells, intraspinal microstimulation and a possible role for dorsal rhizotomy in recovering phrenic activity following spinal cord injury.     

Evaluating the evidence: is phrenic nerve stimulation a safe and effective tool for decreasing ventilator dependence in patients with high cervical spinal cord injuries and central hypoventilation?

Introduction

Case reports, case series and case control studies have looked at the use of phrenic nerve stimulators in the setting of high spinal cord injuries and central hypoventilation syndromes dating back to the 1980s. We evaluated the evidence related to this topic by performing a systematic review of the published literature.

Methods

Search terms “phrenic nerve stimulation,” “phrenic nerve and spinal cord injury,” and “phrenic nerve and central hypoventilation” were entered into standard search engines in a systematic fashion. Articles were reviewed by two study authors and graded independently for class of evidence according to published guidelines. The published evidence was reviewed, and the overall body of evidence was evaluated using the grading of recommendations, assesment, development and evaluations (GRADE) criteria Balshem et al. (J Clin Epidemiol 64:401–406, 2011).

Results

Our initial search yielded 420 articles. There were no class I, II, or III studies. There were 18 relevant class IV articles. There were no discrepancies among article ratings (i.e., kappa = 1). A meta-analysis could not be performed due to the low quality of the available evidence. The overall quality of the body of evidence was evaluated using GRADE criteria and fell within the “very poor” category.

Conclusion

The quality of the published literature for phrenic nerve stimulation is poor. Our review of the literature suggests that phrenic nerve stimulation is a safe and effective option for decreasing ventilator dependence in high spinal cord injuries and central hypoventilation; however, we are left with critical questions that provide crucial directions for future studies.

     

Experimental study of a late response recorded from the thoracic wall after phrenic nerve stimulation

ObjectivesThe phrenic nerve cervical stimulation induces an early motor diaphragmatic M response that may be recorded from the 7th ipsilateral intercostal space (ICS). Some responses with prolonged latency and of unclear origin can be recorded from the same recording site. The aim of the study was to determine the electrophysiological characteristics and the neuroanatomical pathways underlying the long-latency responses (LLRs) recorded from the 7th ICS.MethodsWe studied seven healthy volunteers, five patients with spinal cord injury and five patients with diaphragmatic palsy. All underwent phrenic nerve conduction study. An LLR was sought for at different stimulation sites using various stimulus intensities.ResultsA polyphasic LLR was recorded from the 7th ICS in all healthy subjects. It was mainly elicited by nociceptive stimulations, not only of the phrenic, but also of the median nerves. Its latency was longer than 70 ms, with a wide inter- and intra-individual variability. Amplitude was highly variable and some habituation phenomenon occurred. The LLR was retained in most tetraplegic patients after phrenic nerve stimulation, but absent otherwise. It was present in all patients with diaphragmatic palsy after phrenic nerve stimulation.ConclusionThe LLR is likely to be produced by both intercostal and diaphragm muscles. It is a polysynaptic and multisegmental spinal response, probably conveyed by small-diameter nociceptive A-δ and/or C fibres and modulated by a supraspinal control.SignificanceThe LLR recorded from the chest wall may constitute, by analogy with the nociceptive component of the lower limb flexion reflex in humans, a protective and withdrawal spinal reflex response.     

Management of chronic ventilatory insufficiency with electrical diaphragm pacing

We have had experience with diaphragm pacing in 24 patients at the Toronto Western Hospital. Fourteen patients have undergone bilateral implants to treat chronic ventilatory insufficiency (CVI) caused by traumatic tetraplegia at the C1/2 level (eight patients), neurogenic apnea (five) and one case of neonatal apnea. Unilateral stimulators for nocturnal pacing have been implanted in five patients with central alveolar hypoventilation (sleep apnea) and five patients who suffered CVI resulting from various etiologies. Of the patients who were ventilatory dependent, 80% were successfully weaned and in the entire series, 58% of the patients are living. Diaphragm pacing was successful in 67%, partially successful in 8% and ineffective in 25%. The major complications were: death by pneumonia, failure of the radio receivers, and infection. Diaphragm pacing is the treatment of choice for patients who are ventilator dependent and tetraplegic from upper cervical trauma or in some cases of neurogenic apnea; it may be life saving for patients who suffer central alveolar hypoventilation.     

