Dissertationen zum Thema „Lungs“

Bibliography: leaves 168-184. The work in this study encompasses oxygen free radical related inflammation in the peripheral lung and in lung cells. Animal and human studies have been used. Methods include cell culture with function studies, protein chemistry, animal and human physiology, and cell and lung structure through histopathology, and various forms of electron microscopy. The work resulting from this thesis has formed an important basis for understanding acute and chronic lung injury.

Introduction: CF (cystic fibrosis) and PCD (primary ciliary dyskinesia) are obstructive airway diseases characterised by frequent infections and neutrophilic inflammation. However, PCD has a much milder course than CF. Pilot data showed that in PCD (n=8) the relationship between LCI (lung clearance index) derived from multiple breath washout (MBW), and FEV1 (forced expiratory volume in 1 second) differed from the established correlation in CF. This thesis sought to identify the reasons. Materials and Methods: Larger PCD (n=38) and CF cohorts (n=125), a non-CF bronchiectasis comparator group (n=28), and healthy controls (n=44) were recruited. All performed LCI and spirometry, and subgroups had more complex MBW parameters (conventional and modified phase III analysis and curvilinearity) calculated and HRCT scans scored. Results: As in the pilot data, there was no relationship between LCI and FEV1 in PCD, unlike in CF. PCD patients had fewer structural abnormalities than CF despite similar or worse spirometry and LCI, and the relationship between HRCT and spirometry or LCI in PCD was again different from that seen in CF. MBW analyses showed that Scond* is near-normal in PCD, suggesting less flow asynchrony, compared with CF. Conclusions: There are differences in the nature of distal airway disease between PCD and CF. As the non-CF bronchiectasis patients were similar to CF (rather than PCD), this likely results from the primary mucociliary clearance defect in PCD compared with secondary impairment in the other two conditions. This may be important as care of PCD patients is extrapolated from that of CF patients, which may not be appropriate. It is important not to extrapolate outcome measures uncritically between different disease groups, both clinically and when planning randomised controlled trials. Finally, a better understanding of what causes the better prognosis in PCD may help identify future new treatment avenues in CF.

This study examined the effects of lung expansion and changes in temperature on fluid movement by the lungs in the initial period after birth. In addition, experiments with amiloride support the belief that fluid reabsorption acts via a sodium transport mechanism. Lungs from fetal guinea pigs (56-67 days of gestation) were supported in vitro for three hours, and lung liquid production rates were measured using a dye dilution technique. The average production rate in the first hour of untreated preparations was 1.30 ±0.22 ml/kg body weight per hour, and this did not change significantly during the remainder of the experiment (n=30). This rate is comparable to secretion rates previously reported from chronically catheterized sheep. In 36 further preparations, the lungs were transferred from 37°C to fresh Krebs-Hanseleit saline at one of the following temperatures, for one hour (an ABA design): (a) 29°C; (b) 32°C; (c) 34°C; (d) 35°C; (e) 36°C; (f) 39°C. In all cases, the temperature change resulted in an immediate and significant fall in secretion. All lungs showed a tendency towards recovery when returned to starting conditions, except those subjected to a temperature increase. Reductions of 2-3°C, those normally seen in the delivery room, had the greatest effect and caused not only a decrease in secretion, but promoted fluid reabsorption. Amiloride at 10⁻⁶M had no effect on control preparations, but completely blocked the reabsorption stimulated by a temperature drop of 2°C. Expansion of the lungs, which occurs naturally as a newborn attempts to take its first breaths, was also examined. Thirty fetal lungs were expanded by one of the following amounts: (a) 18%; (b) 31%; (c) 43%; (d) 50%; (e) 72%. All expansions resulted in a significant fall in secretion rate, with the effect being proportional to the degree of expansion. Amiloride at 10⁻⁶M again blocked the strong reabsorption occurring with 70% expansion. Further studies investigated the possibility that expansion causes reabsorption via the local release of a substance occurring in the lungs. When one set of lungs was expanded in the presence of a second, unexpanded set, both showed a significant decrease in secretion, suggesting that the expanded lung had released some factor which affected the otherwise untreated lung. However, studies with α- and β- adrenergic blockers showed that it is unlikely the expanded lung was liberating either adrenaline or nor-adrenaline. The results of this study show that two changes which are likely to occur in the period immediately after birth, namely a 2-3°C decrease in core temperature, and lung expansion, may be important in promoting the vital reabsorption of fluid. They suggest that expansion may release substances locally in the lungs which stimulate this reabsorption, and that the fluid is removed from the potential air spaces via sodium transport mechanisms.
Science, Faculty of
Zoology, Department of
Graduate

