Effects of Inspiratory Muscle Training on Exertional Breathlessness in Patients With Unilateral Diaphragm Paralysis
Effects of Inspiratory Muscle Training on Exertional Breathlessness in Patients With Unilateral Diaphragm Paralysis
Treatment options for unilateral diaphragm paralysis are limited. Diaphragmatic plication via
 mini thoracotomy is sometimes considered in the University Hospital Leuven if severe symptoms
 persist for longer than 12 months after initial diagnosis. Preliminary data indicate that
 daily inspiratory muscle strength and endurance training can lead to increased
 nondiaphragmatic inspiratory muscle recruitment and help those with symptoms from
 diaphragmatic paralysis. Randomized controlled trials comparing intervention groups with
 improvements achieved by natural recovery in the first months after diagnosis are however so
 far lacking. The objective of the current study is therefore to investigate the effects of
 daily inspiratory muscle training in the first 6 months following diagnosis of unilateral
 diaphragmatic paralysis. The investigators hypothesize that respiratory muscle training in
 symptomatic patients with UDP (in comparison with a control group) will reduce symptoms of
 exertional dyspnea (primary outcome) and will improve respiratory muscle function (at rest
 and during exercise) and pulmonary function (sitting and supine).
1. RATIONALE AND BACKGROUND Diaphragmatic paralysis is an uncommon, yet underdiagnosed cause
 of dyspnea. Although the diaphragm performs most of the work, normal ventilation also
 requires the simultaneous contraction of other respiratory muscles (ie, scalene, parasternal
 portion of the internal and external intercostal muscles, sternocleidomastoid, trapezius). An
 increased effort in the struggle to breathe may fatigue the accessory muscles and lead to
 ventilatory failure. It is thus far not clear whether specific training of the respiratory
 muscle can improve or restore diaphragm function or accessory respiratory muscle function in
 these patients.

 Depending on the etiology of the diaphragmatic paralysis, the prognosis of unilateral disease
 usually is good. Patients with phrenic injuries may recover fully or partially. At times,
 patients may also spontaneously recover from idiopathic disease. Patients who do not recover
 from unilateral diaphragmatic dysfunction generally lead relatively normal lives. Many
 patients however keep reporting symptoms of dyspnea that interfere with performance of daily
 activities. In this group, dyspnea typically develops with exertion, leading to increased
 ventilatory demands. Dyspnea can also be elicited by changes in posture (e.g. lying supine,
 bending forward). Depending on the activity profile of the subjects this might have an impact
 on quality of life. The investigators will therefore evaluate symptoms and recruitment of
 respiratory muscles of these patients during exertion (i.e. while performing an exercise test
 on a cycle ergometer).

 The morbidity of the unilateral paralysis is mainly based on the underlying pulmonary
 functional status and the etiology of the paralysis. Most of the patients that are referred
 to the University Hospital Leuven report symptoms of dyspnea during exertion or with changes
 in posture. Diaphragmatic paralysis is more likely to affect the left hemidiaphragm.
 Unilateral diaphragmatic paralysis is characterized by abnormalities of pulmonary and
 respiratory muscle function. Patients develop restrictive ventilatory impairment, and the
 vital capacity and total lung capacity frequently are below 70% of the predicted normal
 values. Lung capacity is reduced further when the patient assumes the supine position.

 In contrast to bilateral disease, physicians can usually diagnose unilateral paralysis with
 only radiographic studies. Because accessory muscle contraction may create the appearance of
 diaphragmatic movement, fluoroscopy studies may be misleading the physician when diagnosing
 bilateral diaphragmatic paralysis. In fluoroscopic sniff testing, paradoxical elevation of
 the paralyzed diaphragm is observed with inspiration and confirms diaphragmatic paralysis.
 However, the sniff test is not very specific; 6% of normal persons exhibit paradoxical motion
 on fluoroscopy. Computerized tomography may be indicated in certain patients to evaluate for
 potential causes of diaphragmatic paralysis that are due to mediastinal pathology and
 malignancy. MRI may be indicated in certain patients to determine the presence of pathologic
 conditions involving the spinal column or nerve roots that are causing diaphragmatic
 paralysis.

