Robin D. Stevenson

Measurement of physiological recovery from exacerbation of chronic obstructive pulmonary disease using within-breath forced oscillometry

Background: Within-breath reactance from forced oscillometry estimates resistance via its inspiratory component (Xrs,insp) and flow limitation via its expiratory component (Xrs,exp). Aim: To assess whether reactance can detect recovery from an exacerbation of chronic obstructive pulmonary disease (COPD). Method: 39 subjects with a COPD exacerbation were assessed on three occasions over 6 weeks using post-bronchodilator forced oscillometry, arterial blood gases, spirometry including inspiratory capacity, symptoms and health-related quality of life (HRQOL). Results: Significant improvements were seen in all spirometric variables except the ratio of forced expiratory volume in 1 s (FEV1) to vital capacity, ranging in mean (SEM) size from 11.0 (2.2)% predicted for peak expiratory flow to 12.1 (2.3)% predicted for vital capacity at 6 weeks. There was an associated increase in arterial partial pressure of oxygen (PaO2). There were significant mean (SEM) increases in both Xrs,insp and Xrs,exp (27.4 (6.7)% and 37.1 (10.0)%, respectively) but no change in oscillometry resistance (Rrs) values. Symptom scales and HRQOL scores improved. For most variables, the largest improvement occurred within the first week with spirometry having the best signal-to-noise ratio. Changes in symptoms and HRQOL correlated best with changes in FEV1, PaO2 and Xrs,insp. Conclusions: The physiological changes seen following an exacerbation of COPD comprised both an improvement in operating lung volumes and a reduction in airway resistance. Given the ease with which forced oscillometry can be performed in these subjects, measurements of Xrs,insp and Xrs,exp could be useful for tracking recovery.

Exercise intolerance following heart transplantation: The role of pulmonary diffusing capacity impairment

STUDY OBJECTIVES Although impairment of the diffusing capacity of the lung for carbon monoxide (DLCO) in heart transplant recipients is well-documented, there are limited data on its impact on exercise capacity in these patients. The aim of this study was to determine the effect of DLCO reduction on exercise capacity in heart transplant recipients. DESIGN Descriptive cohort study. SETTING A regional cardiopulmonary transplant center. PARTICIPANTS Twenty-six heart transplant recipients who were studied before and after transplantation compared with 26 healthy volunteers. MEASUREMENTS Spirometry and static lung volumes were measured using body plethysmography, DLCO was measured using the single-breath technique, and progressive cardiopulmonary exercise was performed using a bicycle ergometer, continuous transcutaneous blood gas monitoring, and on-line analysis of minute ventilation, oxygen uptake (VO(2)), and carbon dioxide production. RESULTS Before transplantation, the mean percent predicted for hemoglobin-corrected DLCO was reduced in patients (73.2%) compared to healthy control subjects (98.8%; p < 0.001) and declined significantly after transplantation (60.1%; p < 0.05). Although the mean maximal symptom-limited VO(2) (VO(2)max) increased after transplantation (increase, 41.3 to 48.6% of predicted; p < 0.05), it remained substantially lower than normal (92.9%; p < 0.001). There was a significant correlation between DLCO and VO(2)max after transplantation (r = 0.61; p = 0.001), but not before transplantation (r = 0.09; p = 0.66). DLCO was also inversely correlated with other respiratory responses to exercise, including the following: the ventilatory response to exercise (r = -0.44; p < 0.05); dead space to tidal volume ratio (r = -43; p < 0.05); and the alveolar-arterial oxygen gradient (r = -0. 45; p < 0.05), but there was no correlation between any of these variables and DLCO before transplantation. CONCLUSION DLCO reduction after heart transplantation appears to represent persistent gas exchange impairment and contributes to exercise limitation in heart transplant recipients.

