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  • Louren Helsh 2:17 pm on October 23, 2020 Permalink | Reply  

    Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma. Part 6 

    By contrast, both very low-flow and very high-flow rates were not obtained in all children. FEno at a “very” high flow (> 150 mL/s) was obtained in only 20 participants, whereas measurements did not satisfy the criteria of stability in the remaining patients. Most frequent aspect in these cases was a progressive decrease in FEno without a stable plateau. FEno was only interpretable at a “very” low flow (< 40 mL/s) in 25 asthmatic children. At this very low flow, the time needed to obtain a stable NO plateau was > 12 s, and stable V was difficult to sustain for younger patients in this condition close to apnea. The mean values of the very low flows and the low flows allowing resolution of the equation of Silkoff were 25 ± 9 mL/s and 39 ± 10 mL/s, respectively. We applied the equation in these 25 children. Thus, modeling was achieved in all 60 participants using the linear method and in 25 asthmatic participants using the nonlinear method.

    In the 25 asthmatic participants for whom both models were used, Dno X Cw,no, which reflected Qbr,maxNO with the nonlinear method, was significantly correlated to Qbr,maxNO calculated with the linear method (Fig 1, top, A); the mean values of these two parameters were 77 ± 68 nL/min and 81 ± 73 nL/min, respectively. Similarly, FAno computed with the linear method was significantly correlated to FAno calculated by the analysis of Silkoff(Fig 1, bottom, B); their mean values were 5.8 ± 2.5 ppb and 6.8 ± 4.6 ppb, respectively. Because the linear model could be applied to the entire population only FAno and Qbr,maxNO calculated using the linear model are reported hereafter.

    Comparison of NO Indexes Between Symptomatic and Nonsymptomatic Asthmatic Patients and Healthy Children

    The results of Qbr,maxNO, FAno, and FEno calculated at a V of 50 mL/s (FEno,50) are summarized in Figure 2. Symptomatic children were characterized by an increase in both Qbr,maxNO and FAno as compared to asymptomatic asthmatic patients and healthy children (Table 1). For healthy children, the observed values of Qbr,maxNO were not significantly different from predicted values that were calculated based on the relationship established for healthy nonsmoker adults:

    Qbr,maxNO (nanoliters per minute) = 0.666 X height(centimeters) – 78 (see Materials and Methods).

    FAno contributed substantially to FEno, the proportion of FEno due to FAno increased with the flow rate: respective contribution of FAno in FEno in symptomatic, asymptomatic, and healthy children is illustrated in Figure 3. No correlation was found between alveolar and proximal airway NO, namely FAno and Qbr,maxNO.

    Correlation With Functional Respiratory Tests in Asthmatic Children

    Pulmonary function tests demonstrated no significant difference between recently mildly symptomatic (n = 15) and asymptomatic (n = 30) asthmatic children: FEV1 % of predicted, 90 ± 16.5% vs 93 ± 13.5%; MEF25_75 % of predicted, 68 ± 28% vs 70 ± 22%; respectively.

  • Louren Helsh 2:15 pm on October 23, 2020 Permalink | Reply  

    Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma. Part 5 

    All available measurements of FEno and V were used to compute these parameters. Several measurements at very low flow (< 40 mL/s) enhance the validity of the results concerning Dno and Cw,no.

    In this model, the product (Dno X Cw,no) is the largest amount of NO that can be delivered by the nonexpansible compartment. The product (Dno X Cw,no) obtained by the nonlinear method reflects the same proximal airway ability to produce NO than Qbr,maxNO calculated by the linear method.

    Lung Function Tests

    Spirometry measurements and flow-volume curves were obtained using a spirometer (PF/DX 1085; SensorMedics; St. Paul, MN) after NO measurements. Pulmonary function tests were performed at least 12 h after discontinuation of long-acting P2-agonists (if possible). The highest values of three technically satisfactory forced expirations were taken and expressed as the percentages of predicted normal values. Maximal expiratory flow between 25% and 75% of FVC (MEF25_75) was used as an index of small-airway caliber. The children were classified into two subgroups according to whether their MEF25_75 value was < 50% of predicted or > 50% of predicted.

    Statistical Analysis

    Data are expressed as means ± SD. Comparison of the three groups (asymptomatic, recently symptomatic asthmatic children, and healthy children) was done using analysis of variance. When a significant difference was found, individual means were compared using the modified t test. Correlations between variables were analyzed using least-square regression techniques, and multiple regression analysis was also performed using NO measurement as the dependent variable and symptoms and/or peripheral obstruction as independent variables. For all comparisons, p < 0.05 was considered significant.


    Forty-five consecutive children or adolescents with asthma were enrolled (mean age, 12.3 ± 2.7 years; mean height, 147 ± 15 cm). Thirty-eight participants (84%) had positive skin test results for one or more airborne allergens. All participants used inhaled corticosteroid therapy (beclomethasone, n = 23; budesonide, n = 8; fluticasone, n = 14). Fifteen patients had mild and recent symptoms; the others (n = 30) were asymptomatic. The average dose of inhaled steroids and their mean height were similar in these two groups of asthmatic patients (data not shown). Fifteen healthy children, with no significantly different mean height as compared to asthmatic groups (143.7 ± 10.1 cm), were also enrolled.

