Ongoing Projects in Clinical Physiology

New techniques for ventilatory support

A number of studies have been conducted comparing fully controlled mechanical ventilation (MV) and spontaneous breathing combined with a basic mechanical support (APRV or BIPAP). A consistent finding has been that spontaneous breaths improve lung aeration and function by recruiting lung tissue and increasing respiratory compliance and gas exchange compared to mechanical ventilation. The advantages and even superiority of spontaneous breathing are important findings that guide in the development of improved ventilatory techniques. It has focused our interest in another Swedish invention, neurally adjusted ventilatory assist, NAVA. This technique is based on the recording of the diaphragm EMG to guide the ventilator in tailoring the breath according to the demand by the patient (i.e. the respiratory centre of the brain).

Ventilator-induced lung injury

When using conventional mechanical ventilation an optimal ventilator setting is critical, an issue that has been intensely discussed during the last 10 or 15 years. A desire is to provide “protective ventilation”. However, it still remains to define what “protective” really is. Our own studies have focused on the application of suitable positive end expiratory pressure, PEEP. Low PEEP will allow collapse of lung tissue, and more importantly, cyclic recruitment and collapse of airways and alveoli. Studies how to find optimum PEEP levels have been performed. They have also stimulated us to do studies using PET and inflammatory markers together with CT to detect onset of inflammatory responses to ventilatory support and relate inflammation to morphological changes as assessed by CT.

Asthma disease phenotyping and natural history of asthma disease

An asthma cohort of 411 subjects (schoolchildren and young adults) was formed between 2010 and 2012 within the frame of a VINNOVA-funded for research on Minimally Invasive Diagnostics in Allergies and hypersensitivities (MIDAS). Information on respiratory symptoms, disease control, measurements of exhaled nitric oxide (NO), nasal NO, exhaled carbon monoxide, lung function and methacholine reactivity were done along with sampling of blood for measurements of inflammation and allergic sensitization markers. The overall aim was to map asthma disease with emphasis on inflammation and allergic sensitisation pattern as a basis for future therapeutic interventions. A total of six PhD students are working with results from the MIDAS study and five manuscripts have been published on the material and several are being prepared. A follow-up of the MIDAS study has been performed during 2013-2015 and we are currently analysing natural history of the disease, with focus on stability of different asthma phenotypes as well as the predictive value of some of the baseline characteristics for disease deterioration.

We are also involved in analysis of the Swedish Global Asthma and Allergy Excellence Network (GA2LEN) - study where we have analysed determinants of exhaled nitric oxide in patients with asthma along extensive mapping of different inflammatory markers in the blood (eosinophil activation markers along with other type 2 inflammation markers). Finally, we are investigating the value of combining markers of inflammation in the airways (exhaled nitric oxide) with markers of eosinophil inflammation in the blood (blood eosinophils or serum eosinophil cationic protein) in MIDAS, GA2LEN and National Health, Nutritrion and Examination Survey (NHANES). We could report that simultaneously elevated levels of both this type of markers relate to disease exacerbation and poor control.

Importance of lung function characterization and lung function monitoring in COPD – a series of prospective studies

Spirometry is used to define COPD and has been used to grade severity of COPD. However it becomes more recognized that FEV1 is not an optimal correlate of the exercise capacity and has limited value even in disease prognosis. In a prospective study, we have investigated the value of a complete lung function characterization (including DLCO measurements and lung volumes) for prognosing exercise capacity decline. The main finding was that DLCO was the only predictor of a decline in exercise capacity over a 5-year period. COPD exacerbations have big socio-economic impact and therefore it is important to understand its predictors in order to prevent exacerbations. We assess the value of extensive lung function characterization (including DLCO, gas washout, exhaled NO and forced oscillation technique measurements) along with exercise ability, inflammation markers for predicting exacerbations in COPD patients in an ongoing, multicentre study – Tools for Identifying Exacerbations (TIE) study. We have included approximately 500 patients during 2014-2015 that will be followed-up with yearly clinical visits for two ears. Five PhD students are involved at the present moment in the TIE-study. In an EU-funded project, Clinical tRials for elderly patients with MultiplE Disease (CHROMED), we are investigating the value of telemonitoring lung function by forced oscillation technique in elderly subjects with COPD and comorbidities. Data from the CHROMED project are analysed at the present moment.

