Errata has been inserted inside back pages. / Bibliography: leaves 180-186. / viii, 186 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Effects of stenoses on characteristics such as pressure drops, flow velocities and shearing stresses on the arterial walls are examined and their significance on the progression of arterial diseases is discussed. / Thesis (Ph.D.)--University of Adelaide, Dept. of Applied Mathematics, 1996

Experiments described in this thesis address the pathogenesis of aortic valve sclerosis/stenosis using a bench to bedside approach. In particular, the thesis begins with development of a technique using ultrasonic backscatter analyses to quantitate the early stages of aortic stenosis. Subsequent chapters utilized this methodology to quantitate aortic valve structural changes in a model and intervention study of aortic stenosis in rabbits. The last chapters are human studies designed to identify factors associated with presence of aortic sclerosis/stenosis; with particular interest in potential association of endothelial dysfunction/inflammation/platelet aggregation with abnormal aortic valve structure quantitated by ultrasonic backscatter. In Chapter 1 (Introduction) the relevant literature is reviewed. Development of ultrasonic backscatter to quantitate aortic sclerosis (Chapter 2) Aortic valve sclerosis (ASc) is detected when there is visual assessment of focal increases in echogenicity of the aortic valve most commonly assessed by echocardiography. However, there is no previously described method to quantitate degree of aortic valve structural abnormality as ASc is not associated with marked hemodynamic obstruction quantifiable by Doppler echocardiography. The current study used ultrasonic backscatter to quantitate aortic valve structural abnormality in patients assessed as having ASc based on valve appearances, compared to young healthy volunteers with normal aortic valves. The results of the study indicate: 1) that the mean levels of aortic valve backscatter in ASc patients are approximately 60% greater than in young healthy volunteers (ie aortic valve backscatter scores ≥ 16dB are not consistent with normal aortic valve structure), 2) ultrasonic backscatter scores in ASc patients are directly correlated with subjective scoring of sclerosis and with a positive trend with transvalvular pressure gradients in patients with mild-moderate aortic stenosis, and most importantly, 3) ultrasonic backscatter is a reproducible technique, with mean differences between estimates based on repeat echocardiograms of 2.3 ± 1.7 (9.1%). These results indicate that ultrasonic backscatter could be used as a quantitative measure of aortic valve structural abnormality in epidemiology and for examination of interventions. In vivo studies Development of an animal model of aortic stenosis with vitamin D2 (Chapter 3) The aim of the study was to develop an appropriate animal model for AS. The study used vitamin D2 alone at 25,000IU/4 days weekly (vit-D2) for 8 weeks to induce AS in rabbits. Results showed that: 1) rabbits in the vit-D2 group had significantly increased in transvalvular velocity and pressure gradients compared to rabbits in the control group (normal chow + drinking water); this was consistent for aortic valve ultrasonic backscatter scores; 2) aortic valve immunohistochemistry/histology showed marked calcification, neutral lipids, macrophage, and leukocyte infiltrations for rabbits in the vit- D2 group (ie consistent with histology of human AS); 3) significant elevation of asymmetric dimethylarginine (ADMA) concentrations in the vit-D2 group occurred compared to controls over the 8 weeks treatment period; the change in ADMA concentrations correlated significantly with the change in transvalvular pressure gradients for rabbits in the vit-D2 group; 4) rabbits in the vit-D2 group had significantly impaired endothelium-dependent acetylcholine-induced aortic relaxation, and this effect was completely abolished by the nitric oxide synthase inhibitor (L-NAME); 5) the addition of 0.5% cholesterol-supplemented diet to the vitamin D2 regimen did not accentuate the development of AS. Thus, treatment with vitamin D2 at 25,000IU/4 days weekly for 8 weeks significantly induced AS with similar aortic valve pathology to that of human AS; therefore, the model is suitable for use in examining potential therapeutic interventions in AS. Effects of ramipril on development of AS in rabbits (Chapter 4) Using this animal model, this study aimed to examine the effects of the angiotensinconverting