Bronchopulmonary dysplasia: clinical grading in relation to ventilation/perfusion mismatch measured by single photon emission computed tomography.

Bronchopulmonary dysplasia (BPD) is a significant cause of morbidity in the preterm population. Clinical severity grading based on the need for supplemental oxygen and/or need for positive airway pressure at 36 weeks postmenstrual age does not yield reproducible predictive values for later pulmonary morbidity. Single photon emission computed tomography (SPECT) was used to measure the distribution of lung ventilation (V) and perfusion (Q) in 30 BPD preterm infants at a median age of 37 weeks postmenstrual age. The V and Q were traced with 5 MBq Technegas and Technetium-labeled albumin macro aggregates, respectively, and the V/Q match-mismatch was used to quantify the extent of lung function impairment. The latter was then compared with the clinical severity grading at 36 weeks, and time spent on mechanical ventilation, continuous positive airway pressure (CPAP) and supplemental oxygen. Of those with mild and moderate BPD 3/9 and 3/11 patients, respectively, showed significant V/Q mismatches. By contrast, 4/10 patients with severe BPD showed a satisfactory V/Q matching distribution. An unsatisfactory V/Q match was not correlated with time spent on supplemental oxygen or CPAP, but was significantly negatively correlated with time spent on mechanical ventilation. SPECT provides unique additional information about regional lung function. The results suggest that the current clinical severity grading can be improved and/or complemented with SPECT.

Novel alterations in the epigenetic signature of MeCP2-targeted promoters in lymphocytes of Rett syndrome patients.

Rett syndrome (RTT) is a neurodevelopmental disorder with neurological symptoms, such as motor disorders and mental retardation. In most cases, RTT is caused by mutations in the DNA binding protein MeCP2. In mice, MeCP2 gene deletion has been reported to result in genome-wide increased histone acetylation. Transcriptional regulation of neurotrophic factor BDNF and transcription factor DLX5, essential for proper neurogenesis, is further altered in MeCP2-deleted animals. We therefore investigated the chromatin environment of MeCP2 target genes BDNF and DLX5 in lymphocytes from RTT patients and human controls, and analyzed the density of histones H3, H2B and H1, as well as the levels of methylation and acetylation on selected lysines of histone H3. Notably, we found a general increase in the density of histone H3 in RTT patients' lymphocytes compared with controls, and decreased levels of trimethylation of lysine 4 on histone H3 (H3K4me3), a modification associated with transcriptional activation. The levels of acetylation of lysine 9 (H3K9ac) and 27 (H3K27ac) did not show any statistically significant changes when normalized to the decreased histone H3 levels; nevertheless, an average decrease in acetylation was noted. Our results reveal an unexpected alteration of the chromatin state of established MeCP2 target genes in lymphocytes of human subjects with RTT.

Postoperative regional distribution of pulmonary ventilation and perfusion in infants with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Advances in management of patients with congenital diaphragmatic hernia (CDH) have improved mortality rates but with a risk of increased pulmonary morbidity. The prognosis for CDH survivors remains difficult to predict owing to the lack of adequate methods. We used single photon emission computed tomography (SPECT) to measure the regional distribution of ventilation and perfusion in CDH infants to quantify the degree of lung function impairment and relate it to neonatal clinical disease severity. METHODS: Single photon emission computed tomography was performed in 12 CDH infants at the mean age of six months. Ventilation and perfusion were traced with 5 MBq Technegas and technetium-labelled albumin macro-aggregates, respectively. Neonatal clinical data collected during the patient's stay in the pediatric intensive care unit was correlated with the SPECT data. RESULTS: Single photon emission computed tomography revealed varying degrees of ventilation-perfusion abnormalities which correlated with the presence of pulmonary artery hypertension, days on ventilator and days on extracorporeal membrane oxygenation. CONCLUSIONS: The grade of clinical disease severity in infants following CDH repair is closely related to the ventilation-perfusion abnormality as seen using SPECT. The persistence of pulmonary artery hypertension into the postoperative neonatal period appears to be an important pathophysiological factor related to ventilation-perfusion abnormalities. Single photon emission computed tomography provides valuable clinical information for patient follow-up.

