Increased Dead Space Ventilation Mediates Reduced Exercise Capacity in Systolic Heart Failure.

RATIONALE: Patients with chronic heart failure have limited exercise capacity, which cannot be completely explained by markers of cardiac dysfunction. Reduced pulmonary diffusing capacity at rest and excessively high ventilation during exercise are common in heart failure. We hypothesized that the reduced pulmonary diffusing capacity in patients with heart failure would predict greater dead space ventilation during exercise and that this would lead to impairment in exercise capacity. OBJECTIVES: To determine the relationship between pulmonary diffusing capacity at rest and dead space ventilation during exercise, and to examine the influence of dead space ventilation on exercise in heart failure. METHODS: We analyzed detailed cardiac and pulmonary data at rest and during maximal incremental cardiopulmonary exercise testing from 87 consecutive heart transplant assessment patients and 18 healthy control subjects. Dead space ventilation was calculated using the Bohr equation. MEASUREMENTS AND MAIN RESULTS: Pulmonary diffusing capacity at rest was a significant predictor of dead space ventilation at maximal exercise (r = -0.524, P < 0.001) in heart failure but not in control subjects. Dead space at maximal exercise also correlated inversely with peak oxygen consumption (r = -0.598, P < 0.001), peak oxygen consumption per kilogram (r = -0.474, P < 0.001), and 6-minute-walk distance (r = -0.317, P = 0.021) in the heart failure group but not in control subjects. CONCLUSIONS: Low resting pulmonary diffusing capacity in heart failure is indicative of high dead space ventilation during exercise, leading to excessive and inefficient ventilation. These findings would support the concept of pulmonary vasculopathy leading to altered ventilation perfusion matching (increased dead space) and resultant dyspnea, independent of markers of cardiac function.

Control theory prediction of resolved Cheyne-Stokes respiration in heart failure.

Cheyne-Stokes respiration (CSR) foretells deleterious outcomes in patients with heart failure. Currently, the size of therapeutic intervention is not guided by the patient's underlying pathophysiology. In theory, the intervention needed to resolve CSR, as a control system instability (loop gain >1), can be predicted knowing the baseline loop gain and how much it falls with therapy.In 12 patients with heart failure, we administered an inspiratory carbon dioxide fraction of 1-3% during CSR (n=95 interventions) as a means to reduce loop gain. We estimated the loop gain on therapy (LGtherapy), using the baseline loop gain (using hyperpnoea length/cycle length) and its expected reduction (18% per 1% inspired carbon dioxide), and tested the specific hypothesis that LGtherapy predicts CSR persistence (LGtherapy >1) versus resolution (LGtherapy <1).As predicted, when LGtherapy >1.0, CSR continued during therapy in 23 out of 25 (92%) trials. A borderline loop gain zone (0.8

Positive expiratory pressure via mask does not improve ventilation inhomogeneity more than huffing and coughing in individuals with stable chronic obstructive pulmonary disease and chronic sputum expectoration.

BACKGROUND: Positive expiratory pressure (PEP) has been used to promote airway clearance in individuals with chronic obstructive pulmonary disease (COPD) for many years; however, its mechanism of action and benefits are unclear. Previous authors have suggested that PEP improves collateral ventilation via changes in lung volumes. OBJECTIVES: It was the aim of this study to determine whether PEP improves ventilation inhomogeneity more than controlled huffing and coughing in individuals with stable COPD. METHODS: Twelve participants with COPD (mean forced expiratory volume in 1 s 45% predicted) and chronic sputum expectoration performed PEP therapy (10-20 cm H2O) or controlled huffing and coughing in random order on alternate study days with a 48-hour washout. Measures of acinar and conductive airway ventilation (S(acin), S(cond)), lung volumes, spirometry and sputum wet weight were recorded before, immediately after and 90 min following treatment. Ease of expectoration [visual analogue scale (VAS)] and oxyhaemoglobin saturation were assessed immediately following treatment. RESULTS: There were no significant differences between the effect of either test condition at any time point for any test parameter. Mean Sacin immediately following PEP and control conditions was 0.465 and 0.438 litre(-1), respectively (p = 0.45 for comparison between conditions) and mean S(cond) was 0.042 and 0.039 litre(-1) (p = 0.55). PEP therapy did not significantly enhance total mean sputum expectoration compared to controlled huffing and coughing (7.06 vs. 6.15 g; p = 0.51) and did not improve ease of expectoration (VAS PEP 4.8 cm vs. control 4.1 cm; p = 0.53). CONCLUSION: Any therapeutic benefits of PEP in individuals with COPD and chronic sputum expectoration are unlikely to be mediated by improvements in ventilation or lung volumes.