Evaluation of forced oscillation technique to investigate lung function

Forced oscillation technique (FOT) and impulse oscillometry (IOS) are two lung function methods that can be performed in all subjects as they require only tidal breathing and therefore can be used in small children and elderly persons that are not able to participate in conventional lung function tests. We are investigating the value of this method to be used as screening method for obstructive airway disease in patients referred for lung function testing. Furthermore in the follow-up of our asthma cohort of children and young adults with asthma, MIDAS, we are investigating the value of FOT to detect early changes in lung function and the value of FOT measurements in relation to disease control and airways inflammation.

Within the frame of the Swedish CArdioPulmonary bioImage Study (SCAPIS) we have included the measurements of lung function by IOS in order to investigate the value of lung function changes identifyied by IOS in relation to current symptoms, atheriosclerosis and future morbidity.

These methods are also included in the follow-up of patients with cystic fibrosis and esophagus atresia in order to early identify obstruction of peripheral airways and to predict which patients are at higher risk of developing disease worsening or respiratory symptoms, respectively.

Evaluation of new information in cardiac imaging

Comparison of echocardiographic measurements with pressure from the right ventricle and systolic pulmonary pressure and correlation of these findings with actual pressure measurements from right heart catheterization (RHC). The possibility for right ventricular pressure estimation in the absence of tricuspid regurgitation (TR) was of particular interest. This was evaluated by measuring acceleration time (AT) from the forward flow in the pulmonary valve. In addition correlation of estimated pressure from the right atrium (RA) by echocardiography and catheterization was evaluated. Last, calculations of pulmonary resistance (PVR) with a previously suggested formula was compared to PVR from catheterization in a group with high incidence of pulmonary hypertension and an alternative way of presenting echocardiographic PVR was evaluated. Patients with cardiac amyloidosis were evaluated using echocardiography, ECG and right heart catheterization to find out a echocardiographic pattern in these patients. Patients with asymptomatic severe aortic stenosis and preserved ejection fraction were evaluated according to European guidelines to determine the impact of new combinations of echocardiographic variables.

Studies of patients with aortic or mitral regurgitation (LV-regurge) has been started and will go on for the next years. The studies involve a lot of different investigation techniques such as PET, MR, echocardiography and cardio-pulmonary exercise test. These methods will be used for early identification of changes that can lead to severe heart failure.

As an evaluation of 3-dimential echocardiographic imaging, studies have been done to find out if 3-Dimensional echocardiographic area strain is diagnostically superior to longitudinal and circumferential.

The following main projects were pursued in Cardiac Imaging during 2015:

  • A Hjärtlungfonden-funded study of left ventricular function in asymptomatic severe chronic degenerative mitral regurgitation. This study includes echocardiography including stress echo, VO2 uptake by cardiopulmonary exercise test, magnetic resonance, and positron emission tomography, apart from biomarkers. This study is done together with radiology and the PET center.
  • An assessment of test-retest reliability of echocardiographic speckle-tracking strain measurements of the left ventricle in patients with a wide range of ejection fractions. The aim is to assess diagnostic reliability of these parameters when separately acquired by different operators.
  • Echocardiographic  assessment of patients with biopsy-proven cardiac amyloidosis, in parallel with evaluation of new positron emission tomography markers of amyloidosis (together with the PET center). This includes an industry-sponsored study.
  • A retrospective study of the past experience at Akademiska with heart valve replacememt for carcinoid disease. These patients typically have right-sided valvular heart disease, necessitating tricuspid and/or pulmonary valve replacement. We are analyzing survival curves and durability of prosthetic valves in this scenario.
  • An industry-sponsored, echocardiographic substudy of left ventricular function in the evaluation of new antidiabetic drugs (FIDELIO/FIGARO).
  • A study of the value of pulmonary acceleration time as an echocardiographic parameter to assess pulmonary pressures if tricuspid regurgitant velocity cannot be measured. Echocardiography is compared to direct (right-heart catheterization) pressure measurements.
  • A study of longitudinal strain in moderate or severe aortic stenosis, in particular “paradoxic” low-flow, low-gradient aortic stenosis with preserved ejection fraction.