Altered collagen I and premature pulmonary embryonic differentiation in patients with OI type II.

Pulmonary hypoplasia and respiratory failure are primary causes of death in patients with osteogenesis imperfecta (OI) type II. OI is a genetic skeletal disorder caused by pathogenic variants in genes encoding collagen type I. It is still unknown if the collagen defect also affects lung development and structure, causing lung hypoplasia in OI type II. The aim of this study was to investigate the intrinsic characteristics of OI embryonic lung parenchyma and to determine whether altered collagen type I may compromise airway development and lung structure. Lung tissue from nine fetuses with OI type II and six control fetuses, matched by gestational age, was analyzed for TTF-1 and collagen type I expression by immunohistochemistry, to evaluate the state of lung development and amount of collagen. The differentiation of epithelium into type 2 pneumocytes during embryonic development was premature in OI type II fetuses compared to controls (p < 0.05). Collagen type I showed no significant differences between the two groups. However, the amount of alpha2(I) chains was higher in fetuses with OI and the ratio of alpha1(I) to alpha2(I) lower in OI compared to controls. Cell differentiation during lung embryonic development in patients with OI type II is premature and impaired. This may be the underlying cause of pulmonary hypoplasia. Altered cell differentiation can be secondary to mechanical chest factors or a consequence of disrupted type I collagen synthesis. Our findings suggest that collagen type I is a biochemical regulator of pulmonary cell differentiation, influencing lung development.

Quantifying the reduction of respiratory motion by mechanical ventilation with MRI for radiotherapy.

BACKGROUND: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions. METHODS: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds. RESULTS: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity. CONCLUSIONS: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible. TRIAL REGISTRATION: Medical Ethics Committee protocol NL.64693.018.18.

Pathophysiology of respiratory failure in patients with osteogenesis imperfecta: a systematic review.

INTRODUCTION: Respiratory failure is a major cause of death in patients with Osteogenesis Imperfecta. Moreover, respiratory symptoms seem to have a dramatic impact on their quality of life. It has long been thought that lung function disorders in OI are mainly due to changes in the thoracic wall, caused by bone deformities. However, recent studies indicate that alterations in the lung itself can also undermine respiratory health. OBJECTIVES: Is there any intrapulmonary alteration in Osteogenesis Imperfecta that can explain decreased pulmonary function? The aim of this systematic literature review is to investigate to what extent intrapulmonary or extrapulmonary thoracic changes contribute to respiratory dysfunction in Osteogenesis Imperfecta. METHODS: A literature search (in PubMed, Embase, Web of Science, and Cochrane), which included articles from inception to December 2020, was performed in accordance with the PRISMA guidelines. RESULTS: Pulmonary function disorders have been described in many studies as secondary to scoliosis or to thoracic skeletal deformities. The findings of this systematic review suggest that reduced pulmonary function can also be caused by a primary pulmonary problem due to intrinsic collagen alterations. CONCLUSIONS: Based on the most recent studies, the review indicates that pulmonary defects may be a consequence of abnormal collagen type I distorting the intrapulmonary structure of the lung. Lung function deteriorates further when intrapulmonary defects are combined with severe thoracic abnormalities. This systematic review reveals novel findings of the underlying pathological mechanism which have clinical and diagnostic implications for the assessment and treatment of pulmonary function disorders in Osteogenesis Imperfecta.KEY MESSAGESDecreased pulmonary function in Osteogenesis Imperfecta can be attributed to primary pulmonary defects due to intrapulmonary collagen alterations and not solely to secondary problems arising from thoracic skeletal dysplasia.Type I collagen defects play a crucial role in the development of the lung parenchyma and defects, therefore, affect pulmonary function. More awareness is needed among physicians about pulmonary complications in Osteogenesis Imperfecta to develop novel concepts on clinical and diagnostic assessment of pulmonary functional disorders.