This study was designed to gain an understanding of the family experience when an adult member has chronic obstructive pulmonary disease (COPD). It is recognized that illness within the family affects the well-being of the family unit and the health of all members. To understand the impact of COPD upon the family, however, the literature provides only knowledge of the experience of the individual who has COPD and the spouse, not that of the family unit. Thus, the purpose of this study was to describe and explain the COPD experience from the perspective of the family unit. A qualitative method, phenomenology, was chosen for this investigation. Data were collected through semi-structured interviews with eight families who shared their experiences. From the content analysis of these data, three themes that were common throughout the families' accounts were identified and developed to describe and explain family life with COPD. The first theme, disease-dictated family life, describes four aspects of a common lifestyle that is imposed on the family by the characteristics of COPD. The second theme, isolation, describes the isolation that accompanies the illness experience, for the family group and the individual members within the group. The final theme, family work, describes the four primary challenges the families face and the coping strategies they use to deal with them. These findings revealed that COPD acts as an intense stressor within the family, requiring extensive family work to cope with COPD in a way that maintains the well-being of the family unit. Furthermore, it was found that living with COPD in many ways inhibits the resources within the family and those external sources of support that foster the family's ability to manage the stress associated with living with COPD. The implications for nursing practice and nursing research were delineated in light of the research findings.
Applied Science, Faculty of
Nursing, School of
Graduate

This is a document explaining in detail my artistic practice from childhood to the day I graduated VCU. It will perhaps only be understood by those who have themselves already felt such ways, or similar ways – words and ghosts are mostly invisible.

The generation of oxygen free radicals by the cytosolic enzyme, xanthine oxidase (XO), has been implicated in post-ischemic or reperfusion damage in several organs. XO catalyzes the conversion of hypoxanthine to urate with the concomitant production of superoxide anion free radical (0₂̅˙) and hydrogen peroxide (H₂O₂). Oxygen free radical-mediated injury has also been demonstrated in inflammatory lung disease. The possible involvement of XO in oxidative injury in the lung has not yet been studied. Therefore, this research project was designed to determine whether XO is present in the lung and to investigate its characteristics in porcine, bovine, rat and human lung and other tissues. Immunochemical analysis of xanthine oxidase in the tissues employed on polyclonal antibody raised to bovine milk XO. Proteins were separated by SDS-polyacrylamide gel electrophoresis of tissue homogenates. Proteins were transfered from the gels to nitrocellulose filters by Western blotting. After incubating the filters with a antisera containing the antibody to the purified bovine XO. XO on the filter was detected by its reaction with an enzyme-conjugated second antibody. XO was immunologically detectable in bovine lung and milk. Rat lung, kidney and liver all showed XO reactivity. XO was detectable in porcine liver but not detectable in porcine lung or kidney. Thus, the antibody to bovine XO was cross-reactive with porcine and rat XO. XO protein was not immunologically detectable in human lung possibly because the antibody was not cross reactive with the bovine antibody. In vivo, xanthine oxidase exists predominantly as a dehydrogenase rather than an oxidase. In this form as xanthine dehydrogenase (XDH) the enxyme does not produce either 0₂̅˙ or H₂O₂. The activity of both XDH and XO was measured in several tissues using a fluorometric assay which uses an artifical substrate, pterin which is catalytically converted to the fluorescent product isoxanthopterin (IXP). XO activity in porcine liver was of 1.1 x 10⁻³ µg IXP/mg protein/min although XO activity was not detectable in porcine lung and kidney, in rat lung of 1.7 x 10⁻² µg IXP/mg protein/min, rat kidney of 1.5 x 10⁻² µg IXP/mg protein/min, and rat liver of 2.2 x 10⁻² µg IXP/mg protein/min. Seven human lung biopsy samples were obtained after lung resection and initially tested for viability by determination of NADH oxidase activity and then assayed for XO-XDH. Three of these samples showed NADH oxidase activity indicating tissue viability, but only one of these three showed measurable XO activity of 5.35 x 10⁻⁶ µg IXP/mg protein/min. Irreversible conversion of XDH to XO is thought to be the result of limited proteolysis by a Ca²⁺/calmodulin activated protease, whereas reversible conversion of the enzyme occurs by oxidation of critical thiol groups. Studies on the rate and nature of fluorescence assay to detect catalytic activities of both enzyme forms. Incubation of lung homogenates with trypsin for 60 min caused irreverisble conversion of 90% of the XDH to XO. In contrast, incubation of homogenates at 15°C for 10 hours caused conversion of 100% of the XDH to XO. This conversion was reversible to the extent of 80% by reduction of thiol groups with dithiothreitol (DTT). The effects of free Ca²⁺ on the conversion of XDH to X0 was examined by using EDTA, a chelator of Ca²⁺ and other divalent cations; and EGTA, a more specific chelator of Ca²⁺. The presence of these chelating agents during homogenization of either normoxic or ischemic rat lung tissue did not inhibit reversible enzyme conversion. Increased XO activity was reversible by DTT. In the normoxic rat lung, homogenates prepared with EDTA and EGTA showed a similar conversion of 95% of XDH to XO which was reversible to 70% with DTT. In the ischemic rat lung, samples prepared with EDTA and EGTA showed a'conversion of 80% and 95% XDH to XO which was similar to control samples. The extent of reversibility to XDH was 75% with DTT incubation. In addition, perfusion of rat lungs with EDTA and DTT via a pulmonary artery cannula prior to 60 min of ischemia and homogenization did not affect the extent of XDH to XO conversion. These results indicate that irreversible Ca²⁺-mediated proteolytic conversion of XDH to XO does not occur to a great extent in the rat lung during either normoxia or ischemia. However, reversible conversion of XDH to XO does occur, suggesting that reversible thiol dependent conversion may play a role in the lung under both physiological and pathophysiological states.
Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate

Infants with bronchopulmonary dysplasia (BPD), showed impaired body growth when compared to control infants. In terms of changes in the biochemical composition of the lung, BPD infants had higher DNA, soluble protein, collagen and desmosine contents as well as increased concentrations of DNA, collagen and desmosine in their lungs when compared to the growth patterns obtained for the lungs of control infants. Pathologically BPD was classified into 4 grades. Grade I BPD, was a phase of acute lung injury, grades II and III were proliferative phases. In grade IV BPD, lung structure returned towards normal. Evidence of fibrosis was seen by a significant increase in collagen concentration in grades II and III while desmosine concentration was seen to increase in grades III and IV suggesting that the increase in collagen and desmosine contents in the lungs of BPD infants may be controlled by two different mechanisms. Collagen type I/III ratio was seen to decrease progressively from grade II to grade IV BPD in comparison to age matched controls, indicating a higher proportion of type III collagen in the lungs of infants with BPD. From the clinical analysis and the results obtained from discriminant analysis procedure, it was seen that there was a high degree of correlation between the continuation of the disease and collagen accumulation in the lungs suggesting that pulmonary fibrosis with excessive collagen accumulation is an integral part of BPD. This fibrotic process seemed to correlate significantly with assisted ventilation and high oxygen supplementation received by the infants, but it was difficult to assess the individual contribution of the two treatments in the pathogenesis of BPD. Other variables such as severity of the initial disease and the length of survival of the infants, made the assessment of individual contribution much more difficult.
Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate

Thesis (Ph.D.)--Tufts University, 2006.
Submitted to the School of Nutrition Science and Policy. Adviser: Xiang-Dong Wang. Includes bibliographical references. Access restricted to members of the Tufts University community. Also available via the World Wide Web;

