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Adaptation of the growing lung to increased Vo2: III. The effect of exposure to cold environment in rats.

This study was undertaken to further test the hypothesis that increased Vo2 operates as a stimulus for enhanced lung growth leading to a pulmonary diffusing capacity adapted to the body's O2 requirements. Vo2 was augmented by raising 4-week-old rats for 3 weeks at 11 degrees C ambient temperature, with controls kept at 24 degrees C; this led to an increase in Vo2 averaged over 24 h by 64%. In contrast to previous experiments with waltzing mice this regime did not affect body growth, as the final body weights were identical in both groups. In the cold-exposed rats the lung volume was larger by 24%, due to an increase by 26% in air volume (at about TLC), 13% in capillary blood volume and 19% in tissue volume. The alveolar and capillary surface areas were increased by 18%, and Dm and Dl by 17% and 21% respectively. It is concluded that the hypothesis of adaptation of pulmonary gas exchange capacity to increased Vo2 cannot be rejected. Whilst in previous experiments some doubts had to be retained as to the specificity of the stimulus, because of its rather marked effect on body weight, this reservation does not hold in this case. The structural modifications which lead to increased Dl in the various experimental models are discussed.

Adaptation, Physiological↗

Morphometrics of the avian lung. 2. The wild mallard (Anas platyrhynchos) and graylag goose (Anser anser).

The lungs of 5 wild mallard ducks (Anas platyrhynchos) and 5 feral graylag geese (Anser anser) of mean body weight 1.04 and 3.84 kg, respectively, were fixed in situ by intratracheal infusion of 2.3% glutaraldehyde, pH 7.4 and total osmolarity 350 mOsm, at a pressure head of 25 cm, and analysed by standard morphometric techniques. The following data apply to both lungs together, in the fixed state, the first value relating to Anas and the second to Anser in each case: lung volume, 30.4 and 95.3 cm3; volume of exchange tissue, 12.32 and 38.50 cm3; volume of capillary blood, 4.06 and 12.49 cm3; surface area of blood-gas (tissue) barrier per unit body weight, 28.56 and 23.10 cm2/g; surface area of the blood-gas (tissue) barrier per unit volume of lung, 977 and 932 cm2/cm3; surface area of blood-gas (tissue) barrier per unit volume of exchange tissue, 241 and 230 mm2/mm3; harmonic mean thickness of tissue barrier, 0.133 and 0.118 microns; arithmetic mean thickness of tissue barrier, 0.903 and 0.887 microns; harmonic mean thickness of plasma layer, 0.369 and 0.322 microns; mean total morphometric pulmonary diffusing capacity per unit body weight, 3.85 and 3.59 ml O2/min/mm Hg/kg. These morphometric parameters of Anas and Anser are compared with those reported in the literature for the domestic fowl (Gallus gallus), the budgerigar (Melopsittacus undulatus), the house sparrow (Passer domesticus), and the violet-eared hummingbird (Colibri coruscans). The lungs of these six avian species show progressively advancing adaptations, from Gallus, through Anser, Anas, Melopsittacus and Passer, to Colibri, which appear to be consistent with the energetic characteristics of these birds.

Animals↗

Recovery of pulmonary function in farmer's lung. A five-year follow-up study.

The recovery of pulmonary function in farmer's lung (FL) was studied during a 5-yr follow-up in 101 patients (20 men and 81 women, mean age 47 yr). At the initial evaluation all patients had the first diagnosed attack of FL. Spirometry, measurement of pulmonary diffusing capacity, and arterial blood gas analysis were done at the time of the diagnosis and 1, 3, 6, 12, and 24 months thereafter. The last follow-up measurements were made 4 to 6 yr after the initial evaluation. Mean FVC improved significantly for up to 1 yr. In mean DLCO there was improvement for up to 2 yr. Mean PaO2 rose to its maximum within 1 month of the initial examination and did not change significantly thereafter. No patient had diagnosed asthma at the time of the diagnosis of FL, but asthma was later diagnosed in 7 patients during the follow-up. In conclusion, the pulmonary function of FL patients improved for up to 2 yr after the initial acute episode. In general, PaO2 improved most rapidly; the improvement in FVC was slower, and the recovery of DLCO took the longest time.

Adult↗

Interpretation of changes in DLCO and pulmonary function after running five miles.

