Treatment for bilateral diaphragmatic dysfunction using phrenic nerve reconstruction and diaphragm pacemakers

Abstract

 

OBJECTIVES

Bilateral diaphragmatic dysfunction results in severe dyspnoea, usually requiring oxygen therapy and nocturnal ventilatory support. Although treatment options are limited, phrenic nerve reconstruction (PR) offers the opportunity to restore functional activity. This study aims to evaluate combination treatment with PR and placement of a diaphragm pacemaker (DP) compared to DP placement alone in patients with bilateral diaphragmatic dysfunction.

METHODS

Patients with bilateral diaphragmatic dysfunction were prospectively enrolled in the following treatment algorithm: Unilateral PR was performed on the more severely impacted side with bilateral DP implantation. Motor amplitudes, ultrasound measurements of diaphragm thickness, maximal inspiratory pressure, forced expiratory volume, forced vital capacity and subjective patient-reported outcomes were obtained for retrospective analysis following completion of the prospective database.

RESULTS

Fourteen male patients with bilateral diaphragmatic dysfunction confirmed on chest fluoroscopy and electrodiagnostic testing were included. All 14 patients required nocturnal ventilator support, and 8/14 (57.1%) were oxygen-dependent. All patients reported subjective improvement, and all 8 oxygen-dependent patients were able to discontinue oxygen therapy following treatment. Improvements in maximal inspiratory pressure, forced vital capacity and forced expiratory volume were 68%, 47% and 53%, respectively. There was an average improvement of 180% in motor amplitude and a 50% increase in muscle thickness. Comparison of motor amplitude changes revealed significantly greater functional recovery on the PR + DP side.

CONCLUSIONS

PR and simultaneous implantation of a DP may restore functional activity and alleviate symptoms in patients with bilateral diaphragmatic dysfunction. PR plus diaphragm pacing appear to result in greater functional muscle recovery than pacing alone.

INTRODUCTION

Bilateral diaphragmatic dysfunction may occur from degeneration along the neural pathways from the central cervical levels (C3-5) to the corresponding peripheral cervical roots to the phrenic nerves. The extent of muscular dysfunction in each hemi-diaphragm may range from partial denervation or paresis to complete paralysis and even paradoxical paralysis (a flail diaphragm). Prior studies have elaborated the severity of restrictive ventilatory deficits associated with bilateral diaphragmatic dysfunction, including a dependence on oxygen and nocturnal positive pressure ventilation [1].

Treatment options for diaphragmatic paralysis include respiratory/physical therapy, oxygen and positive pressure ventilation, oral and inhaled medications, plication of the diaphragm, implantation of a diaphragm pacemaker (DP) and phrenic nerve reconstruction (PR). In patients with bilateral diaphragmatic dysfunction, medical therapy will often be insufficient. Plication of the diaphragm has demonstrated benefit for unilateral paralysis but there have been few investigations evaluating this surgical treatment for bilateral diaphragmatic dysfunction [2–8]. Surgical treatment aimed at restoring physiological diaphragmatic activity has great potential to alleviate symptomatology and restore respiratory function.

Both PR and DP have been evaluated individually as functional treatment options for diaphragmatic paralysis [9–17]. Based on demonstrable efficacy of each intervention, we hypothesize that combination therapy for patients with moderate-to-severe respiratory disturbances due to bilateral diaphragmatic dysfunction is superior to DP placement alone.

MATERIALS AND METHODS

Institutional review board approval was obtained (201304151J), as well as informed consent, in accordance with board approval.