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

This study examined the effects of epinephrine, norepinephrine, AVP and ACh on fluid movement by the lungs of the late-term guinea pig fetus. Catecholamines and AVP are secreted in high amounts by the fetus during delivery, and could be important with respect to fetal lung fluid removal; this event is vital at the time of birth. The lungs were supported in vitro for a duration of three hours, and production rates were measured using a dye-dilution technique. The average resting production rate in terms of ml/kg‧h declined with gestational age (54-67 days gestation; n=171). There was a lesser decline in the average resting production rate in terms of ml/h. The average production rate of untreated preparations in the first hour was 1.60 ± 0.26 ml/kg body weight per hour, and rates did not change significantly during the remaining two hours of experimentation (n=30). This rate is comparable to those reported from chronically catheterized fetal sheep. Treatment was administered during the second hour of experimentation, following an ABA design. Lungs (n=36) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of epinephrine: (a) 10‾⁵ M; (b) 10‾⁶ M; (c) 10‾⁷ M; (d) 5 x 10‾⁸ M; (e) 10‾⁸ M; and (f) 10‾⁹ M. With the exception of the top dose, epinephrine treatment caused an immediate reduction in fluid secretion, or fluid reabsorption. Sodium followed the movement of water in all cases. The effect of epinephrine at 10‾⁷ M was maximal, and the threshold dose for epinephrine was calculated at 1.78 x 10‾¹¹ M. Phentolamine and propranolol had no effect in control preparations. However, phentolamine completely blocked the effect of epinephrine, whereas propranolol was ineffective. Isoproterenol had no effect on pulmonary fluid production. Alpha-adrenergic receptors apparently mediate the effect of epinephrine on pulmonary fluid movement in the fetal guinea pig lung. This conclusion is different from that obtained in fetal sheep, in which beta-adrenergic receptors are utilized. A possible synergism between epinephrine and AVP was examined. Lungs (n=12) were transferred to fresh Krebs-Henseleit saline containing either (a) 0.6 mU/ml AVP, or b) 0.6 mU/ml AVP combined with epinephrine at 10‾⁷ M. Treatment with AVP caused a slow, prolonged reduction in fluid production. Treatment with AVP together with epinephrine did not demonstrate synergism. The effect of norepinephrine (NE) was examined. Lungs (n=36) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of NE: (a) 1.24 x 10‾⁵ M; (b) 1.24 x 10‾⁶ M; (c) 1.24 x 10‾⁷ M; (d) 5.24 x 10‾⁸ M; (e) 1.24 x 10‾⁸ M; and (f) 1.24 x 10‾⁹ M. In all preparations, treatment with NE resulted in an immediate reduction in fluid production, and reabsorptions were observed at the higher doses. Sodium followed the movement of water in every case. The threshold dose was calculated at 3.16 x 10‾¹⁰ M. Phentolamine blocked the effect of NE, reinforcing the importance of pulmonary alpha-adrenergic receptors in the fetal guinea pig. There was no relationship between age and degree of response with treatment of either epinephrine or NE, but fetuses under 78.0 g did not respond to NE. The effect of ACh was examined. Lungs (n=24) were transferred to fresh Krebs-Henseleit saline containing one of the following concentrations of ACh: (a) 10‾⁴ M; (b) 10‾⁵ M; (c) 10‾⁶ M; and (d) 10‾⁸ M. At the three top doses, immediate and powerful reabsorptions of pulmonary fluid were observed in older fetuses (60 days gestation and above); significant falls were observed in the younger fetuses. This result was unexpected, as it was hypothesized that ACh would stimulate fluid production. The threshold dose for ACh was between 10‾⁶ M and 10‾⁸ M. Phentolamine blocked the effect of ACh. This result suggested that reabsorption is a result of an indirect effect of ACh acting through pulmonary alpha receptors. The results in this study show that epinephrine, NE, AVP and ACh are all important promoters of fetal pulmonary fluid removal in the fetal guinea pig. Pulmonary alpha-adrenergic receptors mediate the effects of epinephrine, NE and ACh (indirectly). The conclusions drawn from this study emphasize the importance of species' comparison in fetal research. LIST OF ABBREVIATIONS AVP Arginine Vasopressin NE Norepinephrine DOPA dihydroxyphenylalanine PNMT Phenylethanolamine n-methyltransferase ACh Acetylcholine
Science, Faculty of
Zoology, Department of
Graduate

Thesis (M. Sc. Med.)--University of Sydney, 2008.
Title from title screen (viewed 29 July 2008). Submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2008; thesis submitted 2007. Includes bibliographical references. Also available in print form.

Thesis (M.S.)--West Virginia University, 2001.
Title from document title page. Document formatted into pages; contains vii, 53 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 48-53).