The purpose of this study was to evaluate changes in pulmonary function after running five miles. Of particular interest was the reaffirmation of the previously reported 'uncoupling' or dissociation of pulmonary diffusing capacity (DLCO) and cardiac output (Q) after moderate or strenuous exercise. Cardiopulmonary assessments were made on eight runners before and after completing three separate five mile runs. There were significant reductions in vital capacity (5.7%) and volume at closing with increases in residual volume (22.5%) and closing capacity post-run. Although DLCO did not change, significant change in cardiac output occurred during the DLCO 10 sec breathhold maneuver. The pre-run DLCO maneuver produced a fall in stroke volume (SV) with an increase in HR while maintaining Q. The post-run Q fell during the DLCO maneuver due to a fall in SV with HR remaining constant. The primary basis for previous speculation of the development of a transient pulmonary edema during exercise has been the failure of DLCO to increase immediately after exercise when HR and presumably Q is elevated. To avoid any misinterpretation of changes in DLCO produced by exercise, Q should be measured at the time of the DLCO determination. Our findings suggest that values for DLCO post-exercise are entirely appropriate for the pulmonary blood flow at the time of the DLCO maneuver.

Adult↗

Lung function consequences of dust exposure in asbestos cement manufacturing plants.

A comprehensive study of health effects associated with the mixed dust exposure in this industry has included the collection of clinical, radiographic, lung function, and dust exposure data on 859 workers in two plants. Evidence is presented supporting a dose-response relationship between indexes of dust exposure and lung function, similar to the previously reported relationship with extent of x-ray film changes using the ILO U/C classification. Lung volumes and maximum expiratory flow rates decrease in relation to increasing cumulative dust exposure while pulmonary diffusing capacity (DL) is not dust-dose related. Worders who had crocidolite exposure had smaller lung volumes, lower expiratory flow rates, and reduced DL when compared with those having only chrysotile exposure. When the study population is divided into exposure groups, data thus far analyzed suggest that the chest x-ray film will reveal small opacities as early as significant functional changes can be detected, but individuals may have functional reduction prior to the appearance of x-ray film changes.

Adult↗

Lipid infusion in critically ill patients. Acute effects on hemodynamics and pulmonary gas exchange.

Hemodynamics, pulmonary diffusing capacity (DLCO) blood gases, oxygen consumption (VO2) and carbon dioxide excretion (VCO2) were studied in healthy volunteers and ventilator-treated, critically ill patients before and during infusion of lipid emulsion for 4 h. Triglyceride levels rose from 1.0 mmole/L to 8.5 mmole/L in the volunteers and from 1.4 mmole/L to 6.3 mmole/L in the patients after h. No adverse effects on cardiovascular performance were observed. Increases in VO2, and VCO2 and cardiac output were found in both groups, while RQ remained constant. No changes in DLCO and blood gases occurred.

Adolescent↗

Morphometrics of the avian lung. 4. The structural design of the charadriiform lung.

The lungs of five charadriiform species of bird, two of which are good divers and three predominantly flyers (soarers and gliders) have been analysed by morphometric techniques. Largely the morphometric structural values in the divers significantly exceeded those of the flyers (gulls). The average weight specific surface area of the blood-gas (tissue) barrier in the divers (28.45 +/- 2.05 cm2 X g-1 SD) surpassed that of the flyers (23.5 +/- 3.61 cm2 X g-1 SD). The divers had a higher volume of the pulmonary capillary blood per unit body weight (4.42 +/- 0.11 cm3 X kg-1 SD) than the flyers (2.84 +/- 0.58 cm3 X kg-1 SD). The weight specific volume of the lung in the divers (34.90 +/- 3.11 cm3 X kg-1 SD) exceeded that of the flyers (26.94 +/- 3.15 cm3 X kg-1 SD). The total morphometric pulmonary diffusing capacity per unit body weight in the divers (4.73 +/- 0.05 ml O2 X (min X mm Hg X kg)-1 SD) was higher than that of the flyers (3.09 +/- 0.47 ml O2 X (min X mm Hg X kg)-1 SD). The divers, however, had a notably thicker blood-gas (tissue) barrier with a harmonic mean thickness of 0.212 +/- 0.03 micron SD compared to that of the flyers (0.138 +/- 0.02 micron SD). The data acquired here commensurate the modes of life exhibited by these two groups of bird. The divers, which are relatively energetic birds, expend a lot of energy to move and stay underwater, concomitantly undergoing prolonged asphyxia during submergence and may hence need to extract as much of the oxygen in the pulmonary air as possible to prolong a dive. These birds appear in general to have structurally better adapted lungs than those of the gulls, birds which to a large extent exhibit relatively less energetic soaring and gliding flights.

