Academic literature on the topic 'Lung function'

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.

The evidence of a genetic contribution to lung function measures, both baseline and in response to bronchodilator has been well established. Candidate gene studies have identified more than 100 genes suggested to contribute to variability in lung function. Apart from alpha 1 antitrypsin (AA T) gene; which is the most documented genetic risk factor for COPD, the findings were not consistent and replication of findings was limited. Similarly, most P2-adrenergic receptor agonist pharmacogenetic studies focused on the ADRB2 gene, yet with conflicting reports. Unravelling genetic determinants of lung function measures will help us better understand the normal functioning of the airways, the pathophysiology of respiratory diseases and help develop novel therapies. Work presented in this thesis describes a series of studies undertaken to examine the contribution of common single nucleotide polymorphisms (SNPs) to variability in lung function. Through contributing to large scale meta-analysis of genome-wide association studies (GWASs) in the SpiroMeta consortium (discovery n= 20,288 and replication n=54,276), we were able to identify five novel loci influencing forced expiratory volume in one second (FEV I) or its ratio to forced vital capacity (FEVIIFVC): GSTCD-INTS12(4q24), HTR4 (5q31-q33), AGER(6p21.3), TNS1 (2q35-q36), and THSD4 (15q23). I also showed their corresponding mRNAs to be expressed in airway related cell types. These loci point to novel pathways regulating lung function; potentially through lung development and tissue remodelling pathways, and were at large independent from smoking behaviour. Molecular characterisation of GSTCD-INTSl2identified novel transcripts in the lung, and putative promoter regions were mapped. Interestingly, a degree of correlation of expression was found for GSTCD- INTS 12 mRNAs in multiple airway cell types, suggesting shared regulatory mechanisms. Given the absence of any overlap between previously reported candidate genes for lung function and SpiroMeta GW AS loci, an evaluation of candidate genes was undertaken in theunique SpiroMeta sample (n=20,288) which did not support a role for the majority of the candidate genes tested. A potential role for AAT among smokers and PDE4D in the general population was however, suggested. The GW AS of response to salbutamol in severe asthma subjects has identified a number of novel loci; particularly the association of DLClon chromosome 8.This novel pathway association (GTPase activating protein! GTP-GDP/ Rho A) offers the potential to develop new therapies and to design personalised medicine approaches to help individuals with asthma. Future work will involve refining the association regions through population based re-sequencing approaches followed by detailed functional characterisation of associated genes to delineate the mechanisms underlying their associations with lung function.

Dissertation (PhD)--University of Stellenbosch, 2003.
ENGLISH ABSTRACT: Background to the study OLA can give rise to certain problems: 1. A significant decrease in lung volume is reported to occur in the dependent lung during OLA in the LDP. This decrease in lung volume can result in an acute increase in opposition to RV ejection. The potential problem is that the right ventricle is a thin walled structure that can generate considerably less work than the thicker walled LV. It possesses little reserve to deal with an acute rise in afterload as may occur during acute lung injury or after lung resection. Therefore, this increase in afterload during OLA may potentially impair RV-PA coupling. Albeit this potential problem exists, the changes in RV afterload and how the right ventricle performs during OLA have not been well studied. 2. Arterial hypoxemia, due mainly to venous blood being shunted via the non-ventilated lung, may present a clinical problem during one lung ventilation. a. The relative resistances of the pulmonary vascular beds of the dependent ventilated and nondependent non-ventilated lungs are an important factor governing shunting and thus arterial oxygenation during one lung anesthesia. A high non-ventilated lung PVR and low ventilated lung PVR will facilitate good arterial oxygenation during OLA. An increase in non-ventilated lung PVR is governed predominantly by hypoxic pulmonary vasoconstriction. A low opposition to pulmonary blood flow in the dependent lung is facilitated predominantly by a high alveolar oxygen tension and normal lung volume, albeit other factors also play a role in this regard. b. The saturation and oxygen content of mixed venous blood will contribute significantly to the arterial oxygenation in the presence of a large shunt as occurs during OLA. i. On the one hand, venous desaturation as a cause of hypoxemia during one lung anesthesia has not as yet been systematically addressed in the literature. ii. On the other hand, if RV afterload increases to such a degree that it leads poor RV performance, this may cause impairment of global circulatory efficiency and lead to mixed venous desaturation. The question that has been raised is whether inotrope infusions could improve RV and LV performance, cardiac output, and thereby the efficiency of the circulation. Increases in the efficiency of the circulation will result in an improvement in mixed venous and arterial oxygenation in the presence of a large shunt. Nonetheless, the administration of inotrope infusions in the presence of a shunt and during OLA has been reported to aggravate hypoxemia. Thus at the time of conducting the study, conflicting reports of whether increasing cardiac output and thereby mixed venous oxygenation would increase or decrease arterial oxygenation during OLA In the light of the above, the researcher thus investigated RV afterload, RV performance and coupling to its load during OLA. The study also addressed the question whether different levels of inotrope infusion or PEEP hadbeneficial or deleterious effects on RV afterload, RV performance and coupling to its load during OLA. Furthermore, if cardiac output increased during OLA secondary to the infusion of inotropes, would this improve the efficiency of the circulation, mixed venous oxygenation and thus the arterial oxygenation during OLA, or would it worsen shunt and arterial oxygenation during OLA? Control group: OLA and the opposition to pulmonary flow Pulmonary arterial elastance increased by between 18 to 36% during OLA and mean PAP rose by 32% after initiation of OLA This increase in mean PAP on initiation of OLA is greater than that observed by certain investigators but similar to that seen previously in patients with damaged lungs. The question arose as to why pulmonary artery pressure rises during OLA? From consideration of Ohm’s law, pressure may be regarded as the product of flow and resistance (Mark, Slaughter et al. 2000). The increase in mean PAP during OLA is due to two reasons. 