Use of reactance to estimate transpulmonary resistance

This study examines the relationship of respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillometry with transpulmonary resistance (RL) measured by oesophageal manometry. Simultaneous forced oscillometry using a single frequency of 5 Hz and oesophageal manometry were performed on five asthmatics during bronchoprovocation. The data obtained were used to derive prediction equations for RL from oscillometric parameters, which were tested on a further six asthmatics and 35 nonasthmatic subjects. In the first five asthmatic subjects, RL correlated more strongly with Xrs than with Rrs. In the second set of asthmatics, RL ranged 0.0005–4.57 kPa·s·L−1, with a median of 0.21 kPa·s·L−1. The RL values predicted from Xrs showed a mean±sd difference of −0.067±0.25 kPa·s·L−1 compared with the values measured in this set of patients. Xrs in subjects with other respiratory conditions appeared to follow the same relationship with RL as in asthmatics. Lumped element modelling suggested that the linear relationship between Xrs and RL was a consequence of the increasing contribution of central and upper airway wall shunts as peripheral airway resistance rose, and that this effect was much larger than that due to changes in static elastance. In conclusion, the reactance of the respiratory system can predict transpulmonary resistance more accurately than can the resistance of the respiratory system.

Clinical InvestigationsTRANSPLANTATIONExercise Intolerance Following Heart Transplantation: The Role of Pulmonary Diffusing Capacity Impairment

STUDY OBJECTIVES Although impairment of the diffusing capacity of the lung for carbon monoxide (DLCO) in heart transplant recipients is well-documented, there are limited data on its impact on exercise capacity in these patients. The aim of this study was to determine the effect of DLCO reduction on exercise capacity in heart transplant recipients. DESIGN Descriptive cohort study. SETTING A regional cardiopulmonary transplant center. PARTICIPANTS Twenty-six heart transplant recipients who were studied before and after transplantation compared with 26 healthy volunteers. MEASUREMENTS Spirometry and static lung volumes were measured using body plethysmography, DLCO was measured using the single-breath technique, and progressive cardiopulmonary exercise was performed using a bicycle ergometer, continuous transcutaneous blood gas monitoring, and on-line analysis of minute ventilation, oxygen uptake (VO(2)), and carbon dioxide production. RESULTS Before transplantation, the mean percent predicted for hemoglobin-corrected DLCO was reduced in patients (73.2%) compared to healthy control subjects (98.8%; p < 0.001) and declined significantly after transplantation (60.1%; p < 0.05). Although the mean maximal symptom-limited VO(2) (VO(2)max) increased after transplantation (increase, 41.3 to 48.6% of predicted; p < 0.05), it remained substantially lower than normal (92.9%; p < 0.001). There was a significant correlation between DLCO and VO(2)max after transplantation (r = 0.61; p = 0.001), but not before transplantation (r = 0.09; p = 0.66). DLCO was also inversely correlated with other respiratory responses to exercise, including the following: the ventilatory response to exercise (r = -0.44; p < 0.05); dead space to tidal volume ratio (r = -43; p < 0.05); and the alveolar-arterial oxygen gradient (r = -0. 45; p < 0.05), but there was no correlation between any of these variables and DLCO before transplantation. CONCLUSION DLCO reduction after heart transplantation appears to represent persistent gas exchange impairment and contributes to exercise limitation in heart transplant recipients.

The European Respiratory Society spirometry tent: a unique form of screening for airway obstruction.

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004–2009. Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used. Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0±18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0–4.1) for the youngest age (≤19 yrs), 1.9 (1.2–3.0) for the oldest age (≥80 yrs), 2.4 (2.0–2.9) for current smokers and 2.8 (2.2–3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.

High-dose cyclophosphamide and VP 16 as late dosage intensification therapy for small cell carcinoma of lung.