Continuous measurement of multiple inert and respiratory gas exchange in an anaesthetic breathing system by continuous indirect calorimetry.

A method was tested which permits continuous monitoring from a breathing system of the rate of uptake of multiple gas species, such as occurs in patients during inhalational anaesthesia. The method is an indirect calorimetry technique which uses fresh gas rotameters for control, regulation and measurement of the gas flows into the system, with continuous sampling of mixed exhaust gas, and frequent automated recalibration to maintain accuracy. Its accuracy was tested in 16 patients undergoing pre-cardiopulmonary bypass coronary artery surgery, breathing mixtures of oxygen/air and sevoflurane with/without nitrous oxide, by comparison with the reverse Fick method. Overall mean bias [95% confidence interval (CI)] of rate of uptake was 17.9 [7.3 to 28.5] ml min(-1) for oxygen, 0.04 [-0.42 to 0.50] ml min(-1) for sevoflurane, 10.9 [-16.1 to 37.8] for CO(2), and 8.8 [-14.8 to 32.4] ml min(-1) for nitrous oxide where present. The method proved to be accurate and precise, and allows continuous monitoring of exchange of multiple gases using standard gas analysis devices.

Measurement of anesthetics in blood using a conventional infrared clinical gas analyzer.

BACKGROUND: Measurement of the partial pressure of volatile anesthetics in blood is usually done using a "headspace equilibration" method with gas chromatography. However, it is not often performed in clinical studies because of the technical, equipment, and logistic requirements. To improve the accessibility of this measurement, we tested the use of a common infrared clinical gas analyzer, the Datex-Ohmeda Capnomac, for this purpose. METHODS: After characterization of the linearity of the device in measuring the volatile anesthetic concentration in the presence of nitrous oxide, carbon dioxide, and water vapor, blood was tonometered with known concentrations of sevoflurane (actual value between 0.5% and 5.0%) in oxygen and oxygen/nitrous oxide mixtures, as well as mixtures of isoflurane and desflurane in oxygen. RESULTS: Mean bias (standard deviation) overall for sevoflurane in oxygen relative to the tonometered reference partial pressure was -4.5 (4.8%) of the actual concentration. This was not altered significantly by measurement in 40% oxygen/60% nitrous oxide. For isoflurane and desflurane it was -3.9 (3.3%) and -4.6 (3.8%), respectively, of the actual concentration. CONCLUSIONS: The accuracy and precision of measurement of volatile anesthetic gas partial pressures in blood by a double headspace equilibration technique, using a clinical infrared gas analyzer, were comparable to that achieved by previous studies using gas chromatography.

Continuous indirect calorimetry--a laboratory simulation of a new method for non-invasive metabolic monitoring of patients under anaesthesia or in critical care.

A method was tested which permits continuous real time monitoring of O(2) uptake in patients attached to a breathing system. The method is an indirect calorimetry technique which uses fresh gas rotameters for control, regulation and measurement of the gas flows into the system, with continuous sampling of mixed exhaust gas. Testing of this approach was conducted using a lung gas exchange simulator, in order to determine its accuracy and precision under controlled conditions, when compared to a range of simulated O(2) uptake values. The overall mean bias (standard error) was -1.3 mL min(-1) (0.3) and the standard deviation was 6.5. The performance of the method was found to be consistent across a wide range of fresh gas flow rates and O(2) concentrations from 30 to 80%. The method warrants in vivo testing under clinical conditions.

Maximal exercise does not increase ventilation heterogeneity in healthy trained adults.

The effect of exercise on ventilation heterogeneity has not been investigated. We hypothesized that a maximal exercise bout would increase ventilation heterogeneity. We also hypothesized that increased ventilation heterogeneity would be associated with exercise-induced arterial hypoxemia (EIAH). Healthy trained adult males were prospectively assessed for ventilation heterogeneity using lung clearance index (LCI), Scond, and Sacinat baseline, postexercise and at recovery, using the multiple breath nitrogen washout technique. The maximal exercise bout consisted of a maximal, incremental cardiopulmonary exercise test at 25 watt increments. Eighteen subjects were recruited with mean ± SDage of 35 ± 9 years. There were no significant changes inLCI, Scond, or Sacinfollowing exercise or at recovery. While there was an overall reduction in SpO2with exercise (99.3 ± 1 to 93.7 ± 3%,P < 0.0001), the reduction in SpO2was not associated with changes inLCI, Scondor Sacin Ventilation heterogeneity is not increased following a maximal exercise bout in healthy trained adults. Furthermore,EIAHis not associated with changes in ventilation heterogeneity in healthy trained adults.