A quarter of the world's population experience wheezing. These sounds have been used for diagnosis since the time of the Ebers Papyrus (ca. 1500 BC), but the underlying physical mechanism responsible for the sounds is still poorly understood. The main purpose of this thesis is to change this, developing a theory for the onset of wheezing using both experimental and analytical approaches, with implications for both scientific understanding and clinical diagnosis. Wheezing is caused by a fluid structure interaction between the airways and the air flowing through them. We have developed the first systematic set of experiments of direct relevance to this physical phenomena. We have also developed new tools in shell theory using geometric algebra to improve our physical understanding of the self-excited oscillations observed when air flows through flexible tubes. In shell theory, the use of rotors from geometric algebra has enabled us to develop improved physical understanding of how changes of curvature, which are of direct importance to constitutive laws, come about. This has enabled a scaling analysis to be applied to the self-excited oscillations of flexible tubes, showing for the first time that bending energy is dominated by strain energy. We made novel use of multiple camera reconstruction to validate this scaling analysis by directly measuring the bending and strain energies during oscillations. The dominance of strain energy allows a simplification of the governing shell equations. We have developed the first theory for the onset of self-excited oscillations of flexible tubes based on a flutter instability. This has been validated with our experimental work, and provides a predictive tool that can be used to understand wheezing in the airways of the lung. Our theory for the onset of wheezing relates the frequency of oscillation to the airway geometry and material properties. This will allow diagnoses based on wheezing sounds to become more specific, which will allow the stethoscope, which has changed little in the last 200 years, to be brought into the 21st century.

Oncogenic mutations in lung cancer further our knowledge about cancer initiation and progression, and may guide personalized treatment. The fact that targeted therapy is most effective in subsets of patients with defined molecular targets indicates the need for classification of clinically-related molecular tumor phenotypes based on the presence of oncogenic mutations, including EGFR mutations and EML4-ALK rearrangements. The identification of EGFR mutations, in up to half of lung adenocarcinomas in Asians, could predict clinical sensitivity to tyrosine kinase inhibitor (TKI). However, testing for mutations is not always possible due to tumor tissue availability. The therapeutic decision sometimes remains a clinical one especially for elderly lung cancer patients but no known mutation status. We studied the survival outcomes of targeted therapy versus conventional chemotherapy in elderly patients with lung cancer when we did not yet have routine EGFR mutation testing and demonstrated comparable survival outcomes in targeted therapy compared to chemotherapy, implying that survival with targeted therapy could be better if the treatment population could be selected with EGFR mutations. Though testing for EGFR mutation in tumor biopsy have later become routine practice and remains the accepted reference for therapeutic decision, the detection of EGFR mutations in plasma DNA with high diagnostic performance will be useful adjunct for diagnostic and therapeutic monitoring. Among patients with EGFR mutations in tumor biopsy, the concurrent detection of EGFR mutation in plasma DNA was found to confer a less favorable prognosis in terms of overall survival than those patients with EGFR mutations in tumor biopsy but the corresponding mutation was not detected in plasma. Other oncogenic mutations with therapeutic implications in lung tumors are yet to be fully explored, like ALK, KRAS, ROS1 or NTRK1 mutations. It is not exactly the tumor – but the mutations in the tumor that need to be explored with reference to clinical behavior. Even with EGFR mutation with well-established clinical implications, further exploration into its mechanistic functions will help in understanding of drug resistance. Lung cancer cell lines established from patients with known mutation profiles could be useful tools for studying the biology of known molecular targets as well as for therapeutic testing. Four new lung adenocarcinoma and one mesothelioma cell lines were established from patients with different clinical characteristics and oncogenic mutation profiles. These cell lines with defined mutation profiles will provide tools for exploration of lung cancer and mesothelioma biology with respect to molecular therapeutic targets. The Large Tumor Suppressor 2 (LATS2) gene was a differentially expressed gene between EGFR mutant and wildtype lung adenocarcinomas. The differential LATS2 expression levels were predictive of survival in patients with resected lung AD and may modulate tumor growth via different signaling pathways in EGFR mutant and wild-type tumors. The identification of oncogenic mutations has led to a new paradigm of targeted therapy in lung cancer. Further improvements in outcome of lung cancer management will stem from research into the biology of oncogenic mutations and their clinico-pathological correlations, which would fuel parallel development of clinically efficacious targeted therapies.
published_or_final_version
Medicine
Master
Doctor of Medicine