[Can we not do without oxygen administration through a nasal cannula?] / Kan dat neusbrilletje met zuurstof niet af?

Nasal cannulae for oxygen administration are applied abundantly in clinical medicine, even though their use may cause patient discomfort. Although nasal cannulae may be effective in increasing oxygen uptake to some degree, they are unlikely to prevent severe hypoxaemia. Furthermore, they are often used when arterial oxygen saturation is already ≥ 90%, in which case additional oxygenation is usually not required, nor does it relieve the sensation of dyspnoea.

[High nasal flow, the solution for hypoxaemia?] / 'Hoge nasale flow', de oplossing voor zuurstofgebrek?

High nasal flow (HNF) is a new method to deliver a high flow of oxygen (up to 60 l/min) through a nasal cannula. The inspiratory oxygen fraction can be set in a range from 21 to 100%. The inspired air is adjusted to body temperature and saturation. Many patients find it more comfortable than a conventional oxygen mask. In spite of these advantages, the mechanism of action is not completely understood and empirical evidence for its use is limited. This article provides a simplified explanation of variable positive airway pressure generation by HNF and related flushing of the anatomic dead space. Based on a short discussion of recent studies, it is concluded that HNF is a promising technique but that questions remain about the indications for use in clinical practice.

[Pulmonary infection caused by non-tuberculous mycobacteria in two patients with bronchiectasis]. / Infectie met niet-tuberculeuze mycobacteriën bij 2 patiënten met bronchiëctasieën.

Two patients, a woman aged 67 years and a man aged 80 years, had chronic cough among other respiratory symptoms. In the woman, chest radiograph and CT-scan revealed partial atelectasis of the middle lobe and bronchiectasis. In the man, an interstitial pattern was seen on chest radiograph, and CT scan showed diffuse bronchiectasis. In both the man and the woman, non-tuberculous mycobacteria were identified (Mycobacterium avium complex and Mycobacterium abscessus, respectively). Treatment was successful in both patients. Non-tuberculous mycobacteria can cause considerable pulmonary infection in patients with bronchiectasis.

Cardiovascular response to physical exercise in adult patients after atrial correction for transposition of the great arteries assessed with magnetic resonance imaging.

OBJECTIVE: To assess with magnetic resonance imaging (MRI) cardiovascular function in response to exercise in patients after atrial correction of transposition of the great arteries (TGA). METHODS: Cardiac function at rest and during submaximal exercise was assessed with MRI in 27 patients with TGA (mean (SD) age 26 (5) years) late (23 (2) years) after atrial correction and in 14 control participants (25 (5) years old). RESULTS: At rest, only right ventricular ejection fraction was significantly lower in patients than in controls (56 (7)% v 65 (7)%, p < 0.05). In response to exercise, increases in right ventricular end diastolic (155 (55) ml to 163 (57) ml, p < 0.05) and right ventricular end systolic volumes (70 (34) ml to 75 (36) ml, p < 0.05) were observed in patients. Furthermore, right and left ventricular stroke volumes and ejection fraction did not increase significantly in patients. Changes in right ventricular ejection fraction with exercise correlated with diminished exercise capacity (r = 0.43, p < 0.05). CONCLUSIONS: In patients with atrially corrected TGA, MRI showed an abnormal response to exercise of both systemic right and left ventricles. Exercise MRI provides a tool for close monitoring of cardiovascular function in these patients, who are at risk for late death.

Prolonged cardiac recovery from exercise in asymptomatic adults late after atrial correction of transposition of the great arteries: evaluation with magnetic resonance flow mapping.