1. Firstly, the pressure versus flow curve is likely to be steeper during OLA. This is because pulmonary vascular recruitment and dilatation (pulmonary vascular reserve) is more limited in scope in these patients than is usual and most likely accounts for the increase in pulmonary artery pressure during OLA. The reasons for the limited pulmonary vascular reserve in the DL during OLA include: a. The pulmonary vascular bed of patients subjected to OLA is frequently abnormal because of its underlying pathology, b. During OLA in the lateral decubitus position, lung volume decreases to a greater degree than during two-lung anesthesia (Klingstedt, Hedenstierna et al. 1990). c. This decrease in lung volume will be further aggravated by DLT malpositions, secretions and blood, and absorption atelectasis due to the use of high concentrations of oxygen (Hedenstierna 1998; Krucylak, Naunheim et al. 1996). d. Excessive amounts of extrinsic or intrinsic PEEP during OLA can compress the intra-alveolar capillaries and deleteriously affect the pulmonary vascular resistance (Ducros, Moutafis et al. 1999; Inomata, Nishikawa et al. 1997; Bardoczky, Yernault et al. 1996; Yokota, Toriumi et al. 1996). 2. Secondly, there is greater flow through this vascular bed that possesses a higher resistance. It is noteworthy that the increase in mean PAP did not exceed a value of 25 mm Hg during OLA, even though cardiac output increased by 30%. However, in studies conducted in patients with “damaged lungs”, greater increases in PA pressure (accompanied by a decrease in RVEF) have been reported to occur on PA ligation. A question arises as to why differences exist between PA clamping and OLA? The answer may well be that the observed plateau in the rise of PA pressure during OLA is as a result of progressive diversion of flow to the NDL as PA pressure rises. Support for such a suggestion comes from the observation that concomitant with increases in PA pressure during OLA, HPV is progressively inhibited and shunt fraction progressively rises. This increase in shunt fraction that has been observed to occur as PA pressure rises, reflects an increase in diversion of pulmonary blood flow to the NDL. The impact of diversion of this blood to the NDL is that it possibly acts as a safety mechanism limiting increases in PA pressure and other indices of opposition to pulmonary flow during OLA. This “blow-off effect” will protect the RV until PA clamping occurs.Control group: OLA and RV function The current study represented the opportunity to investigate the significance of the abovementioned increases in PA pressures and elastance on RV performance during OLA. The current study indicates that at the moderate (30%) increases in PAP that accompanied the initiation of OLA, RV performance, as judged by stroke volume, cardiac index, RVEF and RVSWI, did not deteriorate compared to the baseline awake status. In fact, cardiac output increased following surgical incision: this was probably due to sympathetic nervous system stimulation. This observation also fits in with other studies in which RV performance usually only begins to deteriorate when indices of opposition to RV ejection reach 200 to 250% of baseline. Furthermore, a constant preload, as indicated by unchanged central venous and pulmonary artery wedge pressures, and right ventricular end-diastolic volumes were observed throughout the study period. In other words, this increase in RV afyterlad did not cuse the RV to dilate durign OLA. The relationship between stroke work and afterload will vary, depending on the contractile reserve of the ventricle. In this regard, it could be concluded that under the conditions operative in the current study, the RV was operating on the upslope of the RVSWI versus Ea relationship. This supports the observation that RV function is well preserved during OLA. In conclusion, regarding the indices of opposition to pulmonary flow and RV performance during OLA, it can be concluded that: 1. Opposition to RV ejection increases. This is evidenced by a 30% rise in mean PAP and 18 to 36% increase in pulmonary arterial elastance. 2. Right ventricular performance as indicated by RVSWI, RVEF and stroke volume does not decrease during OLA compared with when the patients awake or subjected to two-lung anesthesia. 3. Furthermore, coupling between the RV and its load is well preserved during OLA. This would imply that the RV operates at close to maximal efficiency during OLA and that RV stroke work reserve is present during OLA. It is likely that the RV, which continues operating as a flow pump as it does in normal life, easily copes with the small increases in RV afterload during OLA. Dobutamine during OLA: opposition to pulmonary flow and RV performance The effects of dobutamine infusions on RV performance during OLA can be summarised as follows: 1. Low rates of dobutamine infusion (3 ug.kg-1.min-1) increased cardiac output, stroke volume, and RVSWI. The administration of dobutamine 3 ug.kg-1.min-1 was not accompanied by increases in RV afterload. Therefore, low infusion rates of dobutamine did benefit RV-PA coupling during OLA. 2. However, administration of higher dosages of dobutamine (5 and 7 ug.kg-1.min-1) during OLA was associated with increases in certain indices of opposition to pulmonary blood flow. For example, PA elastance, mean PA pressure, and PVR increased by 30% to 40% compared to both when the patients were awake and when both lungs were being ventilated. Furthermore, PA compliance decreased by up to 61% when dobutamine 5 and 7 ug.kg-1.min-1 were infused compared to the OLA step when dobutaminewas not administered. The increases in mean PAP and PVR are considered to be of limited clinical significance. However, the decrease in PA compliance during the infusion of the highest dosage of dobutamine is clinically significant. PA compliance represents one of the factors determining vascular impedance in the Windkessel model of the circulation. The increases in opposition to pulmonary flow and lack of progressive increase in indices of RV performance are in contrast to what is expected to occur on administration of increasing dosages of the inotrope and pulmonary vasodilator, dobutamine. The reasons for the increase in opposition to pulmonary flow include exhaustion of the pulmonary vascular reserve during OLA at the high cardiac indices of 5 to 5.5 l.min-1.m-2. This aspect overshadowed the expected pulmonary vasodilator effects of dobutamine. Moreover, it is probable that the increase in RV afterload was significant enough to prevent right ventricular performance increasing as would be expected with the administration of progressively higher dosages of inotrope. While dobutamine was being administered during OLA, mean PAP increased to a maximum of 24.9 ± 6.2 mm Hg at a cardiac index of 5.5 ± 1.2 l.min-1.m-2. However during OLA, in the control group, mean PAP was 24.0 ± 7.7 mm Hg at the maximum cardiac index of 4.4 ± 1.1 l.min-1.m-2. This represented a relatively limited rise in PA pressure compared with administration of dobutamine alone. The most likely reason why there may have been a limited increase in mean PAP while dobutamine was being administered is that the “blow off” effect of the NDL vasculature limited the rise in PA pressure. Oxygenation during OLA With regard to oxygen flux, venous and arterial oxygenation during OLA in the control group, the following was observed: 1. Induction of anesthesia and the approximately 1O Celsius decrease in temperature induced an approximately 40% decrease in VO2 that continued during OLA. 2. Initiation of OLA resulted in an increase in cardiac output compared to baseline OLA and awake states. 3. The consequence was an increase in S􀀀��������O2 from 75% and P􀀀��������O2 from 5.4 kPa when the patients were awake to a P􀀀��������O2 of 9.0 ± 1.7 kPa and S􀀀��������O2 of 90.6 ± 4.7% during one-lung anesthesia. 