No protective role for hypoxic pulmonary vasoconstriction in severe hypergravity-induced arterial hypoxemia.

Supine subjects exposed to hypergravity show a marked arterial desaturation. Previous work from our laboratory has also shown a paradoxical reduction of lung perfusion in dependent lung regions in supine subjects exposed to hypergravity. We reasoned that the increased lung weight during hypergravity caused either direct compression of the blood vessels in the dependent lung tissue or that poor regional ventilation caused reduced perfusion through hypoxic pulmonary vasoconstriction (HPV). The objective of this study was to evaluate the importance of HPV through measurements of arterial oxygenation during exposure to hypergravity with normal and attenuated HPV. A further increased arterial desaturation during hypergravity with attenuated HPV would support the hypothesis that HPV contributes to the paradoxical redistribution of regional perfusion. In a two-phased randomized study we first exposed 12 healthy subjects to 5 G while supine during two single-blinded conditions; control and after 50 mg sildenafil p.o.. In a second phase, 12 supine subjects were exposed to 5 G during three single-blinded conditions; control, after 100 mg sildenafil p.o. and after inhalation of 10 µg iloprost. There was a substantial arterial desaturation by 5-30% units in all subjects with no or only minor differences between conditions. The results speak against HPV as a principal mechanism for the hypergravity-induced reduction of lung perfusion in dependent lung regions in supine humans.

Regional lung blood flow and ventilation in upright humans studied with quantitative SPECT.

We used quantitative Single Photon Emission Computed Tomography (SPECT) to study the effect of the upright posture on regional lung blood flow and ventilation. Nine (upright) plus seven (prone and supine) healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked in sitting upright, supine and prone postures using (113m)In-labeled macroaggregates and inhaled Technegas ((99m)Tc); both remain fixed in the lung after administration. All images were obtained while supine. In comparison with horizontal postures, both blood flow and ventilation were greater in caudal regions when upright. The redistribution was greater for blood flow than for ventilation, resulting in decreasing ventilation-to-perfusion ratios down the lung when upright. We conclude that gravity redistributes regional blood flow and ventilation in the upright posture, while the influence is much less in the supine and prone postures.

Central command and metaboreflex cardiovascular responses to sustained handgrip during microgravity.

Four subjects were studied before and during a 16-day space flight. The test included 2min of rest, 2min of sustained handgrip (SHG), and 2min of post-exercise circulatory occlusion (PECO). Heart rate (HR) and mean arterial pressure (MAP) responses to central command and mechanoreceptor stimulation were determined from the difference between SHG and PECO. Responses to metaboreceptor stimulation were determined from the difference between PECO and rest. Late in-flight (days 12-14) the central command/mechanoreceptor component of the HR response was reduced by 5bpm (P=0.01) from its pre-flight value of 15 (+/-3)bpm (mean (+/-SEM)). At the same time the metaboreflex responses of HR and MAP were unchanged. The attenuated HR response to central command was likely of baroreflex origin. Together with a parallel study of PECO after dynamic leg exercise, our data indicate that central processing of metaboreflex inputs is unchanged in microgravity whereas metaboreflex inputs from weight-bearing muscles are enhanced.

A technique for lung ventilation-perfusion SPECT in neonates and infants.