enzyme inhibitor (ACEi) ramipril on development of AS. Rabbits (n=28) treated for 8 weeks were divided into 2 groups: (a) vitamin D2 alone (n=10) (normal chow + 25,000IU vitamin D2 in drinking water); (b) vitamin D2/Ramipril (n=12) (normal chow+25,000IU vitamin D2/Ramipril (0.5mg/kg) in drinking water). Six further rabbits constituted a normal reference group (no treatment was given). The results for comparisons between vitamin D2/ramipril vs vitamin D2 alone were as follows: 1) ramipril-treated rabbits had significantly less severe hemodynamic obstructions (p<0.05, for both) as assessed by transvalvular velocity, and aortic valve area; with borderline reduction in aortic valve backscatter (p=0.08); 2) ramipril significantly reduced plasma ADMA concentrations; 3) there was improvement in acetylcholine-induced aortic relaxation (p=0.056), with significant improvement in sodium nitroprusside-induced relaxation (p<0.05); 4) there was a strong inverse correlation between acetylcholineinduced aortic relaxation and aortic valve backscatter score (0<0.001), thus providing further evidence of the potential role of nitric oxide in retarding the development of AS in this model. These data provide a strong rationale for the inception of a randomized trial of ACE inhibition as a strategy for limitation of AS progression in humans. Human studies Aortic stenosis is associated with elevated plasma levels of asymmetric dimethylarginine (ADMA) concentrations in humans (Chapter 5). Given the findings that aortic stenosis induced by vitamin D2 in rabbits also caused elevation of plasma ADMA concentrations, a physiological inhibitor of nitric oxide synthase, a mediator and marker of endothelial dysfunction and an indicator of incremental cardiovascular risk. The study sought to determine whether plasma ADMA concentrations are elevated independently of pre-existing coronary risk factors in subjects with at least moderate aortic stenosis (n=42) compared to age-matched patients with normal aortic valves (n=42): as determined both by visual assessment and with aortic valve backscatter scores < 16dB. Results for this study were as follows: 1) plasma ADMA concentrations were not statistically different between the AS and non-AS group (median 0.59 vs 0.54 µmol/L, p=0.13, Mann-Whitney test) on univariate analysis; 2) backward stepwise multiple linear regression showed the presence of AS was a significant predictor of elevated ADMA concentrations (p=0.04, 95% CI =0.001, 0.072). 3) in addition, elevated plasma ADMA concentrations were also associated with history of atrial fibrillation (p=0.009, 95% CI=0.015, 0.100), and negatively associated with creatinine clearance (p=0.01, 95% CI=-0.002, 0.000), and the use of statin therapy (p=0.01, 95% CI=-0.081, -0.011). Therefore, in conclusion, this study found that AS is independently associated with elevation of ADMA concentrations, beyond that implied by “conventional” risk factors for endothelial dysfunction. The clinical status of AS as an incremental marker of cardiovascular risk may reflect ADMA-mediated endothelial dysfunction. Assessment of factors associated with ASc in a random ageing population study (Chapter 6). There have been few clinical studies of factors associated with ASc. Previous population studies have established that ASc is an independent correlate of incremental risk of coronary events. Having established that patients with AS have increased plasma ADMA concentrations (Chapter 5), it was now aimed to determine whether subjects with increased aortic valve backscatter scores (ASc) also have other markers of endothelial dysfunction/NO effects, independent of preexisting coronary risk factors. The study was designed to identify such anomalies, if they existed, on an incremental basis to other putative correlates of ASc, including coronary risk factors, renal dysfunction and vitamin D levels. Random selected subjects (n=253) aged between 51 to 77 years were evaluated. All patients underwent transthoracic echocardiography examination; aortic valve ultrasonic backscatter score (AVBS), was used to quantitate echogenicity of the aortic valve. Conventional coronary risk factors were identified on history. Integrity of NO generation/response was assessed via (i) plasma ADMA concentrations; (ii) inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP); (iii) aortic augmentation index (AIx), a measure of arterial stiffness/wave reflection. All putative correlations with AVBS were examined by univariate and stepwise multiple linear regression