4. During OLA, the significant increase in venous oxygenation resulted in an increase in arterial oxygenation compared to the awake state in spite of the approximately 37% shunt occuring during OLA. 5. Under conditions in the present study, dobutamine administration during OLA did not improve, but maintained the already high venous and arterial oxygenation compared with OLA alone. Therefore, the study hypothesis, that dobutamine would induce improvement in RVF and the increase in cardiac output during OLA would improve arterial oxygenation, does not hold in the current study. The hypothesis that dobutamine administration and improving cardiac output during OLA would increase arterial oxygenation was therefore rejected. However, the rejection of the hypothesis means that the findings of the current study are in contrast to the findings of Mathru et al, and Nomoto and Kawamura. These authors demonstrated that inotrope administration resulted in an increase in arterial oxygenation. Nonetheless, the different results are not at odds with each other. In fact, these differences help to clarify the effect of increases in cardiac output on arterial oxygenation in the presence of asignificant shunt. The differences between the studies can be explained in the following way. Conditions in the current study resulted in a favourable DO2/VO2 ratio and a high starting P􀀀��������O2 even before dobutamine administration was commenced. Therefore the venous saturations were on the flat part of the oxygen dissociation curve and also on the flat part of the relationship between cardiac output and arterial oxygen content originally described by Kelman, Nunn and colleagues. Further increases in cardiac output and the DO2/VO2 ratio would not be expected to, and did not, increase P􀀀��������O2, S􀀀��������O2, or C􀀀��������O2. Thus, arterial oxygenation content and saturation did not change subsequent to the increase in cardiac output associated with the administration of dobutamine in the current study. In contrast, in the Mathru study, the low starting venous saturations and tensions were improved by increases in the DO2/VO2 ratio. As the starting venous saturation was “low,” significant benefit in arterial oxygenation was obtained on increasing cardiac output in that study. One significant concern for the clinician regarding the administration of the inotrope dobutamine during OLA is that it may increase shunt fraction (Qs/Qt) and thereby decrease arterial oxygenation during one lung ventilation. The influence of dobutamine on arterial oxygenation during OLA may theoretically be related to the balance of the following divergent effects: 1. By improving the relationship between oxygen delivery and consumption, dobutamine increases P􀀀��������O2. This increase will benefit arterial oxygenation in the presence of a large shunt, 2. The above has to be weighed against possible increases in VO2 induced by dobutamine, the consequence of which will be a decrease in P􀀀��������O2. Such increases in VO2 were not seen on administration of dobutamine in the current study, 3. An increase in PA pressure accompanying the increased cardiac output will oppose HPV and increase shunt in both the dependent and non-dependent lungs, 4. Direct inhibition of HPV by dobutamine and, 5. The influence of P􀀀��������O2 on HPV (i.e. high levels of venous oxygenation will inhibit whereas low levels will potentiate HPV). Nonetheless, in spite of the concerns (risk) of hypoxemia on administering dobutamine during OLA, dobutamine administration did not decrease PaO2 or arterial oxygen saturation, and neither did it increase the cost of oxygenation compared to when OLA was conducted in the absence of dobutamine infusions. In addition, the findings of studies conducted by Mathru and colleagues, Nomoto and Kawamura and the current study indicate that under usual clinical conditions present during OLA in the LDP, the administration of low dosages of dobutamine do not increase shunt fraction. In fact, the beneficial effect of the increase in cardiac output on venous oxygenation resulted in an increase in arterial oxygenation in the study by Mathru and colleagues; similar mechanisms were most likely operative in the study conducted by Nomoto and Kawamura. Therefore, there is currently no evidence that the administration of dobutamine in dosages of up to 7 ug.kg-1.min-1 increases shunt and worsens arterial oxygenation in humans subjected to OLA in the LDP. It is apparent that the vasodilatory effects of dobutamine resulting in a possible increase in shunt fraction (Qs/Qt) is therefore not the only factor to consider when studying its effects on arterial oxygenation. What is also of great relevance whenconsidering the effects of an inotrope on arterial oxygenation is the effect of inotropic drugs on the venous oxygen content. It is possible that Qs/Qt could be increased by the administration of inotrope. Nonetheless, if venous oxygenation is favourably affected by the administration of dobutamine, then a depressant effect on arterial oxygenation by an increase in the amount of blood passing via the shunt may be negated. If the increase in venous oxygenation is very significant, there may even be benefits in terms of arterial oxygenation, as was the case in the current study. This approach to how the quality of the blood passing via the shunt affects arterial oxygenation shifts the emphasis on prevention and treatment of hypoxemia during OLA from the lung to the efficacy of the circulation. In other words, the emphasis is shifted from what predominantly happens to the non-ventilated lung (HPV) to primarily the efficacy of oxygen flux during OLA. Extrinsic and intrinsic PEEP and OLA The effects of PEEP on hemodynamics and oxygenation observed during OLA in the current study may be summarised as follows. When PEEP5 was applied to the DL during OLA in the current study: 1. Neither right ventricular function, hemodynamics, oxygen flux nor arterial oxygenation was affected by the application of PEEP5 compared to the step when no external PEEP was applied. 2. Significant amounts of intrinsic PEEP were present during OLA in the control group patients. The degree of intrinsic PEEP was weakly related to the degree of obstructive airways disease present on preoperative LFT’s. 3. The most likely reason why PEEP5 did not make a difference to oxygenation or hemodynamics was the existence of similar amounts of intrinsic PEEP during OLA. These findings confirm Myles’s contention that low levels of intrinsic PEEP may have salutary effects on oxygenation during OLA. When PEEP10 was applied to the DL during OLA in the current study, it led to a decrease in stroke volume. This decrease is predominantly due to a decrease in preload, as PVR does not increase to levels that are known to impair RV performance. The decrease in the DO2/VO2 ratio that was induced by PEEP10 predictably decreases P􀀀��������O2 and can potentially lead to impairment of arterial oxygenation. It can therefore be concluded that greater (excessive) amounts of PEEP under more unfavourable circulatory conditions than were observed in the current study, may have deleterious cardio-respiratory effects. In summary, optimising DL volume plays an important role in determining arterial oxygenation. However, the therapeutic index for PEEP is narrow and the anesthesiologist needs to know firstly when the lung volume of the DL approaches FRC and secondly, how to avoid dynamic hyperinflation of that lung. One significant problem is that the best method of monitoring FRC during OLA is not clear at present.