Animals↗

Pulmonary function and circulating adhesion molecules in patients with diabetes mellitus.

BACKGROUND: Lung function in diabetes has been reported in several studies with contradictory results. Diabetes mellitus increases expression of adhesion molecules through hyperglycemia. These molecules play an important role in the pathophysiological dysfunction of the vasculature. OBJECTIVE: To explore the possible relationship between lung function and circulating levels of adhesion molecules in diabetes. METHODS: Sixteen type 1 diabetic patients, 33 type 2 diabetic patients and 22 healthy subjects matched for age and sex were studied. Spirometry measurements were performed and pulmonary diffusion capacity for carbon monoxide (DLco) was measured in sitting and supine positions by the single-breath method corrected by alveolar volume (VA). Glycosylated hemoglobin, retinopathy and nephropathy were included as parameters of metabolic control and diabetic complications. Circulating levels of soluble E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were determined in all subjects. RESULTS: Diabetic subjects showed lower variation in DLco and DLco/VA by changing posture from sitting to supine position (P=0.043 and P<0.001, respectively), and showed reduced total lung capacity (P<0.001) and forced expiratory volume in 1 s/forced vital capacity (P=0.009) compared with healthy control subjects. Serum concentrations of E-selectin were elevated in diabetic patients (P<0.001). There was no difference in serum VCAM-1 concentrations between diabetic and control subjects. On stepwise regression analysis, E-selectin concentrations were the most important contributing factor to the variation in DLco/VA. CONCLUSIONS: Diabetic patients show lower pulmonary volumes and variation in DLco by changing posture from sitting to supine position, and they also show increased levels of E-selectin. A possible explanation is impaired pulmonary microvasculature, because adhesion molecules seem to be sensitive markers of endothelial activation and damage seen in diabetes.

Aged↗

Adaptation of the growing lung to increased oxygen consumption. II. Morphometric analysis.

This paper is the second part of a study investigating the effect of increased O2 consumption on the lungs of growing animals. By means of injections of the drug IDPN (imino-betabeta'-dipropionitrile) hyperkinesia was permanently induced in white mice aged 3 weeks, thus increasing their Vo2 per gram body weight (= specific VO2) by 50%. 3 1/2 months later the lungs of these animals were fixed by standardized procedure, analysed by morphometric techniques and the results compared with those of control mice originating from the same litters. Whereas the specific weights (= weights per gram body weight) of various organs did not differ significantly in the two groups, the specific volume of the lungs fixed with standardized techniques was up by 23% in IDPN mice. The relative composotion of lung parenchyma was also altered: air space volume density was slightly but significantly reduced, whereas tissue and capillary volume densities were both increased by 15%. An analogous increase was detected in alveolar and capillary surface densities. These changes led to significantly higher specific capillary and tissue volumes, as well as higher specific gas exchange surface areas in DIPN mice. Therefore the morphometrically determined specific pulmonary diffusion capacity was increased by more than 40% in the IDPN-treated animals. The findings are compared with those hitherto reported, where a structural adaptation of the gas exchange apparatus to exercise or altered PO2 had been found. In view of our present knowledge of the postnatal lung growth the quantitative structural alterations found in this experiment indicate that the higher O2 requirements in IDPN mice induced an alteration in the septal morphology. This consisted in an augmentation of septal volume possibly due to a lengthening and corrugation of the intralveolar septa. This change is reflected by the increased alveolar surface area in IDPN mice and by the increase of the ratio Sa/Va estimating the air space surface complexity.

Adaptation, Physiological↗

Pulmonary gas exchange in asymptomatic smokers and nonsmokers.