SummaryThis study investigated the use of late dose intensification therapy (LDIT) with cyclophosphamide (180 mg/kg) and VP 16 (1 g/m2) plus autologous bone marrow rescue in 22 patients with small cell lung cancer (SCLC). These patients were selected from a group of 95 patients who received three courses of a five-drug induction regimen comprising cyclophosphamide (750–1000 mg/m2), adriamycin (40 mg/m2), VP 16 (100 mg/m2) for 3 days, methotrexate (50 mg/m2) and vincristine (2 mg) (CAVMO). There were 16 patients with limited disease, 8 of whom were in complete remission (CR) and 8 in partial remission (PR) after the induction therapy. The other 6 patients had extensive disease; 3 of these achieved CR and 3 PR after induction therapy. Of the 11 patients in PR, 5 responded to LDIT; 3 had a further PR, and 2 CR. Subsequent to LDIT radiotherapy 4000 cGy was given to the primary site in 10 of the 22 patients. Since the start of the study, 19 of the 22 patients have relapsed and died (median survival 11 months), while 3 remain alive and in remission at 11, 11, and 24 moths. Comparison of the survival of patients receiving LDIT with that of an equivalent group (with respect to staging and response to induction chemotherapy) of patients who received induction chemotherapy alone showed no significant difference. In this study, LDIT following conventional induction therapy in patients with chemosensitive tumours did not improve survival.

Alveolar macrophage chemotaxis in fire victims with smoke inhalation and burns injury.

Abstract. In vitro migration of alveolar macrophages was studied in 24 fire victims and 19 controls; all subjects were cigarette smokers. Unstimulated (p= 0·01) and stimulated migration towards casein‐(P= 0·01) and zymosan‐activated serum (P= 0·002) of macrophages from smoke inhalation patients (SI) (n=19) was increased when compared to control subjects (CS). Migration of alveolar macrophages from patients with burns without smoke inhalation (burns only, BO) was not increased. Patients with smoke inhalation and no burns (smoke only, SO) (n= 9) had increased migration when compared to controls but this was not statistically significant. Patients with smoke inhalation and burns (SB) (n= 10) had increased unstimulated migration (P= 0·01) and increased migration towards casein (P<0·005), ZAS (P<0·002) and F‐met‐leu‐phe (P<0·05) when compared to controls (CS). Lavage fluid from the fire victims displayed chemotactic activity towards normal human neutrophils and its analysis for the components of the complement cascade proved positive (Clq, Clr, Factor B and C33). These data suggest that activation of alveolar macrophages may contribute to the development of pathophysiological changes in patients with smoke inhalation (SI) and particularly those with smoke inhalation and burns (SB).

The time course of pulmonary transfer factor changes following heart transplantation.

OBJECTIVE The pulmonary transfer factor for carbon monoxide (TLCO) has been reported to decline following heart transplantation, but the time course of this decline is not well documented. The aim of this study was to define the longitudinal changes in TLCO after heart transplantation. METHODS Single breath TLCO, lung volumes and expiratory flow rates were prospectively measured in 57 patients (mean age 49 years, range 19-61) before and at least once after heart transplantation. Thirty seven of the 57 patients had four post-transplant assessment which were performed at 6 weeks, 3, 6 and 12 months in 26 patients and at 12, 18, 24 and 36 months in 11 patients. Results were compared with data from 28 normal subjects (mean age 40 years, range 19-61). RESULTS Before transplantation there was a mild impairment of lung volumes and expiratory flow rates. At 6 weeks after transplantation, there was a further reduction in the forced expiratory volume in one second, forced vital capacity, residual volume and total lung capacity, but all of these increased in the subsequent measurements to exceed their pre-transplant values at about 1 year after transplantation. Haemoglobin-corrected TLCO was also reduced before transplantation compared to normal controls (74.3% and 98.6% of predicted respectively, P < 0.001). Although TLCO per unit alveolar volume (KCO) was relatively preserved in heart transplant candidates, it was still significantly lower than that of normal controls (92.6% and 105.3% of predicted respectively, P < 0.05). After transplantation, mean haemoglobin-corrected TLCO and KCO declined by 12% and 20% of predicted respectively) with the majority of patients having reductions greater than 10% of predicted. The decline in TLCO and KCO was evident at 6 weeks after transplantation with no further changes in the subsequent measurements. CONCLUSIONS TLCO is reduced in heart transplant candidates and declines further after heart transplantation despite improvement in lung volumes and airway function. The early and non-progressive nature of TLCO decline suggests an aetiology exerting its effect on TLCO within the first 6 weeks after transplantation.

