Neural Respiratory Drive in Pulmonary Hypertension
Conditions: Pulmonary Hypertension
Sponsor: Golden Jubilee National Hospital

NRD in PH. Protocol v4. 19th January 2019  
 
1 
 
PROTOCOL 
PROJECT SUMMARY 
Neural respiratory drive in patients with pulmonary hypertension, its correlation with disease 
severity and how it changes with therapy 
 
GENERAL INFORMATION 
Chief Investigator  
Martin Johnson 
 
RATIONALE AND BACKGROUND INFORMATION 
Pulmonary hypertension is a rare and progressive condition. It results in significant symptom burden 
for patients. Despite advancements in medical therapy, it remains a debilitating disease. 
Patients with the condition remain under follow up at specialist centres. Initial diagnosis involves 
invasive tests that measure the pressure inside the blood vessels in the lungs. Follow up of the 
patients involves less invasive measurements; at the Scottish Pulmonary Vascular Unit (SPVU), this 
would be 6 minute walk test and blood tests.  
Neural respiratory drive (NRD) is a novel physiological marker that is calculated by measuring 
parasternal electromyogram (EMG). This is a measure of the electrical signals sent by the brain to 
the muscles either side of the breast bone. It is not possible to measure the output of brainstem 
neurons involved with respiration directly but EMG of respiratory muscles provides a way of 
calculating NRD by measuring the myoelectrical signals of the respiratory muscles. Studies have been 
performed to show that measuring parasternal muscles gives similar results to measuring diaphragm 
EMG while having the advantage of being non-invasive(1).  
Parasternal EMG recordings have been used in research involving patients with cystic fibrosis(2) and 
chronic obstructive pulmonary disease(3). In these conditions, it has been shown to be a useful 
marker for assessing response to treatment and as a risk stratification tool in predicting which 
patients are more likely to have clinical worsening.  
In patients with pulmonary hypertension, it would be useful to develop a non-invasive measurement 
that could potentially be used to guide clinical decision making. EMG is a measurement that can be 
taken quickly and is non-invasive. It has not previously been studied in patients with pulmonary 
hypertension.  
Our study would provide baseline data on neural respiratory drive in patients with pulmonary 
hypertension. In addition to acquiring novel data in NRD in patients with pulmonary hypertension, 
our study would aim to investigate for correlation between change in neural respiratory drive and 
change in clinical condition, both measured by clinical assessment and by the clinical investigations 

NRD in PH. Protocol v4. 19th January 2019  
 
2 
 
already used in standard care. This would be following commencement treatment for pulmonary 
hypertension as decided by MDT. This may include medications or, in some cases, surgery.  
We hypothesise that neural respiratory drive is raised in patients with pulmonary hypertension, 
correlates with the severity of the disease and changes with therapy. 
 
STUDY GOALS AND OBJECTIVES 
To assess neural respiratory drive in patients under investigation for potential pulmonary 
hypertension.  
To assess change in neural respiratory drive following intervention for pulmonary hypertension. 
(Interventions will include medications and/or surgery. These interventions represent the normal 
clinical care of the patients involved.) 
To correlate any change in NRD with other clinical parameters measured as part of normal 
diagnostic process (for baseline measurements) or further non-invasive tests (as part of follow up) 
 
STUDY DESIGN 
We propose two observational studies 
1. Cross-sectional study to assess patients during their diagnostic admission.  
2. Following this, some patients will be commenced on therapy as decided by multidisciplinary 
team. In these, we will look for longitudinal changes in NRD. These changes will be 
compared to other results obtained as part of normal clinical care to look for any 
association. 
Inclusion criteria 
- 
Age 18 and above 
- 
Able to give informed consent 
- 
Patients being investigated for pulmonary hypertension 
Exclusion criteria 
- 
Unable to provide consent 
- 
Patient is pregnant 
- 
Patient has a diagnosed neuromuscular disorder 
METHODOLOGY 
Patients will be recruited from the Scottish Pulmonary Vascular Unit based at Golden Jubilee 
National Hospital. Patients referred to the centre are admitted for 4 days to undertake tests in order 
to formulate a diagnosis. We propose adding an additional, non-invasive test to this to assess neural 