analyses. On the basis of echocardiographic appearances, ASc was present in 63 subjects (25.4%); mean AVBS scores was 14.9±4.6dB (SD) vs 11.2±3.9dB (SD) in the presence vs absence of ASc (p<0.001). Univariate analyses revealed that platelet responsiveness to NO was inversely correlated with AVBS (β=-0.16, p=0.02); but [ADMA] and AIx were not. On multiple linear regression, significant correlates of increased AVBS were: (i) advanced age (β=0.21, p=0.003), (ii) low body mass index (β=-0.23, p=0.001); and (iii) impaired platelet responsiveness to NO (β=-0.16, p=0.02). In Chapter 7, the implications of the overall findings in this thesis are discussed in relation to future perspective. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1309350 / Thesis(Ph.D.) -- School of Medicine, 2008

Experiments described in this thesis address the pathogenesis of aortic valve sclerosis/stenosis using a bench to bedside approach. In particular, the thesis begins with development of a technique using ultrasonic backscatter analyses to quantitate the early stages of aortic stenosis. Subsequent chapters utilized this methodology to quantitate aortic valve structural changes in a model and intervention study of aortic stenosis in rabbits. The last chapters are human studies designed to identify factors associated with presence of aortic sclerosis/stenosis; with particular interest in potential association of endothelial dysfunction/inflammation/platelet aggregation with abnormal aortic valve structure quantitated by ultrasonic backscatter. In Chapter 1 (Introduction) the relevant literature is reviewed. Development of ultrasonic backscatter to quantitate aortic sclerosis (Chapter 2) Aortic valve sclerosis (ASc) is detected when there is visual assessment of focal increases in echogenicity of the aortic valve most commonly assessed by echocardiography. However, there is no previously described method to quantitate degree of aortic valve structural abnormality as ASc is not associated with marked hemodynamic obstruction quantifiable by Doppler echocardiography. The current study used ultrasonic backscatter to quantitate aortic valve structural abnormality in patients assessed as having ASc based on valve appearances, compared to young healthy volunteers with normal aortic valves. The results of the study indicate: 1) that the mean levels of aortic valve backscatter in ASc patients are approximately 60% greater than in young healthy volunteers (ie aortic valve backscatter scores ≥ 16dB are not consistent with normal aortic valve structure), 2) ultrasonic backscatter scores in ASc patients are directly correlated with subjective scoring of sclerosis and with a positive trend with transvalvular pressure gradients in patients with mild-moderate aortic stenosis, and most importantly, 3) ultrasonic backscatter is a reproducible technique, with mean differences between estimates based on repeat echocardiograms of 2.3 ± 1.7 (9.1%). These results indicate that ultrasonic backscatter could be used as a quantitative measure of aortic valve structural abnormality in epidemiology and for examination of interventions. In vivo studies Development of an animal model of aortic stenosis with vitamin D2 (Chapter 3) The aim of the study was to develop an appropriate animal model for AS. The study used vitamin D2 alone at 25,000IU/4 days weekly (vit-D2) for 8 weeks to induce AS in rabbits. Results showed that: 1) rabbits in the vit-D2 group had significantly increased in transvalvular velocity and pressure gradients compared to rabbits in the control group (normal chow + drinking water); this was consistent for aortic valve ultrasonic backscatter scores; 2) aortic valve immunohistochemistry/histology showed marked calcification, neutral lipids, macrophage, and leukocyte infiltrations for rabbits in the vit- D2 group (ie consistent with histology of human AS); 3) significant elevation of asymmetric dimethylarginine (ADMA) concentrations in the vit-D2 group occurred compared to controls over the 8 weeks treatment period; the change in ADMA concentrations correlated significantly with the change in transvalvular pressure gradients for rabbits in the vit-D2 group; 4) rabbits in the vit-D2 group had significantly impaired endothelium-dependent acetylcholine-induced aortic relaxation, and this effect was completely abolished by the nitric oxide synthase inhibitor (L-NAME); 5) the addition of 0.5% cholesterol-supplemented diet to the vitamin D2 regimen did not accentuate the development of AS. Thus, treatment with vitamin D2 at 