A retrospective review of 14 consecutive patients with bilateral diaphragmatic dysfunction enrolled in a prospective treatment algorithm at 2 tertiary referral centres between April 2015 and August 2019 was performed to evaluate combination treatment (PR + DP). All patients included in the study were diagnosed with symptomatic bilateral diaphragmatic dysfunction secondary to cervical radiculopathy, degeneration or stenosis. Diagnosis was confirmed upon chest fluoroscopy with supporting phrenic nerve conduction studies and diaphragmatic electromyography that demonstrated bilateral phrenic neuropathies, a reduction or absence in the diaphragm motor amplitudes, and preservation of intact voluntary motor units. Criteria for exclusion from the study included significant cardiac or other medical comorbidities and injury greater than 5 years; although there were no strict age-related criteria for exclusion, patients over 75 years. deemed to have poor preoperative functional status were also excluded from the study. Additional testing included cervical magnetic resonance imaging (MRI) and preoperative neurosurgical evaluation if there was evidence of spinal cord compression or moderate-to-severe cervical degenerative disc disease. Surgical intervention was offered after 8 months of conservative management, including medical therapy, oxygen supplementation and positive pressure ventilation via continuous positive airway pressure or bilevel positive airway pressure, without evidence of spontaneous improvement and persistent symptoms.

Surgical procedure

Unilateral PR was performed through a cervical approach on the more severely impacted side with simultaneous bilateral laparoscopic DP implantation (Synapse Biomedical, Oberlin, Ohio). The technical details of PR and laparoscopic DP implantation have been given in prior publications [13–15, 18, 19]. Briefly, PR involves decompression neurolysis of the phrenic nerve and the C3, C4 and C5 peripheral cervical roots to release any adhesions or scar tissue encasing and/or compressing the nerves. Any external compression caused by overlying vascular structures such as the transverse cervical vessels were also treated with ligation and division of the vessels. Based upon the aetiology of the paralysis, neurolysis is performed in combination with nerve grafting or nerve transfer. The former option involves using an interposition sural nerve graft to bypass a specific site of injury caused by chronic compression. Meanwhile, neurotization involves a nerve transfer to bring additional neural stimulation to the paralysed diaphragm. A sural nerve graft may also be utilized for neurotization if the donor nerve does not reach the phrenic nerve and additional length is necessary. Laparoscopic DP is performed by placing 2 electrodes into each hemi-diaphragm to approximate the nerve–muscle interface. The electrodes are attached to an electronic pulse generator to stimulate the phrenic nerves and muscle to cause contraction in the diaphragm [13–15, 18, 19]. DPs are FDA approved for ventilator-dependent patients with spinal cord injuries.

The basis for this combination treatment algorithm is to minimize the potential risk of additional iatrogenic nerve injury or exacerbating perioperative respiratory disturbances while still addressing the bilateral component of the disorder. Avoiding nerve manipulation on the more functional side minimizes the potential for worsening the existing respiratory dysfunction, while bilateral DP provides neuromuscular stimulation to both hemi-diaphragms. Each patient serves as his own control, which is optimal to avoid any confounding variables due to wide variety of causes, comorbidities and duration of symptoms. As the more severely affected side is selected for intervention with PR and DP, the study is designed to truly determine the benefits of combination treatment. One year postoperatively, patients are offered PR on the untreated side if there is evidence of improvement. After 2 years, the pacemaker is considered for explantation if functional and symptomatic recovery is deemed equivalent with or without the pacer.

Pre- and postoperative testing

All patients were followed up prospectively during the study period. Parameters for assessment include motor amplitudes (MA), ultrasound measurements of resting diaphragm muscle thickness (US), maximal inspiratory pressure (MIP), forced expiratory volume (FEV), forced vital capacity (FVC) and patient-reported outcomes. Testing was performed preoperatively and after 1-year follow-up and peri- and postoperative complications were reported. Each patient served as his own control in order to determine the benefit of combination treatment with PR and DP compared to DP alone.

Motor amplitudes/ultrasound

Electromyography of the diaphragm was performed by placing the ground electrode on the upper sternum, the active surface electrode over the lower sternum and the reference electrode 16 cm away over the anterior lower rib margin. The electromyography was recorded using a 50-mm, 26-gauge intramuscular monopolar needle electrode (Care Fusion, Middleton, WI, USA) in the diaphragm and intercostal muscles. Ultrasound guidance was used to place the needle in the 8th or 9th intercostal space along the anterior axillary line. Each area was examined at rest and during volitional respiratory efforts. Measurements of resting diaphragm thickness were recorded in centimetres.