Supraspinal involvement in the phrenic-to-phrenic inhibitory reflex

Phrenic afferents are capable of attenuating the phrenic motor response elicited by the intercostal-to-phrenic excitatory reflex in decerebrate, paralyzed cats. High spinal transection eliminates the attenuating effect of the bilateral phrenic-to-phrenic inhibitory reflex. These results indicate that although phrenic nerve afferents do exert an inhibitory influence in the cervical spinal cord, some of the inhibitory effects are likely to involve supraspinal mechanisms.     

The Effectiveness of Early Tracheostomy (within at least 10 Days) in Cervical Spinal Cord Injury Patients

Objective

This study aimed to determine the optimal time for tracheostomy by evaluating the benefits and safety of early versus late tracheostomy in spinal cord injury (SCI) patients.

Methods

We retrospectively reviewed a total of 254 patients with spinal cord injury. Of them, we selected 21 spinal cord injury patients who required tracheostomy due to long-term mechanical ventilation and analyzed their medical records. The patients were categorized into two groups. Early tracheostomy was performed day 1-10 from intubation in 10 patients and the late tracheostomy was performed after day 10 in 11 cases. We also evaluated the duration of mechanical ventilation, stay in the ICU and complications related to tracheostomy, the injury level of and clinical severity. All data was analyzed using SPSS 18.0/WIN.

Results

The early tracheostomy offered clear advantages for shortening the total ICU stay (20.8 day vs. 38.0 day, p=0.010). There was also statistically significant reduction in the total length of time on mechanical ventilation (5.2 day vs. 29.2 day, p=0.009). However, the reductions in the incidence of pneumonia (40% vs. 82%) and the length of ICU stay post to tracheostomy (6 day vs. 15 day) were found to be statistically not significant. There were also no statistically significant differences in the injury level and clinical severity between the groups.

Conclusion

We concluded that the early tracheostomy (at least 10 days) is beneficial for SCI patients who are likely to require prolonged mechanical ventilation.     

Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-Injured Rats

Microglia can modulate spinal nociceptive transmission. Yet, their role in spinal cord stimulation (SCS)-induced pain inhibition is unclear. Here, we examined how SCS affects microglial activation in the lumbar cord of rats with chronic constriction injury (CCI) of the sciatic nerve. Male rats received conventional SCS (50 Hz, 80% motor threshold, 180 min, 2 sessions/day) or sham stimulation on days 18–20 post-CCI. SCS transiently attenuated the mechanical hypersensitivity in the ipsilateral hind paw and increased OX-42 immunoreactivity in the bilateral dorsal horns. SCS also upregulated the mRNAs of M1-like markers, but not M2-like markers. Inducible NOS protein expression was increased, but brain-derived neurotrophic factor was decreased after SCS. Intrathecal minocycline (1 μg–100 μg), which inhibits microglial activation, dose-dependently attenuated the mechanical hypersensitivity. Pretreatment with low-dose minocycline (1 μg, 30 min) prolonged the SCS-induced pain inhibition. These findings suggest that conventional SCS may paradoxically increase spinal M1-like microglial activity and thereby compromise its own ability to inhibit pain.     

Effects of ipsilateral and contralateral cervical phrenic afferents stimulation on phrenic motor unit activity in the cat

The phrenic-to-phrenic inhibitory reflex has been analyzed using recordings of activity of single C₅-phrenic motor units (PMUs). After ipsilateral or contralateral stimulation of the C₆-phrenic root, early and late PMUs exhibit a similar inhibition. After contralateral stimulation, the duration of the inhibition is smaller and the threshold stimulus is higher than the corresponding values observed after ipsilateral stimulation. The latency of the inhibition is similar for both stimulations. Hemispinalization, contralateral to the recording site, affects weakly the phrenic-to-phrenic reflex. We conclude that early and late PMUs receive a similar inhibitory input from phrenic afferents and that the inhibition observed after cervical phrenic nerve stimulation may involve spinal cord circuits.     

Congenital central hypoventilation syndrome: a pathologic study of the neuromuscular system

An infant with congenital central hypoventilation was managed by bilateral phrenic nerve pacing for 3 months. He died at 8 months of age, following 19 days of continuous bilateral pacing necessitated by the eventual loss of voluntary as well as autonomic ventilatory control. The phrenic nerves showed axonal dystrophy at the site of electrode implantation and more severe distal degeneration. Focal neurogenic atrophy was seen in the diaphragmatic muscle. These changes were attributed to electrical injury resulting from the period of continuous pacing. The most significant neuropathologic finding was a mild generalized decrease in the density of neurons and myelinated nerve fibers in the respiratory centers of the medulla. These morphologic abnormalities were attributed to a sublethal intrauterine lesion that would be the first example of a morphologic correlation with the functional abnormality in congenital central hypoventilation.