Background Gas exchange in extremely preterm (EP) infants must take place in fetal lungs. Childhood lung diffusing capacity of the lung for carbon monoxide (DLCO) is reduced; however, longitudinal development has not been investigated. We describe the growth of DLCO and its subcomponents to adulthood in EP compared with term-born subjects. Methods Two area-based cohorts born at gestational age ≤28 weeks or birthweight ≤1000 g in 1982–1985 (n=48) and 1991–1992 (n=35) were examined twice, at ages 18 and 25 years and 10 and 18 years, respectively, and compared with matched term-born controls. Single-breath DLCO was measured at two oxygen pressures, with subcomponents (membrane diffusion (DM) and pulmonary capillary blood volume (VC)) calculated using the Roughton–Forster equation. Results Age-, sex- and height-standardised transfer coefficients for carbon monoxide (KCO) and DLCO were reduced in EP compared with term-born subjects, and remained so during puberty and early adulthood (p-values for all time-points and both cohorts ≤0.04), whereas alveolar volume (VA) was similar. Development occurred in parallel to term-born controls, with no signs of pubertal catch-up growth nor decline at age 25 years (p-values for lack of parallelism within cohorts 0.99, 0.65, 0.71, 0.94 and 0.44 for z-DLCO, z-VA, z-KCO, DM and VC, respectively). Split by membrane and blood volume components, findings were less clear; however, membrane diffusion seemed most affected. Conclusions Pulmonary diffusing capacity was reduced in EP compared with term-born subjects, and development from childhood to adulthood tracked in parallel to term-born subjects, with no signs of catch-up growth nor decline at age 25 years. Pulmonary diffusing capacity following extremely preterm (EP) birth was reduced compared with term-born subjects. From mid-childhood to adulthood, development tracked in parallel in the EP and term-born groups, with preterms following lower trajectories. https://bit.ly/3ARPD7D

Life on Earth evolved in an aquatic environment, so man has inherited features that contribute to his survival in water. This chapter examines immersion, decompression, hyperbaria, and hyperoxia. Hyperoxia associated with hyperbaria lowers the transfer factor by reducing immediately the reaction rate of carbon monoxide with oxyhaemoglobin. The defences against hyperoxia are damaged by tobacco smoke and other air pollutants. Hypercapnia is an additional risk factor, whilst the risk of oxygen toxicity is reduced if the exposure to hyperoxia is intermittent. Hyperbaric oxygen therapy is of confirmed value for cerebral gas embolisation, gas gangrene, carbon monoxide poisoning, delayed radiation injuries, and some types of tissue ischaemia. The use of a hyperbaric chamber permits the recompression of subjects who have developed acute decompression sickness as a result of diving, work in a caisson, or in relation to aviation.

The fraction of nitric oxide in exhaled gas (FENO) is decreased after exposure to hyperoxia in vivo, although the mechanisms for this decrease is not clear. A key co-factor for nitric oxide synthase (NOS), tetrahydrobiopterin (BH4), has been shown to be oxidized in vitro when exposed to hyperoxia. We hypothesized that the decrease of FENO is due to decreased enzymatic generation of NO due to oxidation of BH4. The present study was performed to investigate the relationship between levels of FENO and plasma BH4 following hyperoxic exposure in humans. Two groups of healthy subjects were exposed to 100% oxygen for 90 minutes. FENO was measured before and 10 minutes (n = 13) or 60 minutes (n = 14) after the exposure. Blood samples were collected at the same time points for quantification of biopterin levels (BH4, BH2 and B) using LC-MS/MS. Each subject was his or her own control, breathing air for 90 minutes on a separate day. Hyperoxia resulted in a 28.6 % decrease in FENO 10 minutes after exposure (p < 0.001), confirming previous findings. Moreover, hyperoxia also caused a 14.2% decrease in plasma BH4 (p = 0.012). No significant differences were observed in the group measured 60 minutes after exposure. No significant correlation was found between the changes in FENO and BH4 after the hyperoxic exposure (r = 0.052, p = 0.795), this might be due to the recovery of BH4 being faster than the recovery of FENO.

