A Realistic Validation Study of a New Nitrogen Multiple-Breath Washout System

Background For reliable assessment of ventilation inhomogeneity, multiple-breath washout (MBW) systems should be realistically validated. We describe a new lung model for in vitro validation under physiological conditions and the assessment of a new nitrogen (N2)MBW system. Methods The N2MBW setup indirectly measures the N2 fraction (FN2) from main-stream carbon dioxide (CO2) and side-stream oxygen (O2) signals: FN2 = 1−FO2−FCO2−FArgon. For in vitro N2MBW, a double chamber plastic lung model was filled with water, heated to 37°C, and ventilated at various lung volumes, respiratory rates, and FCO2. In vivo N2MBW was undertaken in triplets on two occasions in 30 healthy adults. Primary N2MBW outcome was functional residual capacity (FRC). We assessed in vitro error (√[difference]2) between measured and model FRC (100–4174 mL), and error between tests of in vivo FRC, lung clearance index (LCI), and normalized phase III slope indices (Sacin and Scond). Results The model generated 145 FRCs under BTPS conditions and various breathing patterns. Mean (SD) error was 2.3 (1.7)%. In 500 to 4174 mL FRCs, 121 (98%) of FRCs were within 5%. In 100 to 400 mL FRCs, the error was better than 7%. In vivo FRC error between tests was 10.1 (8.2)%. LCI was the most reproducible ventilation inhomogeneity index. Conclusion The lung model generates lung volumes under the conditions encountered during clinical MBW testing and enables realistic validation of MBW systems. The new N2MBW system reliably measures lung volumes and delivers reproducible LCI values

Antiarrhythmic and arrhythmic effects of an Ikr-blocking class III agent. A clinical and electrocardiographic study of almokalant

The interest in class III drugs has increased over the last decades as being potent antiarrhythmic agents in their mode of action by prolongation of repolarization and with no effect on conduction. Class I antiarrhythmic agents have proven effective in conversion of atrial fibrillation (AF), but may cause serious proarrhythmia. Older class III drugs, i.e. amiodarone and sotalol, are also afflicted with adverse effects, which limit their use. However, the pure class III antiarrhythmic drugs, potassium channel blockers, may also induce proarrhythmia, i.e. torsades de pointes (TdP).Almokalant is a selective potassium - Ikr- channel blocker. The aims of the present thesis were to assess the antiarrhythmic and proarrhythmic effects of a 6-hour infusion of almokalant when given to 100 patients with chronic AF or flutter (AFL) aiming at conversion to sinus rhythm (SR), and to find predictors of conversion, and development of TdP in case it should occur. On the following day an identical infusion was given for 90 minutes during SR to 61 of the patients.Paper I evaluated the efficacy of almokalant in conversion of AF or AFL to SR. A second aim was to find predictors of conversion to SR. The electrophysiological effects of almokalant were assessed by surface 12-lead electrocardiogram (ECG) and transesophageal atrial electrograms (TAE). Thirty-two patients converted to SR. The ECG changes observed were consistent with a class III effect. The QT, corrected QT, QTtop intervals and QT dispersion increased, the T wave amplitude and atrial rate decreased, with no differences between patients converting to SR and those who did not. A decrease in T wave amplitude early during infusion was a predictor of conversion to SR.Paper II assessed the proarrhythmic effect of almokalant and ECG variables associated with TdP. Six patients developed TdP, five of these after conversion to SR. Patients who developed TdP were characterized by an abnormal ventricular repolarization when exposed to the drug and, soon after the start of infusion, developed a pronounced QT prolongation, a larger QT dispersion, and marked morphological T wave changes. These ECG changes were observed during AF, as well as after conversion to SR, before the proarrhythmic event. Predictors of TdP were at baseline: female gender, PVCs, diuretics and, after 30 minutes of infusion, the development of sequential bilateral bundle branch aberrancy, PVCs in bigeminy, and a biphasic T wave.Paper III assessed QT dispersion, as a measure of the inhomogeneity of ventricular repolarization, during AF and SR in sixty-one patients, who received almokalant infusion on both study days. QT dispersion did not differ during AF and SR at normal ventricular repolarization. At prolonged repolarization, QT dispersion was larger during SR than during AF. QT dispersion was not related to the QT or RR interval or almokalant plasma concentration. Increased QT dispersion may contribute to the increased risk of TdP shortly after conversion to SR.Paper IV evaluated the occurrence of aberrant conduction during AF at rest and during exercise prior to and during almokalant infusion in 92 of the patients. Almokalant caused a marked, and dose-related, increase in the number of patients with intermittent aberration during rest, which was further increased during exercise. Predictors of the development of aberrant conduction on almokalant were decreased left ventricular ejection fraction, female gender, longer arrhythmia duration, while the use of calcium antagonists decreased the risk. Aberration is an expression of the class III effect and seems to be more common in patients with more advanced myocardial diseas