AFRIKAANSE OPSOMMING: Agtergrond tot die studie Eenlongnarkose mag tot sekere probleme aanleiding gee. ’n Betekenisvolle afname in volume van die onderlong vind in die laterale decubitus posisie tydens eenlongnarkose plaas. Hierdie afname in longvolume mag egter ’n akute verhoging in regter ventrikulêre nalading tot stand bring. Die probleem is egter dat die regter ventrikel ’n dunwandige struktuur is wat potensieel baie minder werk as die dikwandige linker ventrikel kan genereer. Die regter ventrikel het min reserwe om ’n akute verhoging in nalading te weerstaan soos wat gebeur met akute longbesering of na longreseksie. Dus die verhoging in nalading wat gepaard gaan met eenlongnarkose mag die koppeling tussen die regter ventrikel en die pulmonale arterie belemmer. Alhoewel hierdie potensiële probleem bestaan, is die verandering albei in regter ventrikulêre nalading en hoe die regter ventrikel funksioneer tydens eenlongnarkose nog nie goed bestudeer nie. 1. Arteriële hipoksemie, hoofsaaklik te wyte aan die groot aftakking via die long wat nie geventileer word nie, mag kliniese probleme tydens eenlongnarkose teweegbring. 2. Die weerstand wat die pulmonale vaskulêre beddens van die geventileerde en nie-geventileerde longe bied teen bloedvloei is belangrike faktore wat aftakking en dus arteriële oksigenasie tydens eenlongnarkose beheer. ’n Hoë weerstand van die nie-geventileerde long en ’n lae weerstand van die geventileerde long se pulmonale vaskulêre beddens sal bevredigende arteriële oksigenasie tydens eenlongnarkose fasiliteer. ’n Verhoging in die pulmonale vaskulêre weerstand van die nie-geventileerde long is hoofsaaklik te wyte aan hipoksiese pulmonale vasokonstriksie. ’n Lae pulmonale vaskulêre weerstand in die geventileerde onderlong is hoofsaaklik gefasiliteer deur ’n hoë alveolêre suurstofspanning en ’n normale long volume, alhoewel alle faktore ook ’n rol in hierdie verband speel. 3. In die teenwoordigheid van die groot aftakking wat bestaan tydens eenlongnarkose, sal die saturasie en suurstof inhoud van gemeng veneuse bloed ’n betekenisvolle bydrae aan arteriële oksigenasie maak. a. Veneuse saturasie as ’n oorsaak van hipoksemie tydens eenlongnarkose, is nog nie sistematies in die literatuur ondersoek nie. b. Indien regter ventrikulêre nalading tot so ’n mate verhoog dat dit tot swak ventrikulêre uitwerp lei, mag dit ’n oorsaak wees van ontoereikendheid van die globale bloedsomloop en tot gemeng veneuse desaturasie lei. Die vraag is dus of verhoging van die kardiale omset deur inotrope ondersteuning die toereikendheid van die sirkulasie kan verbeter. Verbeterde sirkulasie toereikendheid sal tot ’n verhoging in gemeng veneuse en arteriële oksigenasie lei in die teenwoordigheid van ’n groot aftakking. Nietemin, die toediening van inotrope in die teenwoordigheid van ’n groot aftakking tydens eenlongnarkose gerapporteer om hipoksemie te vererger tydens eenlongnarkose. Dus ten tye van die uitvoer van dié studie, is daar uitdrukking gegee tot teenstrydige opinies in die literatuur oftewel verhoging in kardiale omset arteriële oksigenasie sal verbeter of versleg tydens eenlongnarkose.In die lig van die agtergrond hierbo, het die navorser dus regter ventrikulêre nalading, regter ventrikulêre funksie en koppeling van die regter ventrikel met sy lading tydens eenlongnarkose ondersoek. Die studie het ook die vraag benader of inotroop infusies of PEEP goeie of slegte gevolge sou hê op regter ventrikulêre nalading, regter ventrikulêre funksie en koppeling van die regter ventrikel aan sy lading tydens eenlongnarkose. Sou die kardiale omset en die toereikendheid van die sirkulasie sou verbeter sekondêr tot die toediening van inotrope tydens eenlongnarkose, gemeng veneuse oksigenasie en dus arteriële oksigenasie tydens eenlongnarkose verbeter, of sou dit aftakking en arteriële oksigenasie versleg tydens eenlongnarkose? Kontrole groep Pulmonêre elastansie het tussen 18 en 36% verhoog en gemene pulmonale arterie druk het met 32% tydens eenlongnarkose vermeerder. Die verhoging in gemene pulmonale arterie druk met die aanvang van eenlongnarkose is groter as die waardes gesien deur sekere navorsers maar gelyk met waardes gevind in pasiënte met beskadigde longe. Die vraag ontstaan dan hoekom styg pulmonale arterie druk tydens eenlongnarkose? volgens Ohm se Wet, mag druk as die veelvoud van vloei en weerstand beskou word. Die verhoging in gemene pulmonale arterie druk tydens eenlongnarkose is daarvolgens hoofsaaklik te wyte aan twee redes. 1. Eerstens, die kurwe van druk teenoor vloei is waarskynlik styler tydens eenlongnarkose. Hierdie is omdat pulmonale vaskulêre werwing en verwyding (pulmonale vaskulêre reserwe) is meer beperk as nornaal in pasiënte met longsiekte. Hierdie is die waarskynlikste rede hoekom pulmonale arterie druk tydens eenlongnarkose verhoog. Die redes hoekom die pulmonale vaskulêre reserwe in die onderste long tydens eenlongnarkose beperk is sluit in die volgende: 1.1 Die pulmonale vaskulêre bed van pasiënte onderwerp aan eenlongnarkose mag abnormaal wees weens die onderliggende long patologie, 1.2 Tydens eenlongnarkose in die laterale decubitus posisie, is long volume in hoë mate verminder as tydens tweelongnarkose, 1.3 Die voorafgenoemde vermindering in longvolume sal verder verminder word deur wanposisies van die dubbellumenbuis, sekresies en bloed, en absorpsie atelektase. 1.4 Te hoë vlakke van PEEP, oftewel intrinsiek of ekstrensiek van oorsprong, sal die intraalveolêre vate toedruk en so die pulmonale vaskulêre weerstand verhoog. 