BACKGROUND: Single photon emission tomography (SPECT) of the lung is a well-established non-invasive technique for quantitative assessment of regional lung ventilation and perfusion distribution in children and in adults. However, its application in neonates as well as infants has been scarce because of several practical limitations, such as the trade off between image quality and restricted effective radiation doses and the lack of suitable inhalations agents and administration techniques. METHODS: In this paper, a new technique for quantitative regional lung SPECT based on a passive Technegas administration procedure is described and clinically applied. The first clinical findings in neonates are reported. RESULTS: This technique overcomes some of the limitations of commercial ventilation systems by making patient compliance unnecessary, avoiding difficult breathing manoeuvres and by minimizing both facemask dead space and inspiratory-expiratory resistance. CONCLUSION: This technique satisfies requirements for routine applications in neonates, infants and even older patients and has a potential use also for mechanically ventilated patients. It has the potential to allow a more precise functionally oriented diagnosis, which is of importance for treatment and follow-up in patients with severe lung diseases.

Disturbances in cardiorespiratory function during day and night in Rett syndrome.

Rett syndrome causes severe autonomic dysregulation, probably due to brainstem dysfunction. Because the brainstem plays a decisive role in cardiorespiratory regulation during sleep, we investigated cardiorespiratory function in 12 girls with Rett syndrome, day and night, for 1 week in their home environment. Heart rate and breathing were recorded via standard three-lead electrocardiogram. Depth and frequency of respiratory movements were measured via changes in impedance. All children were scored clinically, and the association with cardiorespiratory function was examined. The total recording time for all patients was 1114 hours (535 during wakefulness; 579 during sleep), and 77 +/- 22 hours (median +/- standard error of the mean) per individual. All subjects manifested apnea, shallow breathing, or hypoventilation, when awake and during sleep. A majority had bradycardia or tachycardia. The frequencies of respiratory and heart alarms were similar during wakefulness and sleep. Bradycardia events predominated during sleep. The only significant correlation between clinical score and cardiorespiratory regulation was found for muscular-skeletal function and breathing abnormalities during wakefulness. We conclude that Rett syndrome is characterized by disturbed breathing and heart rate during sleep. The severity of cardiorespiratory dysfunction exhibited marked intra- and interindividual differences.

Posture primarily affects lung tissue distribution with minor effect on blood flow and ventilation.

We used quantitative single photon emission computed tomography to estimate the proportion of the observed redistribution of blood flow and ventilation that is due to lung tissue shift with a change in posture. Seven healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked using radiotracers that remain fixed in the lung after administration. The radiotracers were administered in prone or supine at separate occasions, at both occasions followed by imaging in both postures. Images showed greater blood flow and ventilation to regions dependent at the time of imaging, regardless of posture at radiotracer administration. The results suggest that a shift in lung parenchyma has a major influence on the imaged distributions. We conclude that a change from the supine to the prone posture primarily causes a change in the vertical distribution of lung tissue. The effect on the vertical distribution of blood flow and ventilation within the lung parenchyma is much less.

Paradoxical redistribution of pulmonary blood flow in prone and supine humans exposed to hypergravity.

We hypothesized that exposure to hypergravity in the supine and prone postures causes a redistribution of pulmonary blood flow to dependent lung regions. Four normal subjects were exposed to hypergravity by use of a human centrifuge. Regional lung perfusion was estimated by single-photon-emission computed tomography (SPECT) after administration of (99m)Tc-labeled albumin macroaggregates during normal and three times normal gravity conditions in the supine and prone postures. All images were obtained during normal gravity. Exposure to hypergravity caused a redistribution of blood flow from dependent to nondependent lung regions in all subjects in both postures. We speculate that this unexpected and paradoxical redistribution is a consequence of airway closure in dependent lung regions causing alveolar hypoxia and hypoxic vasoconstriction. Alternatively, increased vascular resistance in dependent lung regions is caused by distortion of lung parenchyma. The redistribution of blood flow is likely to attenuate rather than contribute to the arterial desaturation caused by hypergravity.

Effects of hypergravity on the distributions of lung ventilation and perfusion in sitting humans assessed with a simple two-step maneuver.