 M-mode ultrasonography is a relatively simple and accurate test for diagnosing paralysis of
 the diaphragm in the adult population and it can be performed at the bedside. The paralyzed
 side shows no active caudal movement of the diaphragm with inspiration and abnormal
 paradoxical movement (ie, cranial movement on inspiration), particularly with the sniff test.
 B-mode ultrasonography of diaphragm thickness in the zone of apposition of the diaphragm to
 the rib cage can also provide a sensitive and specific noninvasive assessment of
 diaphragmatic paralysis. Less than 20% thickening of the diaphragm muscle during inspiration
 is diagnostic of diaphragmatic paralysis. Ultrasonography can also be used to serially
 monitor patients with diaphragmatic paralysis for recovery.

 Phrenic nerve conduction studies can be carried out with placement of an oesophageal
 electrode to record diaphragmatic contractions and stimulation of the nerve in the neck
 either with surface stimulation or with a monopolar needle electrode at the level of the
 cricoid cartilage. Alternatively diaphragmatic electromyography may be carried out. The two
 tests are complementary. Electromyography may reveal a neuropathic versus myopathic pattern,
 depending on the etiology. This can be accomplished by stimulation of the phrenic nerve at
 the neck. Phrenic nerve stimulation can be done with electrical (surface or needle
 electrodes) and magnetic stimulation. Operator expertise is an important factor in testing.
 Technical issues with electromyography include proper electrode placement to avoid
 "cross-talk" from adjacent muscles and variable results due to variable subcutaneous fat
 among individuals. Using intraesophageal EMG electrodes is an alternative technique to avoid
 these issues. A method of unilateral magnetic stimulation of the phrenic nerve with
 concurrent assessment of diaphragm EMG and transdiaphragmatic pressures has also been
 described.

 Measuring the vital capacity in the upright and supine positions is the most important part
 of the pulmonary function test. Diaphragmatic paralysis reduces the measured compliance of
 the lungs and a restrictive pattern can develop. Normally, vital capacity in recumbency
 decreases by 10%. In contrast, patients with unilateral diaphragmatic paralysis show a 15-30%
 decrease in vital capacity in supine position. This decrease is from cephalad displacement of
 abdominal contents.Pulmonary function test results, however, are not always consistent and do
 not always correlate with the severity of dyspnea from diaphragmatic paralysis.

 Patients with diaphragmatic dysfunction and paralysis have a decrease in maximal inspiratory
 pressures (Pi,max). These patients cannot generate high negative inspiratory pressures.
 Therefore, the Pi,max in these patients is often reduced relative to normal values (Pi,max
 <70% predicted). Important to note is that decreased maximal pressures are the hallmark of
 diaphragmatic paralysis.

 The transdiaphragmatic pressure is the criterion standard for diagnosis. Normal
 transdiaphragmatic pressure is approximately 148 cm water in men and 122 cm water in women.
 Unilateral diaphragmatic paralysis is associated with a maximal transdiaphragmatic pressure
 of greater than 70 cm water, and thus does not significantly effect transdiaphragmatic
 pressure generation during normal ventilatory behaviors, but can compromise higher-force,
 nonventilatory, behaviors like coughing or sneezing and also exercise breathing. Twitch
 transdiaphragmatic pressures after bilateral magnetic phrenic nerve stimulation are
 frequently used as a non-volitional assessment to confirm the presence of diaphragm weakness.