After atrial correction of transposition of the great arteries (TGA), dysfunction of the systemic right ventricle at rest and during exercise has been reported. Information on changes in systemic right ventricular function during recovery from exercise is lacking. This study evaluates cardiac recovery from supine exercise using magnetic resonance (MR) imaging in patients with asymptomatic TGA after atrial correction. Flow in the ascending aorta, representing stroke volume of the systemic ventricle, was assessed with MR flow mapping in 10 asymptomatic patients with atrially corrected TGA and in 12 controls at rest during exercise and an 8-minute recovery period. In response to exercise, the patients had a smaller increase in heart rate, stroke volume, and cardiac output than did controls. After exercise, no significant difference in halftime of heart rate recovery was observed (patients, 48 +/- 7 seconds; controls, 39 +/- 4 seconds [p >0.05]). In the patients, the time course of stroke volume recovery was significantly different (p <0.001). Stroke volume in the patients, as a percent difference from rest, remained significantly elevated, from 2.5 minutes (+16 +/- 5% vs +7 +/- 6%; p <0.05) to 8 minutes (+4 +/- 7% vs -3 +/- 5%; p <0.05) after exercise. Subsequently, cardiac output remained significantly elevated, from 4.5 minutes (+27 +/- 13% vs +15 +/- 11%; p <0.05) to 7 minutes (+22 +/- 11% vs +12 +/- 12%; p <0.05) after exercise. We conclude that heart rate recovery is within normal limits in patients with atrially corrected TGA. Furthermore, cardiac recovery from exercise, assessed with MR flow mapping, is prolonged in patients with asymptomatic TGA after atrial correction. Abnormal recovery may reflect dysfunction of the systemic right ventricle and an altered metabolic response to exercise.

Estimation of the VA/(Q+VTIS) distribution from single-breath alkane uptake.

In this paper, it was investigated if the ventilation-perfusion distribution can be estimated from the uptake (U) of inert gases with different solubilities during the single-breath maneuver. A model was implemented that describes U as a function of solubility for inhomogeneously distributed alveolar volume (VA) versus blood and tissue volume (Q + VTIS). The VA/(Q + VTIS) distribution describes the relative contribution of gas-exchange units with different VA/(Q + VTIS) ratios to the expiratory volume. U was derived as the sum of uptakes corresponding to different modes in the distribution, weighted with the relative contribution to the expiratory volume. This permits an estimation of the distribution parameters by fitting U as a function of solubility. The n alkanes were used because of their different solubilities. Analysis of the sensitivity of the estimated VA/(Q + VTIS) distribution parameters to measurement errors showed that mostly two modes can be discerned. The influence of fixed model parameters appeared relatively small. The model could well explain U in normal and emphysematous subjects, with a larger contribution of high VA/(Q + VTIS) ratios in the emphysematous subjects. It was concluded that the VA/(Q + VTIS) distribution can be estimated noninvasively from single-breath alkane uptake.

Role of nitric oxide in the airway response to exercise in healthy and asthmatic subjects.

A role of nitric oxide (NO) has been suggested in the airway response to exercise. However, it is unclear whether NO may act as a protective or a stimulatory factor. Therefore, we examined the role of NO in the airway response to exercise by using N-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor), L-arginine (the NO synthase substrate), or placebo as pretreatment to exercise challenge in 12 healthy nonsmoking, nonatopic subjects and 12 nonsmoking, atopic asthmatic patients in a double-blind, crossover study. Fifteen minutes after inhalation of L-NMMA (10 mg), L-arginine (375 mg), or placebo, standardized bicycle ergometry was performed for 6 min using dry air, while ventilation was kept constant. The forced expiratory volume in 1-s response was expressed as area under the time-response curve (AUC) over 30 min. In healthy subjects, there was no significant change in AUC between L-NMMA and placebo treatment [28.6 +/- 17.0 and 1.3 +/- 20.4 (SE) for placebo and L-NMMA, respectively, P = 0.2]. In the asthmatic group, L-NMMA and L-arginine induced significant changes in exhaled NO (P < 0.01) but had no significant effect on AUC compared with placebo (geometric mean +/- SE: -204.3 +/- 1.5, -186.9 +/- 1.4, and -318.1 +/- 1.2%. h for placebo, L-NMMA, and L-arginine, respectively, P > 0.2). However, there was a borderline significant difference in AUC between L-NMMA and L-arginine treatment (P = 0.052). We conclude that modulation of NO synthesis has no effect on the airway response to exercise in healthy subjects but that NO synthesis inhibition slightly attenuates exercise-induced bronchoconstriction compared with NO synthase substrate supplementation in asthma. These data suggest that the net effect of endogenous NO is not inhibitory during exercise-induced bronchoconstriction in asthma.