Prediction of BOS by the single-breath nitrogen test in double lung transplant recipients

Abstract Background The present study analyses the ability of the alveolar slope of the single-breath nitrogen washout test (N2-slope) to diagnose and predict the development of the bronchiolitis obliterans syndrome (BOS). Methods We present a retrospective analysis of 61 consecutive bilateral lung or heart-lung transplant recipients who were followed at regular control visits during a three year follow-up. The operating characteristics of the N2-slope to diagnose BOS and potential BOS (BOS 0-p) and to predict BOS were determined based on cut off values of 95% specificity. Results The sensitivity of the N2-slope to identify BOS was 96%, and BOS 0-p 100%. The predictive ability to predict BOS with a N2-slope > 478% of the predicted normal was 56%, and if combined with a coincident FEV1 Conclusions The predictive ability of either the N2-slope or of FEV1 to diagnose BOS is limited but the combination of the two appears useful. Follow-up protocols of bilateral lung and heart-lung transplant recipients should consider including tests sensitive to obstruction of the peripheral airways.</p

<i>In vitro</i> variability of functional residual capacity measurement.

<p><i>Bland Altman</i> plot <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone.0036083-Bland1" target="_blank">[16]</a> of measured functional residual capacity (FRC) minus lung model FRC plotted vs. mean of measured and model FRC. Differences (open circles), and mean difference, and upper and lower limits of agreement (mean difference ±1.96 SD of differences) are given as dashed lines for the small lung model and as solid lines for the large lung model. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone-0036083-g002" target="_blank">Figure 2a</a> gives absolute FRC differences (mL). For the small and large lung model, mean differences are −10.2 mL and 12.5 mL, upper limits of agreement are 9.9 mL and 121.9 mL, and lower limits of agreement are −30.3 mL and −96.8 mL, respectively. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone-0036083-g002" target="_blank">Figure 2b</a> gives relative FRC differences (%). For the small and large lung model, mean differences are −3.8% and 0.4%, upper limits of agreement are 3.6% and 4.7%, and lower limits of agreements are −11.2% and −4.0%, respectively.</p

<i>In vivo</i> variability of functional residual capacity.

<p><i>Bland Altman</i> plot <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone.0036083-Bland1" target="_blank">[16]</a> of functional residual capacity (FRC) measured on two study days within three weeks in 30 healthy adults. Absolute FRC differences (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone-0036083-g004" target="_blank">Figure 4a</a>), relative FRC differences (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036083#pone-0036083-g004" target="_blank">Figure 4b</a>), mean difference and upper and lower limits of agreement (lines) are plotted against mean FRC of both tests. Mean difference is −15.4 mL (−1.1%), upper and lower limits of agreement are 793.3 mL (23.2%) and −824.1 mL (−25.4%).</p

Association of measurement error with lung volume.

<p>Functional residual capacity (FRC) measurement error (%) is plotted against lung model FRC. The error data are displayed as open circles for the small model (100–400 mL FRCs) and closed circles for the large model (500–4200 mL FRCs). The dashed line gives the 5% limit of acceptable measurement error, the dotted lines reflect possible nominal volume bias due to reading parallax error (one mm) in the small and large lung model.</p

Study protocol for the lung model.

<p>Functional residual capacity (FRC), tidal volume (V_T), and respiratory rate (RR) generated in triplets are displayed as ranges. Respective dead space reducers (DSR 1–3) were applied to reduce post-capillary dead space to 1.5 mL, 16 mL, and 26.9 mL, respectively. Mean (range) intra-test coefficient of variation (CV) of generated nominal FRCs was 0.1 (0.0–1.8)%.</p

Nitrogen multiple-breath washout outcomes and variability.

<p>Triplicate nitrogen multiple-breath washout (N₂MBW) tests applied to measure functional residual capacity (FRC) <i>in vitro</i> in the small^* (n = 7) and the large^† lung model (n = 41), and in 30 healthy adults^‡. LCI = lung clearance index. S_acin = phase III slope index of <i>acinar</i> ventilation inhomogeneity. S_cond = phase III slope index of conductive ventilation inhomogeneity. CV = intra-test coefficient of variation (SD/mean*100). Mean difference^§ (95% confidence interval) from paired <i>t</i>-tests comparing measured and actual model FRC [<i>in vitro</i>] or N₂MBW outcomes between two test occasions [<i>in vivo</i>]. CR = coefficient of repeatability (1.96*SD of differences between measured and actual model FRC or differences of N₂MBW outcomes between tests). CR is given in respective units or as percentage of the mean. n.a. = not applicable.</p