 The functional limitations in individuals with respiratory disorders are not exclusively
 related to dyspnea. For example, balance impairments and resulting risk of falling are
 increasingly recognized issues in patients with COPD. Regarding the fact that postural
 balance is especially impaired in COPD patients with inspiratory muscle weakness, it can be
 hypothesized that diaphragm dysfunction plays an important role in the observed balance
 impairments. This is supported by the fact that the diaphragm is not only the principal
 inspiratory muscle, but also plays an important role in stabilizing the trunk during balance
 tasks. However, it remains unknown whether patients with diaphragm paresis show balance
 impairments, and whether these can be attributed to a dysfunction of the diaphragm.
 Furthermore, Kaufman et al. who followed up 180 patients with diaphragmatic paralysis,
 suggested that also low back pain might be associated with this disorder due to the fact that
 the postural function of the diaphragm is often disturbed in patients with low back pain.
 Also, individuals with low back pain show an increased diaphragm fatigability. However,
 neither the relation between diaphragmatic paralysis and postural control, neither between
 diaphragmatic paralysis and low back pain has been investigated yet.

 Treatment options for UDP are limited. Diaphragmatic plication via mini thoracotomy is
 sometimes considered in the University Hospital Leuven if severe symptoms persist for longer
 than 12 months after initial diagnosis. Preliminary data indicate that daily inspiratory
 muscle strength and endurance training can lead to increased nondiaphragmatic inspiratory
 muscle recruitment and help those with symptoms from diaphragmatic paralysis. Randomized
 controlled trials comparing intervention groups with improvements achieved by natural
 recovery in the first months after diagnosis are however so far lacking. In addition there is
 a lack of comparable data between healthy subjects and patients.

 The objective of the current study is therefore to investigate the effects of daily
 inspiratory muscle training in the first 6 months following diagnosis of unilateral
 diaphragmatic paralysis. A second objective is to compare (changes in) respiratory muscle
 function and activation patterns between healthy control subjects and patients. The
 investigators hypothesize that respiratory muscle training in symptomatic patients with UDP
 (in comparison with a control group) will reduce symptoms of exertional dyspnea (primary
 outcome) and will improve respiratory muscle function (at rest and during exercise) and
 pulmonary function (sitting and supine). Secondly, we hypothesize that the (changes in)
 recruiting patterns of diaphragmatic and non-diaphragmatic muscles will differ between
 healthy control subjects and patients both at baseline and in response to the intervention.

 2. SPECIFIC OBJECTIVES

 1. Investigate effects of IMT on intensity and quality of dyspnea perception in symptomatic
 patients with unilateral diaphragm paralysis during exercise

 2. To identify and distinguish mechanisms responsible for dyspnea reduction after the
 intervention by exploring inter-relationships between the post-intervention change in
 dyspnea and changes in relevant measures of respiratory muscle function at rest and
 during exercise.

 3. To compare changes in respiratory muscle recruitment patterns and respiratory neural
 drive to the diaphragm, as well as scalene, sternocleidomastoid and parasternal
 intercostal muscles in response to 6 months of inspiratory muscle strength- or endurance
 training during exercise.

 4. To compare differences in (changes in) respiratory muscle recruitment patterns and
 respiratory neural drive to the diaphragm, as well as scalene, sternocleidomastoid and
 parasternal intercostal muscles, and postural control between healthy controls and
 patients.
Inclusion Criteria for UDP patients:

 -  Stable, symptomatic adult UDP patients (age ≥18 yrs)

 -  UDP due to presumed neuralgic amyotrophy

 -  UDP after surgery/anesthesia (as long as there is no trauma/complete section of the
 phrenic nerves)

 -  idiopathic UDP

 -  UDP patients with Baseline Dyspnea Index (BDI) equal or lower than 9 out of 12.

 -  UDP patients who have reduced Pi,max (<70% of predicted normal value), reduced vital
 capacity (<75% predicted normal value in sitting and more than 15% reduction when
 performed supine compared to sitting).

 Exclusion Criteria for UDP patients:

 -  underlying cardiac or respiratory disease that explains symptoms of dyspnea

 -  malignancy (i.e. metastatic lung cancer)

 -  diagnosed psychiatric or cognitive disorders

 -  concomitant progressive neurological, neuromuscular, or vestibular disorders

 -  severe orthopedic problems that have a major impact on performance of functional tests

 Healthy adult (age ≥18 yrs) control subjects:

 - recruitement via two methods. First, friends and family of the MSc student involved in
 this project will be asked to participate. Secondly, posters with information about the
 study will be displayed in the University hospital Leuven.