25,000IU/4 days weekly for 8 weeks significantly induced AS with similar aortic valve pathology to that of human AS; therefore, the model is suitable for use in examining potential therapeutic interventions in AS. Effects of ramipril on development of AS in rabbits (Chapter 4) Using this animal model, this study aimed to examine the effects of the angiotensinconverting enzyme inhibitor (ACEi) ramipril on development of AS. Rabbits (n=28) treated for 8 weeks were divided into 2 groups: (a) vitamin D2 alone (n=10) (normal chow + 25,000IU vitamin D2 in drinking water); (b) vitamin D2/Ramipril (n=12) (normal chow+25,000IU vitamin D2/Ramipril (0.5mg/kg) in drinking water). Six further rabbits constituted a normal reference group (no treatment was given). The results for comparisons between vitamin D2/ramipril vs vitamin D2 alone were as follows: 1) ramipril-treated rabbits had significantly less severe hemodynamic obstructions (p<0.05, for both) as assessed by transvalvular velocity, and aortic valve area; with borderline reduction in aortic valve backscatter (p=0.08); 2) ramipril significantly reduced plasma ADMA concentrations; 3) there was improvement in acetylcholine-induced aortic relaxation (p=0.056), with significant improvement in sodium nitroprusside-induced relaxation (p<0.05); 4) there was a strong inverse correlation between acetylcholineinduced aortic relaxation and aortic valve backscatter score (0<0.001), thus providing further evidence of the potential role of nitric oxide in retarding the development of AS in this model. These data provide a strong rationale for the inception of a randomized trial of ACE inhibition as a strategy for limitation of AS progression in humans. Human studies Aortic stenosis is associated with elevated plasma levels of asymmetric dimethylarginine (ADMA) concentrations in humans (Chapter 5). Given the findings that aortic stenosis induced by vitamin D2 in rabbits also caused elevation of plasma ADMA concentrations, a physiological inhibitor of nitric oxide synthase, a mediator and marker of endothelial dysfunction and an indicator of incremental cardiovascular risk. The study sought to determine whether plasma ADMA concentrations are elevated independently of pre-existing coronary risk factors in subjects with at least moderate aortic stenosis (n=42) compared to age-matched patients with normal aortic valves (n=42): as determined both by visual assessment and with aortic valve backscatter scores < 16dB. Results for this study were as follows: 1) plasma ADMA concentrations were not statistically different between the AS and non-AS group (median 0.59 vs 0.54 µmol/L, p=0.13, Mann-Whitney test) on univariate analysis; 2) backward stepwise multiple linear regression showed the presence of AS was a significant predictor of elevated ADMA concentrations (p=0.04, 95% CI =0.001, 0.072). 3) in addition, elevated plasma ADMA concentrations were also associated with history of atrial fibrillation (p=0.009, 95% CI=0.015, 0.100), and negatively associated with creatinine clearance (p=0.01, 95% CI=-0.002, 0.000), and the use of statin therapy (p=0.01, 95% CI=-0.081, -0.011). Therefore, in conclusion, this study found that AS is independently associated with elevation of ADMA concentrations, beyond that implied by “conventional” risk factors for endothelial dysfunction. The clinical status of AS as an incremental marker of cardiovascular risk may reflect ADMA-mediated endothelial dysfunction. Assessment of factors associated with ASc in a random ageing population study (Chapter 6). There have been few clinical studies of factors associated with ASc. Previous population studies have established that ASc is an independent correlate of incremental risk of coronary events. Having established that patients with AS have increased plasma ADMA concentrations (Chapter 5), it was now aimed to determine whether subjects with increased aortic valve backscatter scores (ASc) also have other markers of endothelial dysfunction/NO effects, independent of preexisting coronary risk factors. The study was designed to identify such anomalies, if they existed, on an incremental basis to other putative correlates of ASc, including coronary risk factors, renal dysfunction and vitamin D levels. Random selected subjects (n=253) aged between 51 to 77 years were evaluated. All patients underwent transthoracic echocardiography examination; aortic valve ultrasonic backscatter score (AVBS), was used to quantitate echogenicity of the aortic valve. Conventional coronary risk factors were identified