Pulmonary gas exchange has been studied in 14 healthy smokers and 16 healthy nonsmokers (mean age: 36 years) breathing hypoxic, normoxic and hyperoxic gas mixtures, in a sitting position, at rest and on exercise. Alveolar-arterial oxygen tension difference is increased in smokers in hypoxia, at rest and on exercise, and the pulmonary diffusing capacity for oxygen is decreased. In normoxia the alveolar-arterial oxygen tension difference is increased on exercise. There is no difference between the two groups in hyperoxia. For the whole group there exists a negative relationship between (A-a)DO2 in normoxia and the diffusion indices measured on exercise. Arterio-alveolar carbon dioxide tension difference and the ratio physiological dead space/tidal volume are almost identical in both groups in any condition. A diffusion defect seems to be the more constant alteration of gas exchange in asymptomatic smokers.

Adult↗

Mechanism of reduction in alveolar-arterial PO2 difference by helium breathing in the exercising horse.

Previous work has shown that replacing N2 in air with He at the same inspired O2 fraction reduces the exercise-induced alveolar-arterial PO2 difference (AaPO2) in horses but has provided no mechanism explaining this effect. We sought to distinguish among possible causes by using the multiple inert gas elimination technique. Six horses were studied on a high-speed treadmill while they breathed either ambient air or normoxic He-O2. O2 uptake reached 138.0 ml.min-1.kg-1 and was not affected by He-O2. Temperature-corrected arterial PO2 was 76.7 Torr (air) and 86.9 Torr (He-O2) (P < 0.01). Corresponding AaPO2 was 22.3 and 15.9 Torr, respectively (P < 0.01). Mean AaPO2 predicted from ventilation-perfusion inequality did not change with He-O2 (12.7 Torr with air and 11.9 Torr with He-O2). Mean arterial PCO2 was 50.1 Torr with air and 44.1 Torr with He-O2 (P < 0.01); minute ventilation and tidal volume were correspondingly higher by 140 l/min and 1.0 liter, respectively, with He-O2. Pulmonary O2 diffusing capacity, cardiac output, and all ventilation-perfusion dispersion indexes did not change with He-O2. Intrapulmonary shunt was insignificant. Higher ventilation with He-O2 explained only approximately 4 Torr of the 10-Torr rise observed in arterial PO2. The remainder (and the corresponding fall in AaPO2) was due to more complete diffusion equilibration as a consequence of the higher minute ventilation and thus alveolar PO2, which reduced the average slope of the O2 dissociation curve, thereby increasing the ratio of diffusive to perfusive conductance.

Animals↗

Comparison of single breath and steady state methods for measurement of lung transfer factor for CO in normal subjects and smokers.

Pulmonary diffusing capacity (lung transfer factor for carbon monoxide) has been assessed by the single breath (TLCOSB) and steady state (TLCOSS) techniques in well matched 90 females, 31 non-smoker and 29 smoker males, 18-50 years of age. Both TLCOSB and TLCOSS are significantly lower in females compared to non-smoker males (P < 0.001). Tobacco smoking statistically significantly reduces TLCOSB as well as TLCOSS in smokers as compared to non-smokers. There is a statistically significant correlation of age with TLCOSS and TLCOSB in all the three groups (r = -0.702, -0.360 and 0.300 for TLCOSB and r = -0.481, -0.355 and 0.380 for TLCOSS in non-smoker males, smoker males and females respectively). TLCOSB is 30.43 +/- 4.89, 27.29 +/- 4.54 and 26.13 +/- 3.60 ml/mmHg/min, while TLCOSS is 19.47 +/- 5.26, 16.69 +/- 3.27 and 18.24 +/- 3.78 ml/mm/Hg/min in non-smoker males, smoker males and females respectively. A fairly good correlation between the TLCOSB and TLCOSS in male, both non-smoker and smoker, as well as the female subjects was observed. TLCOSS is lower than TLCOSB in all the three groups. Even in smokers of moderate intensity both of these tests are influenced to a nearly similar extent.

Adolescent↗

Influence of growth and athletic training on heart and lung functions.