Background: Pulmonary rehabilitation (PR) with exercise training should be considered for all patients with chronic obstructive pulmonary disease (COPD). However, some patients are not achieving significant benefit of exercise training. Aims: To examine improvement in exercise capacity after participation in PR in patients who did (DS) and did not desaturate (NDS) during Incremental Shuttle Walk Test (ISWT). Methods: The study included 89 COPD patients who participated in 6 weeks outpatient PR, aged 42-82 yrs, with a mean FEV1 at baseline of 47% of predicted (SD=15%). Desaturation was defined as a drop in oxygen saturation ≥4% (∆SpO2) and a SpO2<90%. The patients underwent ISWT before and after PR. Independent samples t-test for continuous variables was used to compare DS and NDS at baseline. Paired samples t-test was used to analyse the outcomes pre- and post-PR, and multivariate linear regression analyses to examine the relationship between potential explanatory variables (age, gender, body mass index, FEV1, FVC and FEV1/FVC) and change in ISWT. Results: Of the 89 patients with stable COPD, 45 patients desaturated during ISWT. They were significant older (p=0.040), had significantly lower FEV1 (p=0.004), and walked 60m shorter at ISWT (p=0.046) at baseline compared with NDS. After PR the NDS had a statistically and clinically significant improvement in ISWT (mean change 53m, SD=59m, p<0.001), while the DS had not (mean change 11m, SD=74m, p=0.358). In multivariate linear regression analysis the change in ISWT was only related to ∆SpO2 (p=0.004). Conclusion: Improvement in exercise capacity after participating in PR was only evident in COPD patients who did not desaturate during the ISWT.

Background: Knowledge about the physiological responses to oxygen supplementation in patients with COPD who have normal oxygen saturation (SaO2) at rest but desaturate during exercise are scarce. Aims: To evaluate the effects of oxygen supplementation during exercise on cardiorespiratory responses and dyspnea score in COPD patients who desaturate during exercise (SaO2<88%). Methods: In a double-blinded, randomized crossover study 16 COPD patients (FEV1 50±14% pred, age 65±8 yrs) performed a maximal treadmill test and thereafter two constant work load (CWL) tests at 85% of peak work load. During the CWL-tests, the patients breathed 21% and 30% oxygen in random order on a facemask from a reservoir. Oxygen uptake (VO2), carbon dioxide output (VCO2), ventilation (VE), heart rate, blood pressure and dyspnea score (Borg CR10) were measured pre-exercise and at iso-time at 5 min. Results: All patients completed both CWL-tests. SaO2 at iso-time increased significantly from 84±5% to 96±1% with 30% O2, p<0.001. VO2 was significantly higher (1386±535 vs 1168±457mL/min, p=0,002). Dyspnea score was significantly reduced from 6.3±1.9 to 3.6±1.8 (p=0.003) with 30% O2. Breathing frequency (31±7 to 28±5, p=0.008), heart rate (126±20 to 119±18, p<0.001) and systolic blood pressure (192±16 to 179±17 mmHg, p=0.002) were lower. VE, VCO2 and the change in inspiratory capacity from rest to iso-time did not change significantly. Conclusions: Supplemental oxygen significantly improved cardiorespiratory responses to exercise and reduced exercise induced discomfort in COPD patients who desaturate during exercise.

Purpose:Nitric oxide (NO) has been shown to protect against bubble formation and the risk of decompression sickness. We hypothesize that oxidation of tetrahydrobiopterin (BH4) leads to a decreased production of NO during simulated diving.Methods:Human umbilical vein endothelial cells (HUVEC) were exposed to hyperoxia or simulated diving for 24 hours. The levels of biopterins (BH4, BH2 and B) were determined by LC-MS/MS, and the production of NO by monitoring the conversion of L-arginine to L-citrulline.Results:Exposure to hyperoxia decreased BH4 in a dose-dependent manner; by 48 ± 15% following exposure to 40 kPa O2 (P⟨0.001 vs. control at 20 kPa O2), and 70 ± 16% following exposure to 60 kPa O2. Exposure to 40 kPa O2 decreased NO production by 25 ± 9%, but there was no further decrease when increasing oxygen exposure to 60 kPa (25 ± 10%). No additional effects of simulated diving were observed, indicating no additive or synergistic effects of hyperbaria and hyperoxia on the BH4 level or NO generation.Conclusion:NO generation in intact human endothelial cells was decreased by simulated diving, as well as by hyperoxic exposure, while BH4 levels seem to be affected only by hyperoxia. Hence, the results suggest that BH4 is not the sole determinant of NO generation in HUVEC.