Maximal inspiratory pressure

MIP testing was performed sitting upright in the office using the MicroRPM respiratory pressure metre (Mettawa, IL, USA). Patients self-initiated a 3-s maximal inspiratory effort starting from residual volume. Three recordings were obtained and the mean was calculated. The value was expressed as a percentage using the standard values based on sex and age.

Forced expiratory volume/forced vital capacity

Pulmonary spirometry was performed using standard techniques with patients sitting upright, as most could not tolerate being supine. FEV and FVC were measured (or calculated) and expressed as a percentage of the predicted values, in accordance with standard values based upon patient age, height and sex.

Statistical analysis

Data were analysed using student’s t-test to compare pre- and postoperative results in overall function. A within-group comparison was performed using a Fisher’s exact test to assess the side treated with PR + DP versus the contralateral side receiving only DP. Values of P < 0.05 were considered statistically significant.

RESULTS

There were 14 males with an average age of 53.2 (range 40–63), and average body mass index of 31.8 (range 19.5–47.7). The duration of symptoms due to bilateral diaphragmatic dysfunction was 24 months (range 8–37 months). In all 14 patients, the aetiology of the bilateral paralysis was determined to be from isolated or combined phrenic neuropathy or peripheral cervical radiculopathy due to compression from degenerative cervical joint disease based on preoperative diagnostic testing and intraoperative findings. One patient also had underlying Charcot-Marie-Tooth disease, which was not thought to be related to the diaphragm paralysis. There were no patients who presented with transection of the phrenic nerve due to prior surgery or trauma (Table 1).

Table 1:

Patients with bilateral diaphragmatic paralysis undergoing phrenic nerve reconstruction

Patient	Age	BMI	Side	Aetiology	Comorbidities	Surgery	Graft length (cm)
1	51	47.7	Right	DJD	Hypothyroidism, CHF	Neurolysis C4–C5 and end-to-side levator scapulae nerve to phrenic nerve	None
2	49	19.5	Right	Trauma, DJD		Neurolysis C3–C5, end-to-side levator scapulae nerve to phrenic nerve, and end-to-side C4 to phrenic nerve with sural nerve graft	4
3	54	33.4	Right	DJD	HTN	Neurolysis C3–C5, and end-to-side levator scapulae nerve to phrenic nerve	None
4	56	37.9	Left	Trauma, DJD	HTN, DM	Neurolysis C3–C5, end-to-side levator scapulae nerve to phrenic nerve, and end-to-side C4 to phrenic nerve with sural nerve graft	6
5	53	33.7	Left	DJD, ACDF	HTN, COPD	Neurolysis C3–C5 and end-to-side levator scapulae nerve to phrenic nerve	None
6	54	29.8	Right	DJD, nerve block	HTN, DM, MI	Neurolysis C4–C5 and end-to-side C4 to phrenic nerve with sural nerve graft	7
7	46	29.6	Left	DJD	HTN, COPD, hypothyroidism	Neurolysis C4–C5 and end-to-side spinal accessory nerve branch to phrenic nerve with sural nerve graft	7
8	63	27.5	Right	DJD	HTN, COPD	Neurolysis C4–C5 and end-to-side spinal accessory nerve branch to phrenic nerve with sural nerve graft	7
9	40	35.0	Left	Trauma, nerve block	HTN	Neurolysis C4–C5 and end-to-side spinal accessory nerve branch to phrenic nerve with sural nerve graft	7
10	60	30.6	Right	Trauma, DJD	HTN, DM, CAD	Neurolysis C3–C5, end-to-side levator scapulae nerve to phrenic nerve, and end-to-side C4 to phrenic nerve with sural nerve graft	5
11	47	29.5	Left	DJD		Neurolysis C4–C5 and end-to-side spinal accessory nerve branch to phrenic nerve with sural nerve graft	7
12	54	29.6	Left	Trauma, DJD	HTN	Neurolysis C4–C5 and end-to-side levator scapulae nerve to phrenic nerve	None
13	56	31.8	Left	DJD	CMT, PUD	Neurolysis C4–C5 and end-to-side spinal accessory nerve branch to phrenic nerve with sural nerve graft	6
14	62	29.1	Right	DJD	PUD	Neurolysis C3–C5 and end-to-side dorsal scapular nerve to phrenic nerve	None

ACDF: anterior cervical disc fusions; BMI: body mass index; CAD: coronary artery disease; CHF: congestive heart failure; CMT: Charcot-Marie-Tooth disease; COPD: chronic obstructive pulmonary disease; DJD: degenerative joint disease; DM: diabetes mellitus; HTN: hypertension; MI: myocardial infarction; PUD: peptic ulcer disease.