Studies were performed at rest and during exercise of varied intensity on 52 boys of pre- and post-pubescent age. Each age group consisted of boys who were engaged in a strenuous prolonged hockey training program; this group was compared with a matched control group who did not participate in a regular training program. Any differences observed in the measured lung functions could be explained on the basis of physical size. Relationship of pulmonary capillary blood flow (Qc) and pulmonary diffusing capacity (DLco) to oxygen consumption were similar to those reported for adults and no difference between the trained and control groups was found in either the pre- or post-pubertal aged boys. Similarily, the trained pre-pubertal boys did not differ significantly from their matched control group in respect to the relationships of heart rate (HR) and stroke volume (SV) for any level of oxygen consumption. In contrast, the post-pubertal trained boys had significantly lower HR and higher SV (P less than 0.01) at each level of work than the control group. These differences between the trained and control post-pubertal boys are consistent with training effects observed in adults. The lack of differences between the trained and control pre-pubertal groups was surprising. Whether the differences in the post-pubertal groups due to a detraining effect in the post-pubertal control boys (as compared to the pre-pubertal control group) or to a continued high level of physical activity during and after the on-set of puberty in trained boys cannot be answered by this study. The findings suggest the importance of high intensity exercise programs during the growth period of adolescence if the efficiency of the oxygen delivery system, and possibly its ultimate dimensions, are to be enhanced.

Adolescent↗

Physiologic approach to dialysis-induced hypoxemia. Effects of dialyzer material and dialysate composition.

This study was undertaken to evaluate the effects of membrane-related complement activation and dialysate composition on dialysis-associated hypoxemia. Seven chronic hemodialysis patients were hemodialyzed 3 times sequentially with the following three combinations; Cuprophan membrane with acetate dialysate, polymethylmethacrylate (PMMA) membrane with acetate dialysate, and PMMA membrane with bicarbonate dialysate. During dialysis with acetate dialysate, the pulmonary diffusing capacity (DLco) at 30 min after the start of dialysis was decreased to 88% (p less than 0.01) of the predialysis value with PMMA and to 79% (p less than 0.01) with Cuprophan, and the degree of DLco on PMMA membrane was different from that on Cuprophan (p less than 0.01). The degree of leukopenia with PMMA was less than that with Cuprophan. However, the fall in DLco did not alter the alveolar-arterial O2 tension gradient. Although the changes in transcutaneous PO2 (tcPO2) were not constant in all three combinations, a distinct fall in tcPO2 was observed in the first half of dialysis with acetate dialysate. During dialysis with acetate dialysate but not with bicarbonate, the extracorporeal dialyzer removed an average of 60 ml/min of CO2, and the respiratory quotient dropped from a mean predialysis value of 0.86 to 0.59 (p less than 0.001). The arterial CO2 tension was not significantly changed throughout dialysis, but the alveolar ventilation decreased significantly in proportion to the fall in carbon dioxide output. The arterial tension fell from a control level of 91 +/- 6 to 77 +/- 8 mm Hg (p less than 0.01) in 30 min. It is concluded that, in spite of a fall in DLco, dialysis-induced hypoxemia in this group of patients on maintenance dialysis is caused by CO2 loss via the dialyzer, resulting in reflex hypoventilation.

Acetates↗

DLCO response to experimental cycle-run succession in triathletes.

BACKGROUND: We still know relatively little about the factors that define the ability to perform a good run after cycling in triathlon, however, and the perception of discomfort during the first minutes of this post-cycling running has yet to be satisfactorily explained. The pulmonary diffusion capacity for carbon monoxide (DLCO) has been demonstrated to be impaired after the cycle-run succession. Numerous causes have been suggested to explain this phenomenon, but the exact mechanism has not yet been determined. METHODS: Thirteen young male triathletes participated in four different exercise trials: 30 min of cycling followed by 20 min of running (C-R, 1 min rest between C and R), 30 min of running followed by 20 min of running (R-R, 1 min rest between R and R), 30 min of cycling (C), and 30 min of running (R). DLCO and alveolar volume were simultaneously measured during 9 sec of breath-holding before and 10 min after exercise. The transfer coefficient (KCO=DLCO/VA) was then calculated. During all trials, ventilatory data were collected every minute using an automated breath-by-breath system. RESULTS: The results showed that 1) C-R and C induced significant and identical decreases in DLCO and KCO in post-trial compared with pre-trial measurement (40.41+/-2.24 vs 43.49+/-2.36 ml x min(-1) x mm Hg(-1), p<0.01, and 39.37+/-2.16 vs 42.99+/-2.38 ml x min(-1) x mm Hg(-1), p<0.02, for C-R and C, respectively) and 2) there were no DLCO decreases in post-trial compared with pre-trial measurement in R-R and R. CONCLUSIONS: We concluded that cycling exercise in itself seems to increase the immediate post-exercise DLCO impairment.