Nitric oxide (NO) may protect against gas bubble formation and risk of decompression sickness. We have previously shown that the crucial co-factor tetrahydrobiopterin (BH4) is oxidized in a dose-dependent manner when exposed to hyperoxia similar to diving conditions but with minor effects on the NO production by nitric oxide synthase. By manipulating the intracellular redox state, we further investigated the relationship between BH4 levels and production of NO in human endothelial cells (HUVECs). HUVECs were cultured with and without ascorbic acid (AA) and the glutathione (GSH) synthesis inhibitor buthionine sulfoximine, prior to hyperoxic exposure. The levels of biopterins and GSH were determined in cell lysates while the production of NO was determined in intact cells. Omitting AA resulted in a 91% decrease in BH4 levels (0.49 ± 0.08 to 0.04 ± 0.01 pmol/10⁶ cells, p⟨0.001) at 20 kPa oxygen (O2), and 88% decrease (0.24 ± 0.03 to 0.03 ± 0.01 pmol/10⁶ cells, p=0.01) after exposure to 60 kPa O2. The NO generation was decreased by 23% (74.5 ± 2.2 to 57.3 ± 5.6 pmol/min/mg protein, p⟨0.001) at 20 kPa O2, but no significant change was observed at 60 kPa O2. GSH depletion had no effects on the NO generation. No correlation was found between NO generation and the corresponding intracellular BH4 concentration (p=0.675, r=-0.055) or the BH4 to BH2 ratio (p=0.983, r=0.003), determined across 18 in vitro experiments. Decreased BH4 in HUVECs, due to hyperoxia or lack of ascorbic acid, does not imply corresponding decreases in NO generation.

The original article [1] contains errors in Tables 1 and 3: Table 1 erroneously mentions use of a treadmill which should instead state 'bicycle', and Table 3 has a minor typesetting mistake.

Lung hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of lung hyperinflation and is associated with exercise intolerance. However, knowledge of its effect on longitudinal change in the 6-min walk distance (6MWD) in patients with COPD is scarce. We aimed to study whether the IC/TLC ratio predicts longitudinal change in 6MWD in patients with COPD.

Purpose: Children and adolescents born extremely preterm (EP) have lower dynamic lung volumes and gas transfer capacity than subjects born at term. Most studies also report lower aerobic capacity. We hypothesized that ventilatory efficiency was poorer and that breathing patterns differed in EP−born compared to term−born individuals.Methods: Two area−based cohorts of participants born with gestational age ≤28 weeks or birth weight ≤1000 g in 1982−85 (n = 46) and 1991–92 (n = 35) were compared with individually matched controls born at term. Mean ages were 18 and 10 years, respectively. The participants performed an incremental treadmill exercise test to peak oxygen uptake with data averaged over 20 s intervals. For each participant, the relationship between exhaled minute ventilation (V˙E) and carbon dioxide output (V˙CO2) was described by a linear model, and the relationship between tidal volume (VT) and V˙E by a quadratic model. Multivariate regression analyses were done with curve parameters as dependent variables, and the categories EP vs. term−born, sex, age, height, weight and forced expiratory volume in 1 s (FEV1) as independent variables.Results: In adjusted analyses, the slope of the V˙E−V˙CO2 relationship was significantly steeper in the EP than the term-born group, whereas no group difference was observed for the breathing pattern, which was related to FEV1 only.Conclusion: EP-born participants breathed with higher V˙E for any given CO2 output, indicating lower ventilatory efficiency, possibly contributing to lower aerobic capacity. The breathing patterns did not differ between the EP and term−born groups when adjusted for FEV1.