All patients exhibited moderate-to-severe exertional dyspnoea and orthopnoea, and demonstrated bilateral diaphragmatic dysfunction. This was confirmed on chest fluoroscopy by complete paralysis on both sides, paralysis on one side and reduced activity (paresis) on the contralateral side or paresis bilaterally. Preoperatively, all 14 patients required nocturnal positive pressure ventilation (bilevel positive airway pressure or continuous positive airway pressure), and 8/14 were oxygen-dependent. Seven patients underwent PR on the more severely affected right side, while the remaining 7 patients underwent left-sided reconstruction with both groups also undergoing bilateral DP placement.

Electrodiagnostic evaluation revealed bilateral abnormalities of MA [mean preoperative values: Right = 0.05 mV (range 0–0.12 mV) and Left = 0.04 mV (range 0–0.08 mV, reference 0.75 mV ± 0.54)]. Mean preoperative ultrasound measurements of resting diaphragm thickness were Right = 0.12 cm (range 0.02–0.30 cm) and Left = 0.13 cm (range 0.02–0.27 cm, reference 0.20 cm ± 0.04).

The mean preoperative MIP value was 41 cm H₂O (range 21–66 cm H₂O, reference value for males >40 years 82.8 cm H₂O ± 26.6). The mean preoperative percentage predicted values for FEV and FVC were 51% (range 39–58%, reference 80–120%) and 51% (range 38–73%, reference 80–120%), respectively (Table 2).

Table 2:

Preoperative diagnostic measures

Preoperative measure	Mean value	Range	Reference value
Motor amplitudes (MA)	Right = 0.05 mV Left = 0.04 mV	0–0.12 mV 0–0.08 mV	0.75 mV ± 0.54
Resting diaphragm muscle thickness (US)	Right = 0.12 cm Left = 0.13 cm	0.02–0.30 cm 0.02–0.27 cm	0.20 cm± 0.04
Maximal inspiratory pressure (MIP)	41 cm H2O	21–66 cm H2O	82.8 cm H2O ±26.6 (for males > 40 years)
Forced expiratory volume (FEV)	51%	39–58%	80–120%
Forced vital capacity (FVC)	51%	38–73%	80–120%

Following combination PR + DP, patients were followed up for an average of 25 months (range = 12–52 months). In all 14 patients, there was subjective reporting of improvement in respiratory function at 1 year. This included the self-reporting of 1 or more of the following: alleviation of respiratory distress while supine (reported in 57% of patients), recovering the ability to bend over without discomfort (reported in 14% of patients), resumption of light-to-moderate exercise (reported in 86% of patients), sufficient recovery to discontinue oxygen and/or nocturnal positive pressure therapy. All 8 patients who were oxygen-dependent preoperatively were able to discontinue this therapy by 1-year follow-up.

There was a 68% improvement in MIP values at 1-year follow-up (41–69 cm H₂O, P = 0.01, Fig. 1). Diaphragm motor amplitudes improved by 180% following treatment (0.05–0.14 mV, P < 0.01) and there was a corresponding 50% increase in diaphragm muscle thickness (0.12–0.18 cm, P < 0.05, Figs 2 and 3). The percentage predicted values for FVC increased from 51% to 75% (P < 0.05), and there was a corresponding increase in FEV from 51% to 78% (P < 0.05, Fig. 4).

Figure 1:

Preoperative and postoperative MIP values. A 68% improvement is noted postoperatively (41–69 cm H₂O, P < 0.05). The reference value range is indicated in the grey shaded area (82.8 cm H₂O ± 26.6). MIP: maximal inspiratory pressure; Post-Op: postoperative; Pre-Op: preoperative.