2. Tweedens, is daar groter vloei deur hierdie vaskulêre bed wat ‘n hoër weerstand bevat. Dit is opmerkingswaardig dat die verhoging in gemene pulmonale arterie druk ‘n waarde van 25 mmHg nie oorskry het nie tydens eenlongnarkose, alhoewel kardiale omset met 30% verhoog het. In pasiënte met beskadigde longe, het vorige studies egter bewys dat groter verhoging in PA druk gebeur tydens afbinding van die pulmonale arterie. Die vraag ontstaan dus hoekom daar verskille bestaan tussen wat gebeur tydens afbind van die pulmonale arterie en eenlongnarkose? Die antwoord mag wees dat die beperking in die styging in PA druk tydens eenlongnarkose as gevolg van ‘n progressiewe afleiding van bloedvloei na die nie-geventileerde long gebeur sodra pulmonale arterie druk styg tydens eenlongnarkose. Die implikasie van die afleiding van bloed na die nie geventileerde long is dat dit as ‘n veiligheids meganisme optree en verdere styging in pulmonale arterie druk beperk tydens eenlongnarkose. Hierdie afblaas meganisme sal die regter ventrikel beskerm tot en met PA afbind.Kontrole groep: eenlongnarkose en regter ventrikulêre funksie Die huidige studie bied die geleentheid om die betekenis van die voorafgenoemde verhoging in PA drukke en elastansie op regter ventrikulêre funksie tydens eenlongnarkose te ondersoek. Die huidige studie dui aan dat die 30% verhoging in pulmonale arterie druk wat met die aanvang van eenlongnarkose plaasvind, glad nie regter ventrikulêre funksie belemmer nie indien dit vergelyk word met die basislyn wakker staat. In teendeel, kardiale omset het verhoog na chirurgiese insnyding: hierdie verhoging is waarskynlik te wyte aan simpatiese senuwee stimulasie na die chirurgiese insnyding. Hierdie waarnemings pas in ook met ander studies waartydens regter ventrikulêre ejeksie alleenlik begin om af te neem indien die indekse van opposisie tot regter ventrikulêre ejeksie 200 tot 250% van basislyn bereik. Verder, die induksie van voorlading, naamlik sentrale veneuse druk, pulmonale arterie wigdruk en regter ventrikulêre einddiastoliese volumes is onveranderd tydens die huidige studie; dit beteken die ventrikel het nie gedilateer het nie tydens die verhoging in regter ventrikulêre nalading. Die verband tussen slagwerk en nalading sal varieer, afhanklik van die kontraktiele status van die ventrikel. In hierdie opsig, kon ons aflei dat die regter ventrikel, onder omstandighede wat tydens diė studie plaasgevind het, gefunksioneer het op die stygende been van die verband tussen regter ventrikulêre slagwerk en pulmonale arterie elastansie. Hierdie waarneming ondersteun die argument in die vorige paragraaf dat die regter ventrikel funksie behoue is tydens eenlongnarkose. Ter opsomming omtrent die indekse van opposisie tot pulmonale vloei en regter ventrikulêre funksie tydens eenlongnarkose: 1. Opposisie tot regter ventrikulêre uitwerp verhoog. Die bewys hiervoor is ’n 30% verhoging in gemene pulmonale arterie druk en ’n 36% verhoging in pulmonale arterie elastansie. 2. Ten spyte van die verhoging in weerstand teen RV uitwerping, het regter ventrikulêre funksie (soos bepaal deur regter ventrikulêre slagwerk indeks, regter ventrikulêre ejeksie fraksie en slag volume), nie verminder tydens eenlongnarkose in vergelyking met die waardes verkry wanneer die pasiënte wakker is of aan tweelongnarkose onderwerp is. 3. Ons kon ook aflei dat die koppeling tussen die regter ventrikel en sy lading goed behoue is tydens eenlongnarkose. Die implikasie hiervan is dat regter ventrikulêre slagwerk reserwe teenwoordig is tydens eenlongnarkose. Tydens eenlongnarkose funksioneer die regter ventrikel as ’n vloeipomp, net soos in normale lewe; dit beteken dat en die klein verhoging in regter ventrikulêre nalading wat ondervind word tydens eenlongnarkose maklik getolereer word. Dobutamien tydens eenlongnarkose: opposisie tot pulmonale vloei en regter ventrikulêre funksie Die uitwerking van dobutamien op regter ventrikulêre funksie tydens eenlongnarkose kan as volg opgesom word: 1. Lae dosisse dobutamien (3 μg.kg-1.min-1) verhoog kardiale omset, slagvolume en regter ventrikulêre slagwerkindeks. Die toediening van dobutamien 3 μg.kg-1.min-1 het nie saamgegaan met ‘n verhoging in regter ventrikulêre nalading nie. Dus, lae dosisse van dobutamien het wel die koppeling tussen die regter ventrikel en die pulmonale vaskulatuur tydens eenlongnarkose verbeter.2. Nietemin, albei die hoër dosisse van dobutamien (5 en 7 μg.kg-1.min-1) tydens eenlongnarkose het verhogings in die opposisie tot pulmonale bloedvloei teweeggebring. Byvoorbeeld, PA elastansie, gemene PA druk en pulmonale vaskulêre weerstand het met 30 tot 40% verhoog in vergelyking met die waardes gekry toe die pasiënte wakker was en toe albei longe geventileer is. ’n Belangrike opmerking in hierdie opsig is dat pulmonale arterie vervormbaarheid tydens eenlongnarkose met 61% verminder het tydens albei dobutamien 5 en 7 μg.kg-1.min-1. Die verhogings in gemene pulmonale arterie druk en pulmonale vaskulêre weerstand is, volgens mening, nie van kliniese of statistiese betekenis nie, alhoewel die vermindering in PA vervormbaarheid tydens die dobutamien 7 μg.kg-1.min-1 infusie wel van kliniese betekenis is. PA vervormbaarheid weerspieël een van die faktore wat vaskulêre impedansie in die 3- element Windkessel model van sirkulasie het. Die verhoging in opposisie tot pulmonale vloei en die afwesigheid van progressiewe verhogings in indekse van regter ventrikulêre funksie is nie wat verwag word indien die dosisse van die inotroop en pulmonale vasodilator dobutamien, progressief verhoog word. Die redes hoekom die opposisie tot pulmonale vloei verhoog tydens die toediening van dobutamien sluit in die uitwissing van die pulmonale vaskulêre reserwe tydens eenlongnarkose. Tydens die hoë kardiale indekse van 5 tot 5.5 μg.kg-1.min-1. is die pulmonale vaskulêre reserwe uitgeput en die meganisme het die verwagte pulmonale vaskulêre vasodilatasie van dobutamien oorskadu. Bowendien is dit waarskynlik dat die verhoging in regter ventrikulêre nalading betekenisvol genoeg was om te verhoed dat regter ventrikulêre funksie progressief verhoog soos sou verwag word met die administrasie van hoër dosisse inotroop. Die administrasie van dobutamien tydens eenlongnarkose het gemene pulmonale arterie druk verhoog tot ’n maksimum van 24,9 ± 6.2 mm Hg teen ’n kardiale indeks van 5.5 ± 1.2 l.min-1.m2. Nietemin is gemene pulmonale arterie druk 24.0 ± 7.7 mm Hg teen die maksimum kardiale indeks in die kontrole groep van 4.4 ± 1.1 l.min-1.m-2 tydens eenlongnarkose in die kontrole groep. Hierdie weerspieël dus ’n relatief beperkte verhoging in pulmonale arterie druk in vergelyking met die verhoging in pulmonale arterie druk wat gebeur het tydens die administrasie van dobutamien. Die waarskynlikste rede hoekom daar ’n beperkte verhoging in pulmonale arterie druk sou gewees het tydens die infusie van dobutamien is die afblaas effek van die nie-geventileerde long wat die verhoging in PA druk beperk het. Oksigenasie tydens eenlongnarkose Die volgende waarnemings is gemaak in verband met suurstof vloed, veneuse en arteriële oksigenasie tydens eenlongnarkose in die kontrole groep: 1. Die kombinasie van Induksie van narkose en die 1ºC vermindering in temperatuur het saamgegaan met ’n 40% vermindering in suurstof verbruik tydens twee long narkose. Hierdie vermindering in suurstof verbruik het voortgegaan tydens eenlongnarkose. 