Mechanisms of pulmonary transfer factor decline following heart transplantation

OBJECTIVE Although the decline in the pulmonary transfer factor (TL(CO)) following heart transplantation is well documented, the causes and mechanisms of this decline remain unknown. The aim of this study was to determine the relative contribution of each of TL(CO) components (the diffusing capacity of the alveolar-capillary membrane (D(M)), the pulmonary capillary blood volume (V(C)) and haemoglobin concentration) to TL(CO) reduction in heart transplant recipients. METHODS TL(CO) and its components were measured in 75 heart transplant recipients (mean age 48 years, range 19-61) between 6 weeks and 36 months after transplantation using the Roughton and Forster method and the single-breath technique. Results were compared with data from 38 heart transplant candidates (mean age 51 years, range 34-61) and 26 normal subjects (mean age 47 years, range 27-62). RESULTS The mean percentage predicted TL(CO) was reduced in recipients compared to candidates (56.9 and 69.9%, respectively, P<0. 001) and both were lower than normal controls (97.7%, P<0.001). The mean percent predicted V(C) was also reduced in recipients compared to candidates (52.8% vs. 80.2 (4.2)%, P<0.001) which was also lower than normal subjects (102%, P<0.001). D(M) was equally reduced in recipients and candidates (77.7 and 81.4%, respectively, P=0.48) compared to normal subjects (100.0%, P<0.001). Correction for haemoglobin concentration increased TL(CO) in recipients to 63.5% (P<0.001), but it remained lower than haemoglobin-corrected TL(CO) in candidates (71.1%, P<0.001). In recipients, the intra-capillary resistance (1/thetaV(C)) formed 60% of the total resistance to CO transfer (1/TL(CO)) compared to 50% in candidates and normal subjects. CONCLUSIONS TL(CO) decline following heart transplantation is due to an increase in the intra-capillary resistance, and this appears to be due to a combination of anaemia and reduced pulmonary capillary blood volume, with the diffusing capacity of the alveolar-capillary membrane remaining unchanged.

The measurement of the single-breath transfer factor for carbon monoxide and its components using the Morgan Transflow system

In contrast to the standard single-breath transfer factor for carbon monoxide (TLCO), there are no specific guidelines or recommendations for the measurement of its components, the pulmonary capillary blood volume (VC) and membrane component (DM), by the Roughton and Forster method. Ten randomly selected heart transplant patients (three life-long non-smokers, seven ex-smokers > 1 yr, age range 24-55 years) were assessed on two occasions using either the standard or high-oxygen mixture as the first inspired gas in random order. Ten normal subjects (all non-smokers, age range 23-54 years) were assessed on two occasions using either a long protocol (30 min waiting time between repeat measurements in an individual set) or a short protocol (5 min waiting time). Two technically acceptable results of TLCO were used to derive a mean value for DM and VC for each set of measurements (Transflow, P. K. Morgan, Kent, U.K.). The different sequences of gas mixtures produced no significant differences between the values obtained in ten heart transplant patients for mean TLCO (mmol min-1 kPa-1) (standard first 5.13 +/- 1.15, high-oxygen first 5.14 +/- 1.12; limits of agreement -0.57 to 0.59 for DM or for VC. The long or short protocol produced no significant differences between the means of TLCO (mmol min-1 kPa-1) (long 8.0 +/- 1.9, short 8.0 +/- 1.9; limits of agreement -0.5 to 0.5), DM or VC. This allows the development of a standard test protocol of short duration (about 40 min) making it practical for clinical use without compromising the precision or reproducibility of the results obtained.