    Technical Aspects of Multiple Flow Analysis of FEno in Children

    All 60 subjects were able to perform at least one stable prolonged V rate maneuver in low, intermediate, and high V rate, allowing the determination of the parameters of the linear model. As expected, we observed in the 60 children a marked flow dependency of FEno.

  • Louren Helsh 2:11 pm on October 23, 2020 Permalink | Reply  

    Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma. Part 4 

    One approach, described by Tsoukias and George, takes advantage of the fact that the relationship between Q NO and V appears to be linear above a threshold of 50 mL/s. The second approach, described by Silkoff and colleagues, is based on the nonlinear relationship observed between (Qno and V (< 50 mL/s), which gives additional information on the proximal airway characteristics of the QNO.

    Both the linear and the nonlinear models allow characterizing distal (18th generation and beyond) and proximal airway (Qno by lower airways. It can be assumed that such models can be used in children due to similar physiologic characteristics as in adults; along this line, a study has demonstrated similar value for FAno in healthy children than previously reported in healthy adults.

    Linear Model for Flow Rates > 50 mL/s

    Simultaneously measured FEno and V values were used to calculate QNO as follows:

    Qno = FEno X V X 0.06

    where QNO is expressed in nanoliters per minute, FEno in parts per billion (ppb), and V in milliliters per second (0.06 is a unit correcting factor).

    The calculated QNO was represented as a function of flow rate. Least-square linear regression was performed for flow rates > 50 mL/s. In this range of flows, lumenal NO concentration can be considered as negligible compared to airway wall concentration, so that the proximal airway (Qno is maximal and constant, whatever the flow rate. Tsoukias and George have shown that the slope of this linear relationship is representative of the constant FAno, and the intercept at zero flow of the Qbr,maxNO. At least two measurements at different ranges of V are necessary to determine FAno and Qbr,maxNO by this way. The knowledge of the relationship allows to calculate FEno at different V rates, which are computed as follows:

    FeNO (V) = FAno + Qbr,maxNo/(V X 0.06) where V is the chosen V rate.

    We have previously shown that the height of the subject influences Qbr,maxNO, and consequently exhaled NO, probably by affecting the size of airways. Consequently, it was important to ensure that the three groups of patients were comparable regarding their height. Moreover, the healthy group of children allowed to test whether their height similarly affected Qbr,maxNO than demonstrated in healthy adults.

    Nonlinear Model With Flow Piates < 60 mL/s

    When at least one low flow (40 to 60 mL/s) and one very low flow (< 40 mL/s) were computed, FAno, NO concentration in the airway wall (Cw,no), and proximal airway NO diffusing capacity (Dno) can be computed as described by Silkoff and colleagues:

    FEno = Cw,no X (1 – e-DNO/v) + FAno X e-Dno/V

    where e is exponential, and V is expiratory flow rate. The parameters of the model were calculated by using the solver function in Excel 97 software (Microsoft; Redmond, WA) to minimize the sum of the square residual values for FEno.

  • Louren Helsh 8:04 pm on October 15, 2020 Permalink | Reply  

    The following conclusions can be drawn from this work:

    1. The 2QRS12 reflects better the changes in W in patients with AN than the 2QRS3, at the PW point, and all three ECG systems are not predictive of the HF-W gain. This indicates that there is a nonlinear relationship between changes in W and the ECG, and thus it takes significant W gain for ECG detection. When this stage is reached, the precordial leads are essential for such detection. This may be a reflection of the accumulation of fluid in the dorsal/lateral body plane in patients with AN who are kept supine in critical care units (ie, the gravity effect). Accordingly, we have shown previously a better correlation of the % W and the sum of the QRS complexes from leads V5 and V6 (reflecting the lateral body plane) [ r = 0.65] than the one with the 2QRS12. Moreover, it is revealing that the % W and the sum of the QRS complexes from leads V1 and V2 (reflecting the ventral body plane) [ r = 0.22] did not reach statistical significance (p = 0.26). This overexpression of AN on leads V5 and V6 may be due to the sequestration of fluid in the region of the V5 and V6 leads, leading to further decrease in body resistance. Moreover, such regional fluid accumulation increases the distance of the heart from V5 and V6 recording sites (ie, the Wilson proximity effect). Both of these mechanisms would cause attenuation of surface ECG voltage. The almost complete lack of orthogonality inherent in the limb leads, and the fact that their vectors are expressed in one plane, previously has been commented on.

    2. The correlations of the 2QRS6 and 2QRS2 with the 2QRS12 are such that the first two can be considered reflective of the latter. In the control subjects at hospital discharge and in the hemodialysis patients, the 2QRS6 and 2QRS2 reflected better the 2QRS12 than in the patients with AN. This should be expected since in the patients with AN the fluid accumulates especially in places other than the frontal plane, and thus the correlations among ECG systems are attenuated.

    3. The similarity in the correlations of the 2QRS2 and 2QRS6 with the 2QRS12 and the correlation with r = 0.86 to 0.93, respectively, between the 2QRS2 and the 2QRS6 are undoubtedly due to the redundancy in the ECG information contained in the frontal ECG leads, an issue that was well-researched and discussed by Rautaharju and colleagues. This is not surprising, since by design such correlations would be expected to be expressed by r values of approximately.

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