2. Die aanvang van eenlongnarkose is geassosieerd met ’n verhoging in kardiale omset in vergelyking met albei die basislyn eenlongnarkose en wakker state. 3. Die gevolge van punte 1 en 2 hierbo is dat die gemengde veneuse suurstof saturasie vanaf 75% en die gemeng veneuse suurstof spanning vanaf 5.4 kPa (toe die pasiënte wakker was) gestyg het tydens4. Tydens eenlongnarkose het die betekenisvolle verhoging in veneuse oksigenasie veroorsaak dat daar ’n verhoging in arteriële oksigenasie was in vergelyking met wanneer die pasiënte wakker was. Hierdie styging in arteriele oksigenasie was ten spyte van die 37% aftakking wat teenwoordig was tydens eenlongnarkose. 5. Onder toestande in die huidige studie, het dobutamien tydens eenlongnarkose nog arteriële nog veneuse oksigenasie verbeter nie, maar die arteriele oksigenasie het konstant gebly. ’n Belangrike observasie wat daarmee saamgaan is dat dobutamien toediening nie met ’n daling in arteriële suurstof spanning geassosieer is nie. Vervolgens, die hipotese dat die verhoging in kardiale omset geassosieer met dobutamien toediening tydens eenlongnarkose ’n verhoging in arteriële oksigenasie beweeg bring, is dus verwerp. Die verwerping van die hipotese van die deel van die studie beteken dat die bevindinge die teenoorgestelde is van die studies gepubliseer deur Mathru en sy kollegas en Nomoto en Kawamura. Hierdie outeurs het gedemonstreer dat die toediening van inotrope ’n verhoging in arteriële oksigenasie teweeg gebring het. Nietemin is die teenoorgestelde gevolgtrekkinge nie teenstrydig met mekaar nie. Inteendeel hierdie verskille help ons om die effek van ’n verhoging in kardiale omset of arteriële oksigenasie in die teenwoordigheid van ’n betekenisvolle aftakking duidelik te maak. Die verskille tussen die studies kan op die volgende manier verduidelik word. Toestande wat in die huidige studie teenwoordig was het veroorsaak dat die verband tussen suurstof lewering en verbruik baie hoog was en dat die gemeng veneuse suurstof spanning baie hoog was om mee te begin alvorens dobutamien geinfuseer is. Dus is die veneuse saturasies op die plat deel van albei die suurstof dissosiasie kurwe en ook van die verband tussen kardiale omset en arteriële suurstof inhoud oorspronklik deur Kelman, Nunn en kollegas beskryf. Verdere verhogings in kardiale omset sou dus nie verwag word, en het nie, verhogings in gemeng veneuse suurstof spanning, gemeng veneuse suurstof saturasie of gemeng veneuse suurstof inhoud teweeg gebring. Dus, arteriële suurstof inhoud en saturasie het nie verander na die verhoging in kardiale omset wat teweeg gebring is deur die toediening van dobutamien in die huidige studie. Inteendeel, in die studie deur Mathru en kollegas, is die lae aanvanklike veneuse saturasie en spanning verbeter deur verhogings in die verband tussen suurstoflewering en suurstofverbruik. Omdat die veneuse saturasie aan die begin van die Mathru studie laag was, is betekenisvolle voordeel in arterieël oksigenasie teweeg gebring deur om die kardiale omset te verhoog. ’n Groot bekommernis vir die klinikus is dat die aftakking mag verhoog met die toediening van die inotroop dobutamien tydens eenlongnarkose en, op die manier, arteriële oksigenasie mag verminder. Die invloed van dobutamien op arteriële oksigenasie tydens eenlongnarkose mag teoreties te wyte wees aan die balans van die volgende uiteenlopende faktore: 1. Deur om die verband tussen suurstof lewering en verbruik te verbeter, sal dobutamien gemeng veneuse suurstof spanning verhoog. Hierdie verhoging sal arteriële oksigenasie verbeter in die teenwoordigheid van ’n groot aftakking, 2. Die bogenoemde moet teenoor potensiële verhogings in suurstofverbruik deur dobutamien oorweeg word. Die gevolge hiervan sou potensieel ’n vermindering in gemeng veneuse suurstof spanning wees. Sulke verhogings in suurstof verbruik is nie tydens die huidige studie gesien nie,3. ’n Verhoging in pulmonale arterie druk wat saamgaan met die verhoogde kardiale omset sal hipoksiese pulmonale vasokonstriksie teenwerk wat die aftakking in albei die geventileerde en nie geventileerde longe sal verhoog, 4. Direkte inhibisie van hipoksiese pulmonale vasokonstriksie deur dobutamien en, 5. Die invloed van gemeng veneuse suurstof spanning op hipoksiese pulmonale vasokonstriksie moet ook oorweeg word (d.i. hoe gemeng veneuse suurstof parsiele druk sal hipoksiese pulmonale vasokonstriksie inhibeer). Nietemin, ten spyte van die bekommernisse rondom hipoksemie tydens die toediening van dobutamien tydens eenlongnarkose, het dobutamien toediening nie ’n verlaging in arteriële suurstof spanning teweeg gebring nie, en ook het dit nie die koste van oksigenasie verhoog nie. Verder, die bevindinge van studies tydens eenlongnarkose in die laterale decubitus posisie deur Mathru en sy kollegas, Nomota en Kawamura en ook die huidige studie, dui aan dat die toediening van lae dosisse van dobutamien nie toe ’n verhoging in aftakking lei nie. Inteendeel, die voordelige effekte van die verhoging in kardiale omset op veneuse saturasie het veroorsaak dat daar ’n verhoging in arteriële saturasie is in die studie deur Mathru en sy kollegas soortgelyke meganismes is waarskynlik ook van toepassing in die studie wat gedoen is deur Nomoto en Kawamura. Dus, dwars deur die literatuur, is daar geen huidiglike bewys dat die toediening van dobutamien tot en met dosisse van 7μg.kg-1.min-1 aftakking verhoog of arteriële oksigenasie versleg in mense onderworpe aan eenlongnarkose in die laterale decubitus posisie. Dit is duidelik dat die vasodilatoriese effekte van dobutamien wat moontlik ’n verhoging in aftakking fraksie teweeg kan bring, nie die enigste faktore is om te oorweeg wanneer die middel se invloed op arteriële oksigenasie bestudeer word nie. Dit is ook van kliniese belang om die invloed van inotrope middels op veneuse suurstof inhoud te oorweeg. Dit is moontlik dat ’n aftakking verhoog kan word deur die toediening van ’n inotroop. Nietemin, mag die negatiewe effek wat die toediening van ’n inotroop sal inhou op arteriële oksigenasie deur middel van sy verhoging in aftakking, negeer word indien veneuse oksigenasie voordelig beïnvloed