Introduction: Pulmonary hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of static hyperinflation and is strongly associated with dynamic hyperinflation and exercise tolerance. However, knowledge of its effect on longitudinal change in the 6-minute walk distance (6MWD) in COPD is scarce. Aim: We aimed to study if IC/TLC ratio predicted longitudinal change in 6MWD. Methods: This prospective observational cohort study included 389 patients aged 40-75 yrs with clinically stable COPD in GOLD stages II-IV. 6MWDs were measured at baseline, and after 1 and 3 yrs. Predictor variables at baseline included IC/TLC ratio, spirometry, fat mass index (FMI) and assessment of smoking habits and exacerbations by questionnaires. Generalized estimating equations (GEE) analyses were used to analyze predictors for change in 6MWD. Results: Mean (SE) 6MWD at baseline and after 1 and 3 yrs were 423 (5.7), 431 (6.1) and 400 (7.8) m, respectively. In the multivariable adjusted GEE analysis, there was a predicted annual decline of 59,5 m and the IC/TLC ratio also predicted decline in 6MWD over 3-yrs (interaction IC/TLC*Time, B=87 m, p=0.017). With a 0.1-unit decrease in baseline IC/TLC ratio, the annual decline of 6MWD increased with 8,7 m. Other predictors for reduced 6MWD were reduced FEV1 (p=0.001), increased age (p=0.002), increased FMI (p=0.001), and >2 exacerbations within 12 months prior to inclusion (p=0.006). Conclusion: The level of static hyperinflation at baseline independently predicted longitudinal decline in functional capacity in COPD patients.

Background: The ventilatory limitation in patients with COPD is related to expiratory flow limitation (EFL) and static and dynamic lung hyperinflation (DH). Respiratory timing (duty cycle) is the ratio of inspiratory time (Ti) to total time of a breath (Ttot). A shorter duty cycle could compensate for EFL and DH by giving more time for expiration. Aim: The aim of this study was to examine the relationship between Ti/Ttot and EFL and DH in patients with COPD during incremental exercise. We hypothesised that Ti/Ttot was negatively related to DH and EFL. Methods: Sixty three patients (35 men), mean (SD) age 66 (6)yrs and mean (SD) FEV1 48 (15)% of predicted, performed an incremental treadmill exercise test. DH was measured as the change in inspiratory capacity (ΔIC) from rest to peak exercise, and EFL as the fraction of the tidal volume where flow was equal to or higher than the maximal expiratory flow rate. The relationship between Ti/Ttot and tidal volume was analyzed for each subject and fitted to a linear regression line. The relationship between Ti/Ttot and the explanatory variables age, sex, height, weight, ΔIC, EFL and FEV1 were analyzed by multivariate linear regression analysis. Results: Ti/Ttot was constant throughout the exercise test with a coefficient of variation less than 5% for each subject. Mean Ti/Ttot was 0.40 (SD=0.04). In multivariate regression analysis, Ti/Ttot was related to ΔIC (Standardized Beta (SB) -0.35, p=0.009), FEV1 (SB 0.54, p=0.004) and EFL at rest (SB -0.29, p=0.04), but not to EFL at peak exercise. Conclusion: Ti/Ttot was lower with increasing airway obstruction, DH and resting EFL, which could be an adaptive phenomenon allowing more time for expiration.

RationaleData on the change in diffusion capacity of the lung for carbon monoxide (DLCO) over time are limited. We aimed to examine change in DLCO (ΔDLCO) over a 9-year period and its predictors.MethodsA Norwegian community sample comprising 1,152 subjects aged 18–73 years was examined in 1987 and 1988. Of the 1,109 subjects still alive, 830 (75%) were re-examined in 1996/97. DLCO was measured with the single breath-holding technique. Covariables recorded at baseline included sex, age, height, weight, smoking status, pack years, occupational exposure, educational level, and spirometry. Generalized estimating equations analyses were performed to examine relations between ΔDLCO and the covariables.ResultsAt baseline, mean [standard deviation (SD)] DLCO was 10.8 (2.4) and 7.8 (1.6) mmol·min−1·kPa−1 in men and women, respectively. Mean (SD) ΔDLCO was −0.24 (1.31) mmol·min−1·kPa−1. ΔDLCO was negatively related to baseline age, DLCO, current smoking, and pack years, and positively related to forced expiratory volume in 1 second (FEV1) and weight. Sex, occupational exposure, and educational level were not related to ΔDLCO.ConclusionsIn a community sample, more rapid decline in DLCO during 9 years of observation time was related to higher age, baseline current smoking, more pack years, larger weight, and lower FEV1.