A chemoreflex model of relation between blood pressure and heart rate in sleep apnea syndrome.

In obstructive sleep apnea syndrome (OSAS), pronounced low-frequency (LF) oscillations of blood pressure and interbeat interval (I) occur during recurrent apneas. We investigated the time relations between LF oscillations of diastolic pressure (D) and I in 12 patients with OSAS by means of spectral analysis. A high coherency between I and D was found, allowing a description of the relation by gain and phase. Oscillations in I and D were almost in counterphase in the LF range. Simple physiological models were implemented to interpret the observed features of LF oscillations. Model 1 describes the vagal and sympathetic influence by the carotid body chemoreflex on the circulation. From derivation of the frequency response of this model, gain and phase relations were obtained as would be expected from the action of the chemoreflex. We found that a range of phase relations can be induced by this reflex, depending on the relative vagal and sympathetic efferent influence on the circulation. This range of phase relations was indeed observed in 10 patients. Extended models that also included the orienting reflex (model 1a) or the baroreflex and a mechanical influence of breathing on the circulation (model 2) could not fit the data without a major contribution of the chemoreflex. We conclude that the relation between LF oscillations in I and D in OSAS can be explained by assuming that stimulation of the carotid body chemoreflex is the main source of these oscillations.

Repetitive apneas induce periodic hypertension in normal subjects through hypoxia.

Periodic increases in blood pressure (BP) can occur in the sleep apnea syndrome (SAS) during recurrent apneas. To investigate the mechanisms causing this periodic hypertension, we simulated SAS by imposing a matching breathing pattern on seven healthy awake male volunteers. Continuous finger arterial BP, electrocardiogram, arterial O2 saturation (SaO2), end-tidal CO2, and tidal volume were measured. The role of hypoxia was studied by comparing apneas during depletion of O2 in the spirometer with those during 100% O2 breathing. In all subjects, BP periodically reached values greater than 150/95 mmHg in the hypoxic series. During the hyperoxic apnea series, however, BP remained stable. End-apneic mean BP was shown to be inversely correlated to SaO2 in six subjects in the SaO2 range from 60 to 100%. Although the hypoxic BP pattern closely mimicked that in SAS, the heart rate pattern in four of our subjects remained distinct from that in patients. Atropine could not prevent large BP swings in the hypoxic series. We conclude that SaO2 is a major determinant of periodic hypertension in recurrent apneas. Its effect probably results from chemoreflex modulation of peripheral resistance.

Respiratory variability and associated cardiovascular changes in adults at rest.

Breathing patterns and associated circulatory fluctuations may reflect the action of various regulatory mechanisms as well as mechanical influences of breathing on the circulation. Thus, the study of such patterns can enhance our knowledge of these mechanisms, both in normal and pathological conditions. In this review, literature is evaluated that provides insight into the breath-to-breath variation of respiration in quietly breathing adults. Also when respiration is seemingly random, deterministic patterns in the respiratory variability can often be discerned. The various methods used in the recognition of such patterns and their possible interpretation are discussed. Furthermore, the question is addressed how respiratory variability can affect the circulation and how this can be studied by analysing the time relationships of respiratory and circulatory parameters. This may add to both the understanding of normal cardiovascular regulation and to insight into cardiovascular disturbances under unstable respiratory conditions. As examples of such circumstances, some common conditions are discussed that are often, though not always, associated with pathology, viz. Cheyne-Stokes respiration, snoring and the sleep apnoea syndrome.