on history. Integrity of NO generation/response was assessed via (i) plasma ADMA concentrations; (ii) inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP); (iii) aortic augmentation index (AIx), a measure of arterial stiffness/wave reflection. All putative correlations with AVBS were examined by univariate and stepwise multiple linear regression analyses. On the basis of echocardiographic appearances, ASc was present in 63 subjects (25.4%); mean AVBS scores was 14.9±4.6dB (SD) vs 11.2±3.9dB (SD) in the presence vs absence of ASc (p<0.001). Univariate analyses revealed that platelet responsiveness to NO was inversely correlated with AVBS (β=-0.16, p=0.02); but [ADMA] and AIx were not. On multiple linear regression, significant correlates of increased AVBS were: (i) advanced age (β=0.21, p=0.003), (ii) low body mass index (β=-0.23, p=0.001); and (iii) impaired platelet responsiveness to NO (β=-0.16, p=0.02). In Chapter 7, the implications of the overall findings in this thesis are discussed in relation to future perspective. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1309350 / Thesis(Ph.D.) -- School of Medicine, 2008

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

BACKGROUND Aortic stenosis is a common and potentially fatal condition in which fibro-calcific changes within the valve leaflets lead to the obstruction of blood flow. Severe symptomatic stenosis is an indication for aortic valve replacement and timely referral is essential to prevent adverse clinical events. Calcification is believed to represent the central process driving disease progression. 18F-Fluoride positron emission tomography computed tomography (PET-CT) and CT aortic valve calcium scoring (CT-AVC) quantify calcification activity and burden respectively. The overarching aim of this thesis was to evaluate the applications of these techniques to the study and management of aortic stenosis. METHODS AND RESULTS REPRODUCIBILITY The scan-rescan reproducibility of 18F-fluoride PET-CT and CT-AVC were investigated in 15 patients with mild, moderate and severe aortic stenosis who underwent repeated 18F-fluoride PET-CT scans 3.9±3.3 weeks apart. Modified techniques enhanced image quality and facilitated clear localization of calcification activity. Percentage error was reduced from ±63% to ±10% (tissue-to-background ratio most-diseased segment (MDS) mean of 1.55, bias -0.05, limits of agreement - 0·20 to +0·11). Excellent scan-rescan reproducibility was also observed for CT-AVC scoring (mean of differences 2% [limits of agreement, 16 to -12%]). AORTIC VALVE CALCIUM SCORE: SINGLE CENTRE STUDY Sex-specific CT-AVC thresholds (2065 in men and 1271 in women) have been proposed as a flow-independent technique for diagnosing severe aortic stenosis. In a prospective cohort study, the impact of CT-AVC scores upon echocardiographic measures of severity, disease progression and aortic valve replacement (AVR)/death were examined. Volunteers (20 controls, 20 with aortic sclerosis, 25 with mild, 33 with moderate and 23 with severe aortic stenosis) underwent CT-AVC and echocardiography at baseline and again at either 1 or 2-year time-points. Women required less calcification than men for the same degree of stenosis (p < 0.001). Baseline CT-AVC measurements appeared to provide the best prediction of subsequent disease progression. After adjustment for age, sex, peak aortic jet velocity (Vmax) ≥ 4m/s and aortic valve area (AVA) < 1 cm2, the published CT-AVC thresholds were the only independent predictor of AVR/death (hazard ratio = 6.39, 95% confidence intervals, 2.90-14.05, p < 0.001). AORTIC VALVE CALCIUM SCORE: MULTICENTRE STUDY CT-AVC thresholds were next examined in an international multicenter registry incorporating a wide range of patient populations, scanner vendors and analysis platforms. Eight centres contributed data from 918 patients (age 77±10, 60% male, Vmax 3.88±0.90 m/s) who had undergone ECG-gated CT within 3 months of echocardiography. Of these 708 (77%) had concordant echocardiographic assessments, in whom our own optimum sex-specific CT-AVC thresholds (women 1377, men 2062 AU) were nearly identical to those previously published. These thresholds provided excellent discrimination for severe stenosis (c-statistic: women 0.92, men 0.88) and independently predicted AVR and death after adjustment for age, sex, Vmax ≥4 m/s and AVA < 1 cm2 (hazards ratio, 3.02 [95% confidence intervals, 1.83-4.99], p < 0.001). In patients with discordant echocardiographic assessments (n=210), CT-AVC thresholds