Non-small cell lung cancer (NSCLC) causes most of the cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs), like erlotinib and crizotinib, are commonly used as specific treatments targeting epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Autophagy is a highly conserved cellular process in response to stress. Tumor microenvironment (TME) is composed of both tumor cells and stromal cells. This study aimed to investigate whether autophagy could confer intrinsic and acquired resistance to TKIs in NSCLC, and its role in the presence of TME or in animal models. In the first part of this study, the effect of EGFR TKI or ALK TKI on sensitive NSCLC cells to generate autophagy was investigated, and manipulation of autophagy in these cell lines was performed. Autophagy inhibition was shown to enhance apoptotic effect of TKIs in sensitive NSCLC cells. This part provided strong evidence that TKIs and autophagy inhibitor chloroquine (CQ) work synergistically in sensitive NSCLC cells. Autophagy induction by erlotinib treatment was observed in a HCC827 (lung adenocarcinoma, EGFR exon 19 del) xenograft model, which was in line with the in vitro observation. Correspondingly, the combination of erlotinib (12.5 mg/kg) with CQ (50 mg/kg) in the HCC827 xenograft model achieved greater tumor growth suppression, compared with single drug treatments. In the second part of this study, a model of TME was established to allow study of autophagy under such circumstances. An activated TME with cytokine production, autophagy induction and epithelial-to-mesenchymal transition (EMT) was generated by co-culturing NSCLC cells and human fibroblasts. Sensitivity to TKI under TME was not affected, and combination of chloroquine with TKI under TME remained synergistic compared with single treatments. In the third part of this study, erlotinib-resistant (ER) HCC827 cells were acquired by stepwise exposure to increasing concentrations of erlotinib in cell culture. Common acquired resistance mechanisms to EGFR TKI (EGFR T790M or c-MET amplification) were excluded in this ER HCC827 model, except EMT. Autophagy status in ER HCC827 cells was studied and autophagy manipulation was performed. It was found that CQ and erlotinib worked synergistically to induce cell death even in ER HCC827 cells. In an ER HCC827 xenograft model, significant degree of autophagy and EMT was evident. Interestingly, combining erlotinib (25 mg/kg) with CQ (50 mg/kg) showed better inhibitory effect on tumor growth compared with single treatments. In summary, TKIs induced both apoptosis and autophagy in EGFR-mutated and ALK-rearranged NSCLC cells. Autophagy inhibition by CQ enhanced TKI-induced cell death in sensitive cells. The presence of TME did not confer TKI resistance. Autophagy was highly activated in EGFR-mutated NSCLC cells with acquired resistance to erlotinib. Combination of CQ with erlotinib remained synergistic in the presence of TME and acquired resistance, both in vitro and in vivo.
published_or_final_version
Medicine
Doctoral
Doctor of Philosophy

The effect of lateral electron disequilibrium on patient dose has been investigated. This has been achieved by dosimetry in lung and air cavity phantoms at megavoltage x-ray energies. The scatter function photon beam models for tissue inhomogeneity, such as the ETAR correction algorithm, currently implemented in commercial treatment planning systems do not predict the dose distribution accurately in many situations where lateral electron equilibrium does not exist. The lung phantom is made up of solid water slabs and lung analogue slabs. Using a thimble ionization chamber, a Markus ionization chamber and TLDs the problems of central axis dose reduction and penumbral flaring in lung for x-rays have been investigated. It is found that the ETAR correction predicts the dose at mid lung with varying degrees of accuracy depending on the field size. It was found that internal body cavities, depending on their size, experience underdose or overdose in the distal surfaces of the cavities when compared with the results predicted by an ETAR correction algorithm. Therefore, this energy is not recommended for use in situations where cavities arise