Figure 2:

Results of preoperative and postoperative diaphragm EMG. MA was observed to improve by 180% postoperatively (0.05–0.14 mV, P < 0.05). The reference value range is indicated for comparison (0.56 mV ± 0.54). EMG: electromyography; MA: motor amplitude; Post-Op: postoperative; Pre-Op: preoperative.

Figure 3:

Preoperative and postoperative US measurements of resting diaphragm thickness. A 50% increase in diaphragm thickness is observed postoperatively (0.12–0.18 cm, P < 0.05). Reference value and range are included for comparison (0.20 cm ± 0.04). Post-Op: postoperative; Pre-Op: preoperative; US: ultrasound.

Figure 4:

Pulmonary function test results. Postoperatively, the percentage predicted values for FVC increased from 51% to 75% (P < 0.05) and FEV increased from 51% to 78% (P < 0.05). The reference value range is indicated in the grey shaded area (80–120%). FEV: forced expiratory volume; FVC: forced vital capacity; Post-Op: postoperative; Pre-Op: preoperative.

Diaphragm MA on the side receiving PR + DP improved in all patients; however, on the DP-only side, the MA improved in only 1 patient and was either unchanged or worse in the remaining patients. On the PR + DP side, the US measurements increased in all patients, whereas on the DP-only side, 2 patients improved while the remaining patients experienced either no change or a decrease in diaphragm thickness. Based on MA comparison between the 2 sides in each patient, there was significantly greater functional diaphragmatic improvement on the PR + DP side versus DP alone (P < 0.05). During the most recent follow-up, 12/14 patients underwent contralateral PR within the first postoperative year, and 4/12 patients had bilateral pacemaker explantation.

Complications consisted of pacemaker site infections occurring in 2 patients (13%) that were refractory to antibiotic therapy, thus requiring explantation. In 1 patient (Patient 12), the infection occurred 8 months following initial implantation, and a new diaphragmatic pacemaker was withheld due to an inability for proper hardware hygiene, thus limiting the subsequent recovery of the patient. In the second patient (Patient 14), infection requiring explantation occurred long after the patient had recovered; for this reason, the diaphragmatic pacer was not replaced.

DISCUSSION

Bilateral diaphragmatic dysfunction results in moderate-to-severe respiratory abnormalities, limitations in physical functioning and significant sleep disturbances. Although this condition may be less common than unilateral diaphragmatic paralysis, patients with bilateral disorders require more urgent management to reduce respiratory infection susceptibility and prevent progression to chronic respiratory failure requiring mechanical ventilation. In a review by Kokatnur and Rudrappa (2018), they reported more severe respiratory deficits in bilateral versus unilateral diaphragm paralysis based upon pulmonary spirometry [20]. In bilateral paralysis, FVC will be reduced by 20–30%, compared to FVC reductions of 15–20% in patients with unilateral paralysis. There are several case reports highlighting possible aetiologies and the severe symptomatology associated with bilateral diaphragmatic paralysis [21–27].

In tetraplegic patients with cervical spinal cord injury, the aetiology for bilateral diaphragm dysfunction is well understood and DPs have demonstrable efficacy in reducing or eliminating ventilator dependency [9]. Alternatively, in patients presenting with isolated bilateral diaphragmatic dysfunction, the aetiology is not always clear. In the current series, the preoperative evaluation revealed evidence of degenerative cervical disease of varying severity in all patients. Although it is not possible to identify phrenic nerve or peripheral cervical root compression on radiographic imaging, the extent of spinal degeneration observed on MRI characterized the general condition in the neural pathways and was used to extrapolate the likelihood of peripheral radiculopathy.

We used ultrasound measurements of diaphragm thickness to evaluate functional recovery instead of chest fluoroscopy based on the work of Summerhill et al. (2008). This group utilized ultrasound to evaluate muscle thickness in diaphragmatic recovery and promoted this parameter as one with greater sensitivity and specificity than other imaging modalities, observing gradual improvements over a 15-month period [28]. Chest fluoroscopy is an excellent diagnostic tool to confirm unilateral diaphragmatic paralysis by comparing the non-functional side to the contralateral normal hemi-diaphragm. However, in patients with bilateral diaphragmatic dysfunction, without an ability to identify a normal ‘reference’ side, there is a greater tendency for inaccuracies. We have observed reports that indicate a normal fluoroscopic study in patients with unequivocal bilateral diaphragmatic dysfunction. Furthermore, measuring gradual changes consistent with progressive diaphragmatic recovery is not as feasible using chest fluoroscopy.