is. Verder, indien die verhoging in veneuse oksigenasie wat teweeggebring word deur die toediening van inotrope baie betekenisvol is, mag die gevolg hiervan wees dat arteriële oksigenasie voordelig beïnvloed word soos die geval in die huidige studie was. Die huidige benadering waar die kwaliteit van die bloed wat deur die aftakking vloei die arteriële oksigenasie beïnvloed, skuif die klem van voorkoming en behandeling van hipoksemie tydens eenlongnarkose van die long na die toereikendheid van die sirkulasie. Met ander woorde, die klem is geskuif van wat gebeur in die nie-geventileerde long (hipoksie pulmonale vasokonstriksie) tot primêr die toereikendheid van suurstof flux tydens eenlongnarkose. Ekstrinsieke en intrinsieke PEEP tydens eenlongnarkose Die invloed van PEEP op hemodinamika en oksigenasie tydens eenlongnarkose in die huidige studie mag as volg opgesom word. Toe PEEP5 tydens eenlongnarkose toegedien is: 1. Nie regter ventrikulêre funksie, hemodinamika, suurstof flux nog arteriële oksigenasie is beïnvloed deur die toediening van PEEP5 in vergelyking met die stap wanneer geen eksterne PEEP toegedien is nie. 2. Betekenisvolle hoeveelhede intrinsieke PEEP is teenwoordig tydens eenlongnarkose in die kontrole groep.Die hoeveelheid intrinsieke PEEP wat teenwoordig was, is swak maar betekenisvol verwant aan die graad obstruktiewe lugwegsiekte wat teenwoordig was gemeet deur pre-operatiewe longfunksie toetse. 3. Die waarskynlikste rede hoekom PEEP5 nie ’n verskil gemaak het aan oksigenasie of hemodinamika nie is die teenwoordigheid van soortgelyke hoeveelhede intrinsieke PEEP tydens eenlongnarkose. Hierdie bevinding bevestig Myle’s se beweringe dat lae vlakke intrinsieke PEEP voordelige effekte op oksigenasie tydens eenlongnarkose mag hê. PEEP10 toediening aan die onderlong tydens eenlongnarkose in die huidige studie het tot ’n vermindering in slagvolume gelei. Hierdie vermindering is primêr veroorsaak deur ’n vermindering in voorlading en nie die gevolg van ’n verhoging in pulmonale vaskulêre weerstand nie. Die gevolgtrekking is gemaak omdat regerventrikulere enddiastoliese volume verlaag het maar pulmonale vaskulêre weerstand het nie verhoog tot vlakke wat bekend is om regter ventrikulêre funksie te belemmer nie. Die vermindering in die verhouding tussen suurstof lewering en suurstof verbruik wat geïnduseer is deur PEEP10 het (voorspelbaar) gemeng veneuse suurstof spanning verminder en kon potensieël gelei het tot belemmering in arteriële oksigenasie. Indien minder voordelige sirkulatoriese toestande geheers het tydens die huidige studie, sou groter (oorbodige) hoeveelhede PEEP slegter kardiorespiratoriese gevolge tot gevolg gehad het. Ter opsomming, optimalisering van die volume van die onderlong tydens eenlongnarkose speel ’n belangrike rol in die bepaling van arteriële oksigenasie. Nietemin, die terapeutiese indeks vir PEEP is nou en die narkotiseur het die behoefte om te weet wanneer die volume van die onderlong optimaal is. In die opsig, is ’n betekenisvolle probleem tydens eenlongnarkose dat meting van funksionele residuele kapasiteit nie huidiglik maklik is nie

Background: Lung function is a highly heritable trait. So far there is limited knowledge of the genetic factors that influence lung function. Vascular endothelial growth factor A (VEGF-A) is expressed in the lung at high levels and is known to play a role in angiogenesis and lung remodelling, both in utero and throughout life. A candidate gene study was carried out in order to investigate the role of variants within the VEGF-A gene in determining lung function in childhood and adult life.Methods: Using available longitudinal data previously collected for an unselected birth cohort (Manchester Asthma and Allergy Study-MAAS) the relationship between lung function and single-nucleotide polymorphisms (SNPs) in VEGF-A was assessed. Replication studies were performed in cross-sectional studies of adults from Manchester and children with asthma from Croatia, in whom FEV1/FVC ratio was measured using spirometry. The potential functional roles of two consistently associated SNPs were then further investigated. Finally, using the genome-wide data generated in the discovery cohort (MAAS) I assessed why associations between VEGF-A and lung function had not been reported in recent genome-wide association studies of lung function.Results: Two VEGF-A SNPs, rs10434 and rs3025028, were significantly associated with lung function at multiple ages in a discovery population (MAAS). Subjects with a GG genotype for either SNP had significantly diminished lung function compared to subjects with other genotypes. These findings were replicated in two additional populations (631 parents of children participating in MAAS and in 410 Croatian children with physician-diagnosed asthma aged 6-18 years). SNP rs10434 is located in the 3’UTR and based on its location I hypothesised that it may affect mRNA stability. No significant difference in the rate of VEGF-A mRNA degradation was found between GG and the AA homozygotes. SNP rs3025028 is an intronic SNP in a close proximity to the splice site involved in alternative splicing which generates two different isoforms of VEGF-A; I therefore tested the hypothesis that a change of base at this position could affect the splicing mechanism and cause a change in the ratio of the isoforms. Western blot analysis was used to demonstrate a difference in the ratio of the splice variants VEGF-A165b and total VEGF-A165 (relative to a reference sample) between genotype groups. The VEGF-A165b/panVEGF-A165 ratio was significantly higher at birth (cord plasma), in school-age children and in adults amongst CC compared to GG homozygotes at rs3025038 (p<0.03). Finally, the genome-wide data for the discovery cohort showed that the region containing VEGF-A was not well targeted by either genotyped or imputed SNPs in genome-wide arrays. Conclusion: Evidence was provided to demonstrate that variants within the VEGF-A gene are significantly associated with lung function in both children and adults. Furthermore, data was presented to support a functional role for one of the SNPs (rs3025028). I investigated why associations between VEGF-A and lung function had not previously been reported in recent GWAS and concluded that the region containing VEGF-A was poorly covered by all of the currently available arrays.