Physiologically precise simulation of multiple lung gas exchange during anaesthesia by simultaneous gas infusion and extraction.

UNLABELLED: A lung gas exchange simulator was tested which produces simultaneous uptake and/or elimination of multiple gases by an artificial test lung with physiologically realistic gas expired and exhaust gas flows, using a combination of infusion of diluting/enriching gases into the lung with lung gas extraction. A deterministic algorithm is incorporated which calculates required gas infusion and extraction flow rates for any set of possible target gas exchange values with any given set of fresh gas flows and concentrations. Six different scenarios were simulated, comprising a range of gas exchange values for each gas species which lie within a physiologically realistic range for anaesthetized patients. For each of these experiments the system was tested for 15 consecutive measurements over 25 min by measurement of gas exchange in the system using the Haldane transformation. RESULTS: the mean bias and standard error of the mean bias (SE, in parentheses) relative to the target value was: +0.001 (0.002) l min(-1) for O(2) uptake, -0.002 (0.005) l min(-1) for CO(2) production, -0.001 (0.002) l min(-1) for uptake of nitrous oxide and +0.3 (0.1) ml min(-1) for uptake of a volatile anaesthetic agent (isoflurane). The confidence limits of the mean bias were within 5% of the target value for all gases and scenarios with the exception of those where a low uptake of anaesthetic gas was specified. The confidence limits of the mean bias for the lower uptakes of isoflurane were within 10% of the target value for these scenarios and within 15% for the low uptake of N(2)O. Good accuracy and precision of this approach to lung gas exchange simulation were demonstrated, resulting in a versatile simulator.

Ventilation heterogeneity is increased in patients with chronic heart failure.

In the healthy lung, ventilation is distributed heterogeneously due to factors such as anatomical asymmetry and gravity. This ventilation heterogeneity increases pathologically in conditions such as asthma, chronic obstructive lung disease, and cystic fibrosis. In chronic heart failure, lung biopsy demonstrates evidence of peripheral lung fibrosis and small airways narrowing and distortion. We hypothesized that this would lead to increased ventilation heterogeneity. Furthermore, we proposed that rostral fluid shifts when seated patients lie supine would further increase ventilation heterogeneity. We recruited 30 ambulatory chronic heart failure patients (57 ± 10 years, 83% male, left ventricular ejection fraction 31 ± 12%) as well as 10 healthy controls (51 ± 13 years, 90% male). Heart failure patients were clinically euvolemic. Subjects underwent measurement of ventilation heterogeneity using the multiple-breath nitrogen washout technique in the seated position, followed by repeat measurements after 5 and 45 min in the supine position. Ventilation heterogeneity was calculated using the lung clearance index (LCI), Sacin and Scond which represent overall, acinar, and small conducting airway function, respectively. Lung clearance index (9.6 ± 1.2 vs. 8.6 ± 1.4 lung turnovers, P = 0.034) and Scond (0.029 ± 0.014 vs. 0.006 ± 0.016/L, P = 0.007) were higher in the heart failure patients. There was no difference in Sacin (0.197 ± 0.171 vs. 0.125 ± 0.081/L, P = 0.214). Measures of ventilation heterogeneity did not change in the supine position. This study confirms the presence of peripheral airway pathology in patients with chronic heart failure. This leads to subtle but detectable functional abnormalities which do not change after 45 min in the supine position.

Intermittent positive pressure ventilation increases diastolic pulmonary arterial pressure in advanced COPD.

OBJECTIVES: To measure the impact of intermittent positive pressure ventilation (IPPV) on diastolic pulmonary arterial pressure (dPAP) and pulmonary pulse pressure in patients with advanced COPD. BACKGROUND: The physiological effects of raised intrathoracic pressures upon the pulmonary circulation have not been fully established. METHODS: 22 subjects with severe COPD receiving IPPV were prospectively assessed with pulmonary and radial arterial catheterization. Changes in dPAP were assessed from end-expiration to early inspiration during low and high tidal volume ventilation. RESULTS: Inspiration during low tidal volume IPPV increased the median [IQR] dPAP by 3.9 [2.5-4.8] mm Hg (P < 0.001). During high tidal volume, similar changes were observed. The IPPV-associated change in dPAP was correlated with baseline measures of PaO2 (rho = 0.65, P = 0.005), pH (rho = 0.64, P = 0.006) and right atrial pressure (rho = -0.53, P = 0.011). CONCLUSIONS: In severe COPD, IPPV increases dPAP and reduces pulmonary pulse pressure during inspiration.