SummaryBackgroundFractional expired nitric oxide (FENO) is decreased after exercise. The effect of exercise in the cold upon FENO is unknown.PurposeTo examine changes in FENO after a short, high intensive exercise test in a cold and in a temperate environment.MethodsTwenty healthy well‐trained subjects (eight females) aged 18–28 years performed an 8‐min exercise test at 18°C (SD = 1.0) and −10°C (SD = 1.2) ambient temperature. The tests were performed in a climate chamber in random order. The workload corresponded to 90–95% of peak heart rate (HRpeak) during the last 4 min. FENO was measured offline. Exhaled gas was sampled in Mylar® bags using a collector kit with a flow restrictor and analysed within 2 h. FENO was measured before exercise and repeatedly during the first hour after. ANOVA for repeated measures was used to compare differences in FENO after exercise between environments.ResultsThere was no difference in baseline FENO. A significant difference in FENO between environments was found after warm‐up and from 20 to 30 min after exercise, with FENO being lower after exercise in the cold (P<0.05). The maximal reduction in FENO was seen 5 min after exercise and was not different between environments.ConclusionRecovery of FENO was slower after exercising in −10°C compared with 18°C.

Background: Decreased diffusing capacity of the lung for carbon monoxide (DLCO) is associated with emphysema. DLCO is also related to decreased arterial oxygen tension (PaO2), but there are limited data on associations between PaO2 and computed tomography (CT) derived measures of emphysema and airway wall thickness.Objective: To examine whether CT measures of emphysema and airway wall thickness are associated with level of arterial oxygen tension beyond that provided by measurements of diffusion capacity and spirometry.Methods: The study sample consisted of 271 smoking or ex-smoking COPD patients from the Bergen COPD Cohort Study examined in 2007-2008. Emphysema was assessed as percent of low-attenuation areas < -950 Hounsfield units (%LAA), and airway wall thickness as standardised measure at an internal perimeter of 10 mm (AWT-Pi10). Multiple linear regression models were fitted with PaO2 as the outcome variable, and % LAA, AWT-Pi10, DLCO and carbon monoxide transfer coefficient (KCO) as main explanatory variables. The models were adjusted for sex, age, smoking status, and haemoglobin concentration, as well as forced expiratory volume in one second (FEV1).Results: Sixty two per cent of the subjects were men, mean (SD) age was 64 (7) years, mean (SD) FEV1 in percent predicted was 50 (15)%, and mean PaO2 (SD) was 9.3 (1.1) kPa. The adjusted regression coefficient (CI) for PaO2 was -0.32 (-0.04-(-0.019)) per 10% increase in % LAA (p<0.01). When diffusion capacity and FEV1 were added to the model, respectively, the association lost its statistical significance. No relationship between airway wall thickness and PaO2 was found.Conclusion: CT assessment of airway wall thickness is not associated with arterial oxygen tension in COPD patients. Emphysema score measured by chest CT, is related to decreased PaO2, but cannot replace measurements of diffusion capacity in the clinical evaluation of hypoxaemia.

Activities of daily living in patients with chronic obstructive pulmonary disease (COPD) are limited by exertional dyspnea and reduced exercise capacity. The aims of the study were to examine longitudinal changes in peak oxygen uptake (V̇O2peak), peak minute ventilation (V̇Epeak) and breathing pattern over four years in a group of COPD patients, and to examine potential explanatory variables of change.

The aim of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on microvascular tissue and cell proliferation in the oral mucosa. Twenty patients, aged 51-78 years, were allocated randomly to a treatment or a control group. All had a history of radiotherapy (50-70 Gy) to the orofacial region 2-6 years previously. Tissue samples were taken from the irradiated buccal oral mucosa before HBOT and at 6 months after treatment. In the control group, tissue samples were taken on two occasions, 6 months apart. The samples were subjected to immunohistochemistry staining: double staining with CD31 and D2-40 for microvessels, or Ki-67 for the analysis of cell proliferation. Blood vessel density and area were significantly increased after HBOT (P = 0.002-0.041). D2-40-positive lymphatic vessels were significantly increased in number and area in the sub-epithelial area (P = 0.002 and P = 0.019, respectively). No significant differences were observed in the control group. There were no significant differences in Ki-67-expressing epithelial cells between the two groups. It is concluded that the density and area of blood and lymphatic vessels in the irradiated mucosa are increased by HBOT 6 months after therapy. Epithelial cell proliferation is not affected by HBOT.