Epithelial sodium channels (ENaC) are located throughout the epithelial lining of the respiratory tract and play a crucial role in ion and fluid homeostasis of the lungs. Increasing ENaC activity through stimulation of β₂-adrenergic receptors has been shown to increase sodium and fluid reabsorption from the airspace to the interstitial space. In cystic fibrosis lung disease there is a hyperabsorption of sodium through ENaC which results in dehydration of the airway surface liquid. Previous work has identified a common functional genetic variant of SCNN1A, the gene encoding the ENaC alpha-subunit. This variant manifests as an alanine to threonine substitution at amino acid 663 (T663), with the T663 variant resulting in a more active channel due to a greater number of channels in the membrane. We sought to determine the influence of the T663 variant on exhaled ions, pulmonary function, and the diffusing capacity of the lungs in healthy subjects as well as in patients with cystic fibrosis. We used exercise, which can increase endogenous epinephrine by up to 1000 fold at peak exercise, and albuterol, an exogenous β₂-adrenergic agonist, to stimulate ENaC activity. In healthy individuals we hypothesized that the T663 variant would be beneficial for lung function due to a greater fluid removal, which could improve gas transfer in a healthy lung. In the CF patients we predicted that the T663 variant would be detrimental to lung function due to an exaggerated absorption of sodium and drying/thickening of the mucus layer in the airways. Measurements of exhaled sodium were made in the healthy subjects at baseline, 30, 60, and 90 minutes post-albuterol administration. Subjects with the A663 variant had higher baseline exhaled sodium and a significant decrease in exhaled sodium by 90 minutes after β₂-adrenergic stimulation with albuterol, suggesting a removal of sodium from the airways. No changes in exhaled sodium were seen in the T663 variant in response to albuterol. In response to exercise the A663 variant had a greater increase in the diffusing capacity of the lung than the T663 variant, possibly due to differences in alveolar sodium and therefore fluid handling. Taken together, these results suggest that healthy humans with the A663 variant can increase ENaC activity in response to β₂-adrenergic stimulation, whereas individuals with the T663 variant have a diminished capacity for increasing ENaC activity in response to β₂-adrenergic stimulation. In CF patients, the T663 variant had significantly lower baseline pulmonary function, weight, and body mass index. In response to exercise, patients with the T663 variant had a greater increase in the diffusing capacity of the lungs, possibly due to purinergic inhibition of ENaC. Finally, we recruited additional CF patients to confirm our pulmonary function findings. Individuals with at least one allele resulting in the T663 variant had significantly lower body mass index, and tended to have lower exhaled chloride and pulmonary function. These results suggest greater dehydration of the lung in CF patients with the T663 variant. Overall, these results may suggest that the T663 variant modifies disease severity in CF, although more work is certainly warranted to confirm this result.

Abstract Lung donation is the most risky transplant procedures. With low survival rates, and poor acceptance of donated lungs, those in need of a lung transplant are at high risk of dying. One reason for poor outcomes is the lack of optimal match between donor and recipient when it comes to lung size and shape. Lungs that do not properly fit in the recipient’s chest cavity can fail to inflate fully and quickly start to deteriorate. In such patients, lung contusions can form, edema occurs in healthy lung tissue, and overall lung function declines. To improve patient outcomes after lung transplant, we describe here a developed a computational pipeline which enables donor lungs to be properly matched to recipients. This tool uses CT scans from both the donor and potential recipients to calculate how anatomically different the sets of lungs are, and therefore provide improved matches in both size and shape for the donor lungs.

Review question / Objective: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease characterized by persistent respiratory symptoms and progressive airflow obstruction documented on spirometry. Acupuncture, as a safe and economical non-pharmacology therapy, has pronounced therapeutic effects in COPD patients. Several systematic reviews draw the conclusion that acupuncture could improve patients’ quality of life, exercise capacity and dyspnoea, however, the results about lung function were inconclusive. Recently, increasing number of animal studies has been published to illustrate the effects of acupuncture in improving lung function in COPD animal model. However, the efficacy of acupuncture for experimentally induced COPD have not been systematically investigated yet. A systematic review of animal experiments can benefit future experimental designs, promote the conduct and report of basic researches and provide some guidance to translate the achievements of basic researches to clinical application in acupuncture for COPD. Therefore, we will conduct this systematic review and meta-analysis to evaluate effects of acupuncture on COPD animal model.

Review question / Objective: We aim to evaluate the effect of lung ultrasound (LU) guided therapy on the rates of adverse cardiac events (MACE) in heart failure (HF) patients. Condition being studied: Previous studies have found that B-lines assessed by lung ultrasound can be used for risk stratification in patients with HF and to predict the occurrence of adverse cardiac events. Therefore, similar to BNP, lung ultrasound has clinical value in guiding the management of patients with HF. However, the role of LU in guiding HF therapy is still controversial. Moreover, previous study's samples are too small to explain the over clinical outcomes. Besides, previous meta-analyses study did not perform meta-regression and/or subgroup analyses, or further analyze other parameters, such as heart function, quality of life and length of hospital stay.