Early bronchiolitis obliterans syndrome shows an abnormality of perfusion not ventilation in lung transplant recipients.

Long-term survival of lung transplant patients is limited, principally because of Bronchiolitis Obliterans Syndrome (BOS). BOS is primarily classified based on airflow obstruction however there is recent data to suggest that the rejection process can lead to a restrictive ventilatory defect with involvement of the pulmonary vasculature. This study evaluates perfusion heterogeneity in different BOS stages by measuring the relative dispersion (RD) of an arterial spin labelling MRI blood flow image. Acinar ventilation heterogeneity (Sacin) was determined using the Multiple Breath Nitrogen Washout technique. In 24 post transplant patients with a range of severity in BOS status, Sacin increased as BOS level rose from stage 0 to stage 3. In contrast, RD-perfusion was not elevated at BOS 1 and 2 combined compared to BOS 0 and becoming elevated only at BOS-3. However, RD-perfusion in BOS-0p was elevated compared to BOS-0, without an increase in Sacin. These results suggest that BOS-0p is different in nature from other BOS stages.

Pulmonary arterial remodeling in chronic obstructive pulmonary disease is lobe dependent.

Abstract Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10-0.25 mm in diameter was assessed in COPD-explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed-effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography-based pulmonary arterial pressure (no PH, mild PH, and moderate-to-severe PH). Lobar perfusion and emphysema indices were determined from ventilation-perfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects ([Formula: see text]). Within the COPD group, %WT was greater in the upper lobes ([Formula: see text]) and in the small muscular pulmonary arteries ([Formula: see text]). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling ([Formula: see text]). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD.

Respiratory system reactance is an independent determinant of asthma control.

The mechanisms underlying not well-controlled (NWC) asthma remain poorly understood, but accumulating evidence points to peripheral airway dysfunction as a key contributor. The present study tests whether our recently described respiratory system reactance (Xrs) assessment of peripheral airway dysfunction reveals insight into poor asthma control. The aim of this study was to investigate the contribution of Xrs to asthma control. In 22 subjects with asthma, we measured Xrs (forced oscillation technique), spirometry, lung volumes, and ventilation heterogeneity (inert-gas washout), before and after bronchodilator administration. The relationship between Xrs and lung volume during a deflation maneuver yielded two parameters: the volume at which Xrs abruptly decreased (closing volume) and Xrs at this volume (Xrscrit). Lowered (more negative) Xrscrit reflects reduced apparent lung compliance at high lung volumes due, for example, to heterogeneous airway narrowing and unresolved airway closure or near closure above the critical lung volume. Asthma control was assessed via the 6-point Asthma Control Questionnaire (ACQ6). NWC asthma was defined as ACQ6 > 1.0. In 10 NWC and 12 well-controlled subjects, ACQ6 was strongly associated with postbronchodilator (post-BD) Xrscrit (R(2) = 0.43, P < 0.001), independent of all measured variables, and was a strong predictor of NWC asthma (receiver operator characteristic area = 0.94, P < 0.001). By contrast, Xrs measures at lower lung volumes were not associated with ACQ6. Xrscrit itself was significantly associated with measures of gas trapping and ventilation heterogeneity, thus confirming the link between Xrs and airway closure and heterogeneity. Residual airway dysfunction at high lung volumes assessed via Xrscrit is an independent contributor to asthma control.

Automated detection of the phase III slope during inert gas washout testing.

We describe a method to determine the phase III slope for the purpose of calculating indexes of ventilation heterogeneity, S(acin) and S(cond), from the multiple breath nitrogen washout test (MBNW). Our automated method applies a recursive, segmented linear regression technique to each breath of the MBNW test and determines the best point of transition, or breakpoint, between each phase of the washout. A sample set of 50 MBNW tests (controls, asthma, and COPD) was used to establish the conditions in which the phase III slope obtained from the automated technique best matched that obtained by two manual interpreters. We then applied our technique to a test set of 30 subjects (with an even number of subjects in each of the above groups) and compared these results against the manual analysis of a third independent manual interpreter. Indexes of ventilation heterogeneity were determined using both methods and compared. The phase III slopes determined by the automatic technique best matched the manual interpreter when the phase III slope was calculated from the phase II-III transition point plus the addition of 50% of the phase II volume to the end of the expiration. Calculation of the indexes S(acin) and S(cond) showed no overall difference between analysis methods in either S(acin) (P = 0.14) or S(cond) (P = 0.59) when the set threshold was applied to our automated analysis. Our analysis method provides an alternate means for rapid quantification of the MBNW test, removing operator dependence without alteration in either S(acin) or S(cond).