Purpose To examine ocular lens parameters and structural changes to elucidate mechanisms underlying the myopic shift and cataract-related changes that occur in some patients during hyperbaric oxygen (HBO) therapy. Methods Scheimpflug images (Nidek EAS-1000) of the crystalline lens, measurements of scattered light, objective refraction, keratometry, tonometry, and axial length of the eye were obtained after the first day of HBO therapy and repeated when patients had completed 19 days of the treatment. Results Significant reduction in mean (±SD) optical density was found in the lens nucleus, −2.8 (±4.3) units (p = 0.009) and −2.2 (±4.1) units (p = 0.027) within circular and oval areas, respectively. Significant decrease in mean (±SD) backward scattered light was measured, −0.4 (±0.8) units (p = 0.022). Mean (±SD) myopic shift was −0.58 (±0.39) diopters (p < 0.001), whereas cortical optical density, forward scattered light, lenticular parameters, keratometry, tonometry, anterior chamber depth, and axial length of the eye appeared unchanged. Conclusions Transient myopic shift reported in patients during HBO therapy is attributed to changes in the refractive index of the lens. No changes in lens curvatures or thickness were found after treatment.

SummaryBackgroundNitric oxide (NO) concentration in exhaled gas is a marker of some inflammatory processes in the lung, and endogenous NO plays a role in the physiological responses to exercise and altitude. The aim of this study was to compare changes in exhaled NO concentration 5–60 mins after high‐intensity exercise at 2800 m and at 180 m altitude.MethodsTwenty trained healthy volunteers (12 men), aged 19–28 years, were included in this open, crossover study. Subjects performed two exercise tests at different altitudes, 2800 m and 180 m, in a randomized order. The fraction of NO in exhaled gas (FENO) was measured 5 mins before and 5–60 mins after 8 mins of running on a treadmill at a heart rate (HR) of 90% of peak HR. Peak HR was assessed during a pretest at 180 m. Ambient temperature was 20·1°C (SD = 1·2) and relative humidity 40·2% (SD = 3·2). FENO measurements were corrected for altitude gas density effects and converted to partial pressure of NO (PENOcorr).ResultsPENOcorr was reduced from 1·47 (1·21, 1·73) millipascal (mPa) at baseline to 1·11 (0·87, 1·34) mPa 5 mins after exercise at 2800 m and from 1·54 (1·24, 1·84) to 1·04 (0·87, 1·22) mPa 5 mins after exercise at 180 m. There was no difference in PENOcorr between exercise at 2800 m and 180 m, and PENOcorr was normalized within 20 mins.ConclusionsExercise at 2800 m induces a similar acute reduction in exhaled nitric oxide concentration as compared with 180 m in healthy subjects.

The aim of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on vascular function and tissue oxygenation in irradiated facial skin and gingival mucosa. Twenty-two patients, aged 51-90 years, were randomly allocated to a treatment or control group. All had a history of radiotherapy (50 70 Gy) to the orofacial region 2-20 years previously. Skin and mucosal perfusion were recorded with laser Doppler flowmetry (LDF). Tissue oxygenation was recorded by transcutaneous oximetry (TcPO2). Measurements were taken before HBOT and 3 and 6 months after a mean of 28 HBOT sessions (partial pressure of oxygen of 240 kPa for 90 min). For control subjects, measurements were taken on two occasions 6 months apart. After HBOT, blood flow in mucosa and skin after heat provocation increased significantly (P < 0.05). TcPO2 increased significantly in the irradiated cheek (P < 0.05), but not at reference points outside the field of radiation. There were no differences between the 3- and 6-month follow-ups. In the control group, no significant changes in LDF or TcPO2 were observed. It is concluded that oxygenation and vascular capacity in irradiated facial skin and gingival mucosa are increased by HBOT. The effects persist for at least 6 months.