NRD in PH. Protocol v4. 19th January 2019  
 
3 
 
respiratory drive. Patients will be approached by one of the research nurses and given information 
about the study.  
Neural Respiratory Drive 
NRD can be assessed by measuring parasternal electromyogram (Dual Bio Amp, ADInstruments, 
Oxford, U.K.). Readings are taken by applying two small electrodes in the second intercostal space 
either side of the sternum and one to the shoulder. The electrodes are similar to those used in ECG 
acquisition. A thin belt is worn round the chest to assess respiratory rate. The patient will also 
breathe through a mouthpiece so that flow measurements and respiratory rate can be measured. 
Measurements are then taken during normal breathing and also during maximal breathing effort 
(‘sniff’ procedure). Tests may be taken with patient recumbent at 45 degrees and supine. The test is 
non-invasive, has been safely performed in patients in previous studies and is not anticipated to 
cause any harm or distress. The total time for measurements will be around 20 minutes per patient. 
NRD will be calculated as root mean square of normal tidal breathing as a proportion of maximal 
inspiratory effort (maximum inspiration from functional reserve capacity, taken as a sniff 
manoeuvre).  
At the end of the inpatient stay for diagnosis, some patients are commenced on treatment and 
followed up in clinic. It would be our intention to reassess these patients at clinic to test NRD and 
compare how this changes over time compared to other clinical parameters.   
Information will be collected from case notes from baseline investigations. This will include: 
o 6 minute walk distance (6MWD) with breathing perception score 
o Pulmonary function tests (FEV1, FVC, DLCO, TLC, Va) 
o Right heart catheterisation 
o NTproBNP 
o WHO Functional Class 
o Quality of life (QoL) questionnaire – emphasis 10, CAMPHOR 
o Cardiopulmonary exercise test (CPET) – peak work rate, peak VO2, VE/VCO2. 
o Height, weight, BMI 
All of the above investigations are acquired as part of standard clinical care during inpatient stay.  
Information will be collected from follow up investigations when patients return for routine clinic 
appointment. This will include: 
o 6MWD (with BORG) 
o QoL – emphasis 10, CAMPHOR 
o WHO functional class 
o NTproBNP 
Again, the above tests are acquired as part of standard clinical care at routine follow up. 
In addition, we will collect further readings of NRD in these patients when they attend for their 
standard follow up appointment. For the majority of patients, this will be after 3-4 months. For a 
subset of patients with chronic thromboembolic pulmonary hypertension, this may be up to one 

NRD in PH. Protocol v4. 19th January 2019  
 
4 
 
year after initial readings because these patients may be suitable for surgical intervention, which is 
not done locally and usually takes place 6-12 months after diagnosis at SPVU.  
As such, we intend that a patient will take part in the study for 52 weeks maximum, with most 
patients taking part for 16 weeks, and the study will not require them to have any additional 
attendances at hospital outwith their standard hospital admission for diagnosis and clinic follow up.  
SAFETY CONSIDERATIONS 
The tests/interventions performed as part of the study are in addition to the tests the patients will 
receive as part of standard care are: 
- 
NRD measurement via parasternal EMG recordings 
Parasternal EMG is a non-invasive test that is well tolerated and does not cause any distress. It 
requires around 20 minutes for each patient on each occasion.  
FOLLOW UP 
Patients will be followed up in clinic as part of their standard care. This will continue beyond the 
duration of the study.  
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
Data will be stored on NHS password encrypted computers. They will be analysed using Microsoft 
Excel and SPSS.  
EXPECTED OUTCOMES 
Novel cross-sectional and longitudinal data about neural respiratory drive as assessed by EMG 
measurement in patients being investigated for pulmonary hypertension.  
Changes in NRD in patients following intervention (medicine and/or surgery). 
DURATION OF PROJECT 
The study is proposed to last for 24 months.  
Recruitment – 120 patients with baseline measurements with longitudinal follow up proposed on 60 
patients, taking into account patients who may not be followed up following diagnosis and patients 
who may be lost to follow up.  
POWER AND STATISTICAL ANALYSIS 
There is limited data of EMG measurements in patients with pulmonary hypertension previously. 
Using results from a similar patient group with chronic obstructive pulmonary disease (4), change in 
NRD in patients who clinically improved after treatment showed a reduction in EMG measurements 
of 4%. The baseline measurement in the patient group was 20.3% (EMG of tidal breathing as a 
percentage of maximum effort) with a standard deviation of 9.9. Taking these figures into account 
with a power of 80% and confidence level of 0.05 would give a sample size of 49.  

NRD in PH. Protocol v4. 19th January 2019  
 
5 
 
 
 
 
REFERENCES 
1. Reilly CC, et al. Neural respiratory drive, pulmonary mechanics and breathlessness in 
patients with cystic fibrosis. Thorax 2011; 66: 240–246 
2. Reilly CC, et al. Measurement of parasternal intercostal electromyogram during an infective 
exacerbation in patients with cystic fibrosis. European Respiratory Journal 2012 40: 977-981  
3. Jolley CJ,  Luo YM,  Steier J, et al. Neural respiratory drive and breathlessness in COPD. Eur 
Respir J 2015;45: 355–364 
4. Murphy PB, Kumar A, Reilly C, et al Neural respiratory drive as a physiological biomarker to 
monitor change during acute exacerbations of COPD Thorax 2011;66:602-608. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRD in PH. Protocol v4. 19th January 2019  
 
6 
 
 
 
 
NRD FLOWCHART 
 
 
 
Admission for diagnostic 
investigations for pulmonary 
hypertension 
NRD measured at bedside 
using parasternal EMG –     
20 minutes 
Diagnosis made at MDT and 
decision made about further 
management  
Patients commenced on 
medical therapy for 
pulmonary hypertension 
Patients discharged from 
service or do not have 
pulmonary hypertension 
Patients accepted for 
surgery for Group 4 PH at 
Papworth Hospital 
Follow up measurement of 
NRD at outpatient clinic -       
3 months 
Follow up measurement of 
NRD after surgery -            
6-12 months