Increased gravity impairs pulmonary distributions of ventilation and perfusion. We sought to develop a method for rapid, simultaneous, and noninvasive assessments of ventilation and perfusion distributions during a short-duration hypergravity exposure. Nine sitting subjects were exposed to one, two, and three times normal gravity (1, 2, and 3 G) in the head-to-feet direction and performed a rebreathing and a single-breath washout maneuver with a gas mixture containing C(2)H(2), O(2), and Ar. Expirograms were analyzed for cardiogenic oscillations (COS) and for phase IV amplitude to analyze inhomogeneities in ventilation (Ar) and perfusion [CO(2)-to-Ar ratio (CO(2)/Ar)] distribution, respectively. COS were normalized for changes in stroke volume. COS for Ar increased from 1-G control to 128 +/- 6% (mean +/- SE) at 2 G (P = 0.02 for 1 vs. 2 G) and 165 +/- 13% at 3 G (P = 0.002 for 2 vs. 3 G). Corresponding values for CO(2)/Ar were 135 +/- 12% (P = 0.04) and 146 +/- 13%. Phase IV amplitude for Ar increased to 193 +/- 39% (P = 0.008) at 2 G and 229 +/- 51% at 3 G compared with 1 G. Corresponding values for CO(2)/Ar were 188 +/- 29% (P = 0.02) and 219 +/- 18%. We conclude that not only large-scale ventilation and perfusion inhomogeneities, as reflected by phase IV amplitude, but also smaller-scale inhomogeneities, as reflected by the ratio of COS to stroke volume, increase with hypergravity. Except for small-scale ventilation distribution, most of the impairments observed at 3 G had been attained at 2 G. For some of the parameters and gravity levels, previous comparable data support the present simplified method.

Physiological evaluation of a new quantitative SPECT method measuring regional ventilation and perfusion.

We have developed a new quantitative single-photon-emission computed tomography (SPECT) method that uses (113m)In-labeled albumin macroaggregates and Technegas ((99m)Tc) to estimate the distributions of regional ventilation and perfusion for the whole lung. The multiple inert-gas elimination technique (MIGET) and whole lung respiratory gas exchange were used as physiological evaluations of the SPECT method. Regional ventilation and perfusion were estimated by SPECT in nine healthy volunteers during awake, spontaneous breathing. Radiotracers were administered with subjects sitting upright, and SPECT images were acquired with subjects supine. Whole lung gas exchange of MIGET gases and arterial Po(2) and Pco(2) gases was predicted from estimates of regional ventilation and perfusion. We found a good agreement between measured and SPECT-predicted exchange of MIGET and respiratory gases. Correlations (r(2)) between SPECT-predicted and measured inert-gas excretions and retentions were 0.99. The method offers a new tool for measuring regional ventilation and perfusion in humans.

Differential changes of lung diffusing capacity and tissue volume in hypergravity.

In normal gravity, lung diffusing capacity (DL(CO)) and lung tissue volume (LTV; including pulmonary capillary blood volume) change in concert, for example, during shifts between upright and supine. Accordingly, DL(CO) and LTV might be expected to decrease together in sitting subjects in hypergravity due to peripheral pooling of blood and reduced central blood volume. Nine sitting subjects in a human centrifuge were exposed to one, two, and three times increased gravity in the head-to-feet direction (G(z+)) and rebreathed a gas containing trace amounts of acetylene and carbon monoxide. DL(CO) was 25.2 +/- 2.6, 20.0 +/- 2.1, and 16.7 +/- 1.7 ml. min(-1). mbar(-1) (means +/- SE) at 1, 2, and 3 G(z+), respectively (ANOVA P < 0.001). Corresponding values for LTV increased from 541 +/- 34 to 677 +/- 43, and 756 +/- 71 ml (P < 0.001) at 2 and 3 G(z+). Results are compatible with sequestration of blood in the dependent part of the pulmonary circulation just as in the systemic counterpart. DL(CO,) which under normoxic conditions is mainly determined by its membrane component, decreased despite an increased pulmonary capillary blood volume, most likely as a consequence of a less homogenous distribution of alveolar volume with respect to pulmonary capillary blood volume.