Alan Lunt

Neural respiratory drive in healthy subjects and in COPD

The aim of the present study was to use the diaphragm electromyogram (EMGdi) to compare levels of neural respiratory drive (NRD) in a cohort of healthy subjects and chronic obstructive pulmonary disease (COPD) patients, and to investigate the relationship between NRD and pulmonary function in COPD. EMGdi was recorded at rest and normalised to peak EMGdi recorded during maximum inspiratory manoeuvres (EMGdi % max) in 100 healthy subjects and 30 patients with COPD, using a multipair oesophageal electrode. EMGdi was normalised to the amplitude of the diaphragm compound muscle action potential (CMAPdi,MS) in 64 healthy subjects. The mean±sd EMGdi % max was 9.0±3.4% in healthy subjects and 27.9±9.9% in COPD patients, and correlated with percentage predicted forced expiratory volume in one second, vital capacity and inspiratory capacity in patients. EMGdi % max was higher in healthy subjects aged 51–80 yrs than in those aged 18–50 yrs (11.4±3.4 versus 8.2±2.9%, respectively). Observations in the healthy group were similar when peak EMGdi or CMAPdi,MS were used to normalise EMGdi. Levels of neural respiratory drive were higher in chronic obstructive pulmonary disease patients than healthy subjects, and related to disease severity. Diaphragm compound muscle action potential could be used to normalise diaphragm electromyogram if volitional inspiratory manoeuvres could not be performed, allowing translation of the technique to critically ill and ventilated patients.

Observational study of the effect of obesity on lung volumes

Background Severe obesity causes respiratory morbidity and mortality. The impact of obesity on the mechanics of breathing is not fully understood. Patients and methods We undertook a comprehensive observational study of lung volumes and elasticity in nine obese and nine normal weight subjects, seated and supine, during spontaneous breathing. Seated and supine total lung capacity (TLC) and subdivisions were measured by multibreath helium dilution method. Using balloon catheters, oesophageal (Poes) and gastric (Pgas) pressures were recorded. Transpulmonary pressure (PL) was calculated as mouth pressure (Pmouth)-Poes, and complete expiratory PL volume curves were measured. Results The obese group had a body mass index (BMI) of 46.8 (17.2) kg/m2, and the normal group had a BMI of 23.2 (1.6) kg/m2 (p=0.001). Obese and normals were matched for age (p=0.233), gender (p=0.637) and height (p=0.094). The obese were more restricted than the normals (TLC 88.6 (16.9) vs 104.4 (12.3) %predicted, p=0.033; FEV1/FVC 79.6 (7.3) vs 82.5 (4.2) %, p=0.325), had dramatically reduced expiratory reserve volume (ERV 0.4 (0.4) vs 1.7 (0.6) L, p<0.001) and end-tidal functional residual capacity (FRC) was smaller (37.5 (6.9) vs 46.9 (4.6) %TLC, p=0.004) when seated, but was similar when supine (39.4 (7.7) vs 41.5 (4.3) %TLC, p=0.477). Gastric pressures at FRC were significantly elevated in the obese (seated 19.1 (4.7) vs 12.1 (6.2) cm H2O, p=0.015; supine 14.3 (5.7) vs 7.1 (2.6) cm H2O, p=0.003), as were end-expiratory oesophageal pressures at FRC (seated 5.2 (6.9) vs −2.0 (3.5) cm H2O, p=0.013; supine 14.0 (8.0) vs 5.4 (3.1) cm H2O, p=0.008). BMI correlated with end-expiratory gastric (seated R2=0.43, supine R2=0.66, p<0.01) and oesophageal pressures (seated R2=0.51, supine R2=0.62, p<0.01). Conclusions Obese subjects have markedly increased gastric and oesophageal pressures, both when upright and supine, causing dramatically reduced FRC and ERV, which increases work of breathing.

Neural respiratory drive, pulmonary mechanics and breathlessness in patients with cystic fibrosis

Background Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. Objectives To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness. Methods 15 patients with CF (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded. Results Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p<0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV1) (r=−0.91 and r=−0.82, both p<0.001), hyperinflation (r=0.63 and r=0.56, both p<0.001) and dynamic lung compliance (r=−0.53 and r=−0.59, both p<0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r=0.906, p<0.001) and after (r=0.975, p<0.001) the onset of neuromechanical dissociation. Conclusion sEMGpara%max provides a non-invasive marker of neural drive, which reflects disease severity and exercise-induced breathlessness in CF.

Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness: a systematic review.

Objectives:To critically evaluate and summarize identified evidence for the use of ultrasound to measure peripheral skeletal muscle architecture during critical illness. Data Sources:Seven electronic databases (Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Physiotherapy Evidence Database, Scopus, Excerpta Medica Database, and Web of Science [including Science Citations and Conference Proceedings]) and personal libraries were searched for relevant articles. Cross-referencing further identified references. Study Selection:Quantitative study designs excluding abstracts, published in English, including adult critically ill patients in the ICU, evaluating peripheral skeletal muscle architecture during critical illness with ultrasound were included. Studies using ultrasonographic muscle data as outcome measures in interventional trials were excluded. Data Extraction:Performed by one reviewer using a standardized data extraction form and cross-checked by a second reviewer. Quality appraisal was undertaken by two independent reviewers—studies were classified, graded, and appraised according to standardized algorithms and checklists. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adhered to. Data Synthesis:Seven studies with independent patient cohorts totaling 300 participants were included. One study adopted a case-control design, and the remainder were case series. Ultrasound data demonstrated deficits in a variety of peripheral skeletal muscle architecture variables across a range of muscle groups associated with critical illness. Ultrasound offered more accurate data compared to limb circumference measurement and has excellent reported reliability, but underestimated data acquired via more invasive muscle biopsy. Conclusion:Ultrasound provides clinical utility for assessing the trajectory of change in peripheral skeletal muscle architecture during critical illness, supplementing more detailed characterization, albeit rarely used, from muscle biopsy analysis. Adoption of standardized operating protocols for measurement will facilitate future meta-analysis of data.

Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease

Objectives To test the hypothesis that vascular abnormalities on high-resolution CT (HRCT) would be associated with echocardiographic changes and lung function abnormalities in patients with sickle cell disease (SCD) and the decline in lung function seen in SCD patients. Methods HRCT, echocardiography and lung function assessments were made in 35 adults, 20 of whom had previously been assessed a median of 6.6 years prior to this study. The pulmonary arterial dimensions on HRCT were quantified as the mean segmental pulmonary artery/bronchus (A/B) ratio and the summated cross-sectional area of all pulmonary vessels <5 mm in diameter (cross-sectional area (CSA)<5 mm%). Results The segmental A/B ratio was negatively correlated with FEV1, vital capacity (VC), forced expiratory flow between 25% and 75% of VC (FEF25/75) and arterial oxygen saturation (SpO2) and positively with the residual volume: total lung capacity ratio (RV:TLC) and respiratory system resistance (Rrs). CSA<5 mm% was negatively correlated with FEV1, FEF25/75 and SpO2 and positively with RV, RV:TLC and respiratory system resistance (Rrs). There were significant correlations between cardiac output assessed by echocardiography and the segmental A/B ratio and CSA<5 mm%. Lung function (FEV1 p=0.0004, VC p=0.0347, FEF25/75 p=0.0033) and the segmental A/B ratio (p=0.0347) and CSA<5 mm% (p<0.0001) significantly deteriorated over the follow-up period. Conclusions Abnormalities in pulmonary vascular volumes may explain some of the lung function abnormalities and the decline in lung function seen in adults with SCD.

Longitudinal assessment of lung function in children with sickle cell disease

To prospectively assess longitudinal lung function in children with sickle cell disease (SCD).

Pulmonary Haemodynamics in Sickle Cell Disease Are Driven Predominantly by a High-Output State Rather Than Elevated Pulmonary Vascular Resistance: A Prospective 3-Dimensional Echocardiography/Doppler Study.

Aims Patients with sickle cell disease have significant morbidity and mortality. Pulmonary hypertension is suggested to be an important contributor but its nature and severity in these patients and how best to non-invasively assess it are controversial. We hypothesised that a high-output state rather than primary pulmonary vascular pathology may be the major abnormality in sickle cell disease. This study aimed to evaluate the characteristics and severity of pulmonary hypertension in patients with sickle cell disease using detailed echocardiography. Methods and Results We undertook a prospective study in 122 consecutive stable outpatients with sickle cell disease and 30 age, gender and ethnicity-matched healthy controls. Echocardiographic evaluation included 3D ventricular volumes, sphericity, tissue Doppler, and non-invasive estimation of pulmonary vascular resistance. 36% of patients had a tricuspid regurgitant velocity ≥2.5 m.s-1 but only 2% had elevated pulmonary vascular resistance and the prevalence of right ventricular dysfunction was very low. Patients with raised tricuspid regurgitant velocity had significantly elevated biventricular volumes and globular left ventricular remodelling, related primarily to anaemia. In a subgroup of patients who underwent cardiac catheterization, invasive pulmonary haemodynamics confirmed the echocardiographic findings. Conclusions Elevated cardiac output and left ventricular volume overload secondary to chronic anaemia may be the dominant factor responsible for abnormal cardiopulmonary haemodynamics in patients with sickle cell disease. 3D echocardiography with non-invasive estimation of pulmonary vascular resistance represents a valuable approach for initial evaluation of cardiopulmonary haemodynamics in sickle cell disease.

Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease

Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children.

Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease

Background:Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age-matched controls. Methods:Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls.Results:The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow.Conclusion:Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma.

Airways obstruction and pulmonary capillary blood volume in children with sickle cell disease: Response to Letter

Reply to Letter From: Antonio Marzollo, Raffaella Colombatti, Laura Sainati. We thank Dr. Marzollo and colleagues for their interest in our work. They asked for further analysis regarding the children who had ACS episodes or received hydroxyurea treatment. Seven patients had one or more episodes of ACS, comparison of their results with the rest of the cohort revealed no statistically significant difference, but the small number of children affected by ACS meant that no confident conclusions could be reached. A nonsignificant result was also obtained when we compared the results of children who were (n1⁄4 7) or were not receiving hydroxyurea, again the small numbers mean no confident conclusions could be reached.We are grateful to Dr. Marzollo and colleagues for their appreciation of our work. We are undertaking further research regarding the relationship of pulmonary capillary blood volume and lung function in sickle cell patients and hope to publish this shortly.