Adult↗

Exercise intolerance in patients with chronic heart failure: role of pulmonary diffusing limitation.

In order to test the hypothesis of pulmonary diffusing capacity involvement in exercise limitation in subjects with chronic heart failure (CHF), lung transfer factor (TLCO), oxygen saturation (SaO2), cardiac output (CO) and gas exchange were studied over the course of an incremental exercise test in 10 patients and 10 controls. The TLCO and transfer coefficient for carbon monoxide (TLCO/VA) were measured at rest and during recovery by the single breath method. The SaO2 was followed non-invasively with a finger oximeter and CO was determined according to the carbon dioxide rebreathing method. Analysis of respiratory variables at maximal effort showed significantly lower values in patients with CHF as regards peak oxygen uptake (VO2), minute ventilation (VE), heart rate (HR), oxygen pulse (O2 pulse), and CO with higher ventilatory reserve (VR) than controls. At a comparable workload (30 W), patients with CHF demonstrated higher values for VE and lower values for CO than controls. The TLCO, expressed as percent of predicted values, was significantly lower in CHF patients than controls, respectively, at rest (90.5 +/- 3.75% vs 106.8 +/- 3.8%) and within 5 min after maximal exercise (87 +/- 4.4% vs 117.4 +/- 3.81%). The TLCO/VA showed comparable data between the two groups at rest (81.7 +/- 3.28 vs 90.3 +/- 2.86%). However, significantly lower values of TLCO/VA were obtained for CHF after maximal exercise in comparison to control subjects (77.5 +/- 3.85% vs 96.3 +/- 3.95%). These results confirm the alteration of the main variables in relation to cardiopulmonary exercise limitation in-tHF, and indicate a significant decrease in TLCO and TLCO/VA after maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise↗

Peripheral pooling of bronchographic contrast material: evidence of its relationship to smoking and emphysema.

Sixty-six subjects, mainly derived from various occupational groups and one-third of whom admitted to dyspnoea on exertion, have been grouped according to the appearance of their peripheral airways at bronchography with oily propyliodone. Eleven subjects showed marked peripheral pooling of radiographic contrast material, 22 showed mild or moderate pooling, and in 33 peripheral pools were absent. Pooling was not seen in non-smoking subjects. In the group of subjects without pooling, pulmonary function in non-smokers and subjects with a history of smoking was similar. Subjects with marked pooling had a significantly lower pulmonary diffusing capacity (transfer factor) and evidence of loss of pulmonary elastic recoil when compared with subjects with absent peripheral pooling. These results indicate that bronchographic peripheral pooling is associated with the physiological changes of panacinar pulmonary emphysema and suggest that a causal relationship may exist between the organic bronchiolar lesion of pooling and the peripheral parenchymal lesion of panacinar emphysema.

Adult↗

Pulmonary function in infancy and in childhood following mechanical ventilation in the neonatal period.

Pulmonary function was evaluated in both infancy and childhood in the same 19 prematurely born infants, who required mechanical ventilation (MV) during the neonatal period. Results of our patients were compared with those of control subjects. Upon first evaluation, we found that lung resistance (RL) was significantly elevated (24.85 +/- 6.06 vs. 17.77 +/- 2.39 cmH2O/L/s; P less than 0.01). The mean value of dynamic lung compliance (CLdyn) was low, but the difference compared to controls did not reach significance. From infancy to childhood, elevated RL persisted (9.33 +/- 2.51 vs. 6.52 +/- 1.52 cm H2O/L/s; P less than 0.01), and the decrease of CLdyn became significant (46.86 +/- 12.84 vs. 59.34 +/- 15.68 mL/cmH2O; P less than 0.05). In addition, maximum flow at functional residual capacity was significantly decreased (0.824 +/- 0.284 vs. 1.215 +/- 0.358 L/s; P less than 0.01); whereas pulmonary diffusing capacity for carbon monoxide was similar in the patients (7.62 +/- 2.16 mL/min/mm Hg) and in the controls (8.38 +/- 1.6). Pulmonary dysfunction following premature birth, respiratory distress, and prolonged MV may not resolve from infancy to childhood.

Child↗