The treatment options for diaphragm paralysis are limited and initially focused on plication of the muscle. Recently, diaphragmatic pacemakers have been employed with varying degrees of success. Onders et al. conducted a prospective study of 27 patients undergoing placement of DPs and reported that 13 patients experienced a clinically relevant improvement in respiratory function [11]. With additional advances in peripheral nerve surgery, additional options have become available including nerve grafting and neurotization in conjunction with pacemaker placement. Another small study of 4 ventilator-dependent patients undergoing neurotization of the intercostal nerve to the phrenic nerve with pacing demonstrated excellent results with all 4 patients being able to tolerate breathing without mechanical ventilation [17].

Combination treatment with PR + DP appears to be very effective at reducing and alleviating symptoms and restoring functional activity in patients with bilateral diaphragmatic dysfunction. Subjective reporting of respiratory corrections in all patients and the ability for all oxygen-dependent patients to discontinue treatment was observed. Postoperative values for MIP, FEV and FVC were significantly improved following treatment, all approaching normal ranges. There were also significant improvements in diaphragm MA and US muscle thickness, providing additional evidence for functional recovery.

Our within-group analysis comparing the side receiving PR + DP to the contralateral DP-only side revealed greater functional recovery on the PR + DP side. As expected, a compression neuropathy effecting the cervical roots and phrenic nerves requires direct intervention for optimal recovery. Standard nerve reconstruction techniques, such as decompression and nerve grafting, promote neural regeneration and muscular recovery. There are numerous investigations describing the effectiveness of nerve reconstruction methods for restoring muscular function [13, 17, 19, 29]. The pacemaker likely supports and enhances this regenerative process, while lessening or halting progressive neuromuscular atrophy in the interim. The benefits of electrical stimulation in neural regeneration and recovery have been well elucidated [10, 30]. We also ascribe to the concept that once nerve regeneration has occurred, the continued use of the pacemaker promotes muscular strengthening and shortens the time to maximal recovery. Although 2 patients required pacemaker explantation due to infection of the implant, we do not believe this impacted the validity of the statistical analysis. Although one of the patients required explantation prior to full recovery and had limited recovery in comparison to other participants in the study, the other patient who required pacemaker explantation did so after recovery and therefore did not negatively impact functional return.

Bilateral diaphragmatic paralysis is a rare but extremely debilitating cause of respiratory distress. PR and DP placement result in greater improvement compared to pacemaker alone. Combination treatment is a reasonable option to improve respiratory function in this unique group of patients suffering from diaphragmatic paralysis.

Conflict of interest: none declared.

Author contributions

Matthew R. Kaufman: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Validation; Writing—original draft. Thomas Bauer: Conceptualization; Investigation; Methodology; Validation; Writing—review & editing. Raymond P. Onders: Conceptualization; Investigation; Validation; Writing—review & editing. David P. Brown: Conceptualization; Formal analysis; Methodology; Validation; Writing—review & editing. Eric I. Chang: Data curation; Formal analysis; Investigation; Validation; Writing—review & editing. Kristie Rossi: Data curation; Formal analysis; Project administration; Writing—review & editing. Andrew I. Elkwood: Conceptualization; Investigation; Methodology; Validation; Writing—review & editing. Ethan Paulin: Data curation; Investigation; Methodology; Validation; Writing—review & editing. Reza Jarrahy: Conceptualization; Investigation; Methodology; Validation; Writing—review & editing.

Reviewer information

Interactive CardioVascular and Thoracic Surgery thanks Domenico Galetta, Keyvan Moghissi and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

ABBREVIATIONS

DP

Diaphragm pacemaker

FEV

Forced expiratory volume

FVC

Forced vital capacity

MIP

Maximal inspiratory pressure

MRI

Magnetic resonance imaging

PR

Phrenic nerve reconstruction