Thesis: S.B., Massachusetts Institute of Technology, Department of Mechanical Engineering, May, 2020
Cataloged from the official PDF of thesis.
Includes bibliographical references (page 17).
Lung disease such as pneumonia is one of the leading causes of mortality throughout the world. Currently, many screening techniques performed on the lungs are too expensive, cumbersome, not continuous, and not easily understood without proper medical training. Furthermore, with the pandemic of Covid-19, the demand of screening patients in a non-invasive method has skyrocketed. Stethoscopes require training to understand the abnormalities when listening to the sounds the body makes, also known as auscultation. In this thesis, we sought to develop a lightweight, flexible, wearable fabric that can perform auscultation on the lungs. These fibers were created using the thermal drawing process that allows the fibers to perform various functions depending on the materials used for the draw. The initial solution used a conductive fiber created by injecting a liquid metal into a hollow fiber. This was deemed inadequate as the fiber generated a lot of noise and was only capable of detecting respiratory rates on a body with minimal movement. With minimal movement, this destroyed the purpose of having the fiber be mobile and flexible. The second solution utilized a nanostructured piezoelectric fiber to listen to the sounds the body makes. The piezoelectric fiber was successfully able to detect the sound of a heartbeat, but the lung sounds were overwhelmed due to the loudness of the heart. These sounds were measured with the fiber placed on the chest. For future studies, the fiber will be placed in various locations on the body to determine the optimal location for auscultation of the lungs. Furthermore, the shape of the fiber network will be optimized, creating an amplifying effect in the direction of interest. This will be an attempt to minimize the noise coming from the heart and focus more on the sounds the lung makes.
by Johnny Fung.
S.B.
S.B. Massachusetts Institute of Technology, Department of Mechanical Engineering

Over 26 million Americans suffer from pulmonary disease, resulting in more than 150,000 deaths annually. Lung transplantation remains the only definitive treatment for many patients, but has meager survival rates and only approximately 1,700 of the 2,200 patients added to the lung transplant wait list each year are transplanted. Extracorporeal gas exchangers have been used as an alternative to mechanical ventilation in acute respiratory failure and as a bridge to transplantation in chronic respiratory failure. Current gas exchangers are limited by their high resistance and low biocompatibility that lead to patient complications and device clot formation. Therefore, there exists a dire need for improved devices that can act as destination therapy. To accomplish the goal of destination therapy, this dissertation discusses three studies that were performed to pave the way. First, I examined clot formation and failure patterns of two common clinical devices (Maquet’s CardioHelp (CH) and Quadrox (Qx)) to further our understanding of their limitations with respect to long-term support. Overall, it was demonstrated that the Qx devices fail earlier and more frequently than CH devices and result in a significantly greater reduction in platelet count, and that a four-inlet approach is beneficial. Next, I determined the optimal sweep gas nitric oxide (NO) concentration that minimizes platelet binding and activation while ensuring that blood methemoglobin (metHb) concentrations increase less than 5%. Miniature artificial lungs were attached to rabbits in a pumped veno-venous configuration and run for 4 h with NO added to the sweep gases in concentrations of 0, 100, 250, and 500 ppm (n=8 ea.). 100 ppm significantly reduced the amount of platelet consumption (p < 0.05), reduced platelet activation as measured by soluble p-selectin (p < 0.05), and had negligible increases in metHb and will thus be used in future experiments. Last, I tested the Pulmonary Assist Device (PAD) which was designed for long term use as a bridge to transplantation and destination therapy. Benchtop experiments were performed that confirmed that it meets our design and performance goals. From here, we are equipped to commence with 30-day PAD testing in sheep.

Thesis (MMed)--Stellenbosch University, 2015.
ENGLISH ABSTRACT: Background: The LODOX Statscan is a whole-body digital X-ray scanning device which was adapted for medical usage. The LODOX has an established role in the field of Forensic Pathology where it shows high sensitivity and specificity for the detection of skeletal pathology and foreign bodies. The role of the scanner in the detection of soft tissue pathology in the lungs of adults has not been reported and this study aims to review the radio-pathological correlation and the applicability of LODOX as a viable screening tool in the detection of lung pathology in post mortem cases. Methods: We prospectively reviewed cases which were referred for medico-legal autopsy between November 2012 and March 2013 to the Tygerberg Forensic Pathology Service mortuary, Cape Town, South Africa. All cases meeting the prescribed inclusion criteria underwent LODOX scanning as well as macroscopic and microscopic evaluation of the lungs as permitted by the Inquests Act 58 of 1959. The macroscopic and microscopic variables were considered the “gold standard” when compared with the results of the LODOX. The sensitivity, specificity, positive and negative predictive values were assessed. Results: One hundred and fifty nine cases (159) were included in the study. The most common radiographic patterns reported were the presence of ground glass opacities and consolidation. Overall, low to moderate sensitivity of these LODOX patterns in the prediction of pneumonic microscopic pathology (oedema, acute and chronic inflammation and features of diffuse alveolar damage) was noted. These values were lower than that reported for pneumonia using conventional X-rays. Additionally, these LODOX patterns have a high probability of representing oedema or autolytic/decomposition change. Pneumothorax was the most common pleural pathology detected on LODOX, but autopsy correlation could not be performed. Poor to no correlation was noted with the variables of cavity, malignant tumour, and bronchiectasis, but the prevalence of these conditions in our cohort was low. In general, LODOX predictions were better at excluding pathology which was not present rather than confirming pathology which was present. Conclusions: The LODOX offers excellent evidentiary value in the demonstration of a pneumothorax but currently has limited value as a “stand alone” test in the field of Forensic Pathology. However the continued use of the LODOX as an adjunct examination, as well as prospective study of its applicability, is advised.
AFRIKAANSE OPSOMMING: Agtergrond: Die LODOX Statscan is ‘n heel-liggaam digitale X-straal skandeer apparaat wat aangepas is vir mediese gebruik. Die LODOX het ‘n gevestigde rol in Geregtelike Patologie, waar dit ‘n hoë sensitiwiteit en spesifisiteit het in die opsporing van skeletale patologie en vreemde voorwerpe. Die rol van die skandeerder in die opspoor van sagte weefsel patologie in die longe van volwassenes is nog nie gerapporteer nie, en hierdie studie ondersoek die radio-patologiese korrelasie en toepaslikheid van LODOX as ‘n doeltreffende siftingsmeganisme om long patologie op te spoor in post-mortale gevalle. Metode: Gevalle wat verwys is na die Tygerberg Geregtelike Patologie Diens lykshuis in Kaapstad, Suid-Afrika vir medies-geregtelike outopsies tussen November 2012 en Maart 2013, is prospektief geëvalueer. Alle gevalle wat die voorgeskrewe insluitingskriteria nagekom het, het LODOX skandering asook makroskopiese en mikroskopiese ondersoek van die longe ondergaan, soos toegelaat deur die Wet op Geregtelike Doodsondersoeke Nr 58 van 1959. Die makroskopiese en mikroskopiese veranderlikes is beskou as die “goud standaard” in vergelyking met die resultate van die LODOX. Die sensitiwiteit, spesifisiteit, positiewe en negatiewe voorspellingswaardes is beoordeel. Resultate: Eenhonderd-nege-en-vyftig gevalle (159) is ingesluit in die studie. Die algemeenste radiografiese pattroon wat gerapporteer is, was die teenwoordigheid van gemaalde glas opasiteit en konsolidasie. In geheel is lae to matige sensitiwiteit van hierdie LODOX beelde waargeneem in die voorspelling van pneumoniese mikroskopiese patologie (edeem, akute en chroniese ontsteking, en eienskappe van diffuse alveolêre skade). Hierdie waardes was laer as die wat gerapporteer is vir pneumonie met konvensionele X-strale. Verder het hierdie LODOX beelde ‘n hoë waarskynlikheid om edeem en/of outolise/ontbinding uit te beeld. Pneumotoraks was die algemeenste pleurale patologie wat waargeneem is met die LODOX, maar outopsie korrelasie kon nie gedoen word nie. Swak tot geen korrelasie is gemerk vir die veranderlikes kaviteit, maligne tumor en brongi-ektase, maar die prevalensie van hierdie toestande in ons kohort was laag. Oor die algemeen was LODOX voorspellings beter om patologie wat nie teenwoordig is nie, uit te skakel, eerder as om patologie wat teenwoordig is, te bevestig. Gevolgtrekking: The LODOX is ‘n uitstekende bewysstuk in die aantoon van ‘n pneumotoraks, maar huidiglik het dit beperkte waarde as onafhanklike toets in die veld van Geregtelike Patologie. Desnieteenstaande word die verdere gebruik van LODOX as bydraende ondersoek, sowel as die prospektiewe studie van sy toepaslikheid aanbeveel.