predicted an adverse prognosis. BICUSPID AORTIC VALVES Within the multicentre study, higher continuity-derived estimates of aortic valve area were observed in patients with bicuspid valves (n=68, 1.07±0.35 cm) compared to those with tri-leaflet valves (0.89±0.36 cm p < 0.001,). This was despite no differences in measurements of Vmax (p=0.152), or CT-AVC scores (p=0.313). The accuracy of AVA measurments in bicuspid valves was therefore tested against alternative markers of disease severity. AVA measurements in bicuspid valves demonstrated extremely weak associations with CT-AVC scores (r2=0.08, p=0.02) and failed to correlate with downstream markers of disease severity in the valve and myocardium and against clinical outcomes. AVA measurements in bicuspid patients also failed to independently predict AVR/death after adjustment for Vmax ≥4 m/s, age and gender. In this population CT-AVC thresholds (women 1377, men 2062 AU) again provided excellent discrimination for severe stenosis. CONCLUSIONS Optimised 18F-fluoride PET-CT scans quantify and localise calcification activity, consolidating its potential as a biomarker or end-point in clinical trials of novel therapies. CT calcium scoring of aortic valves is a reproducible technique, which provides diagnostic clarity in addition to powerful prediction of disease progression and adverse clinical events.

Orientador: Erika Veruska Paiva Ortolan / Resumo: Introdução: Por volta de oitenta por cento dos acidentes envolvendo ingestão de cáusticos ocorrem em crianças. A estenose cáustica do esôfago é a sua principal complicação com grande morbidade. Lesões neoplásicas esofágicas podem desenvolver-se como uma complicação tardia desta estenose com um tempo médio de aparecimento entre o acidente e o desenvolvimento neoplásico de 15 a 30 anos. Considerando este risco, biopsias seriadas do esôfago são recomendadas com o objetivo de detecção precoce de displasias. Assim, um conhecimento abrangente da relação biológica entre cáusticos e neoplasia esofágica é de grande importância na identificação de novos biomarcadores que possibilitariam tratamento precoce. MicroRNAs (miRNAs) são RNAs pequenos, não codificadores de proteínas que regulam importantes processos celulares e têm se mostrado como robustos biomarcadores. O perfil global de expressão de miRNAs nesta população, seguida da identificação dos miRNA-alvo, pode levar à identificação da presença e magnitude do dano ao material genético em amostra de tecido esofágico obtido de pacientes portadores de estenose cáustica. Objetivos: Determinar o perfil global da expressão de miRNAs em células da mucosa esofágica de crianças portadoras de lesões por ingestão de cáusticos, com o objetivo de identificar miRNAs como biomarcadores associados a tumorigênese esofágica nesta população específica. Materiais e Métodos: Vinte e sete amostras esofágicas fixadas em formalina e embebidas em parafina (F... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: 80% of the caustic ingestions occur in children. Esophageal stricture is a major chronic complication with great morbidity. Esophageal neoplasms may develop as a late complication of caustic injury with a mean time between caustic ingestion and cancer development of 15-30 years. Serial biopsies are recommended aiming early detection of premalignant changes. Thus a comprehensive knowledge of biological relation between caustic and esophageal cancer is of major importance to identify the biomarkers that could enable an early treatment. MicroRNAs (miRNAs) are small non-coding RNA molecules and regulate key cellular processes during tumorigenesis and have been demonstrated as an useful diagnostic, prognostic and predictive biomarkers. Global miRNA expression profiling analysis in this population, followed by the identification of miRNA target genes, may lead to the identification of the presence and magnitude of damage to genetic material in a sample of esophageal tissue obtained from patients with caustic stenosis. Objectives: We aimed to identify global microRNA (miRNA) expression changes in cells of the esophageal mucosa from children with caustic lesions compared to paired macroscopic and microscopically normal esophageal tissue. Patient and Methods: 27 formalin fixed, paraffin embedded (FFPE) esophageal samples from 15 patients were divided into two groups according to the time elapsed after the injury (Group A: less than 5 years, Group B: more than 5 years). Tho... (Complete abstract click electronic access below) / Doutor

A intubação endotraqueal apresenta indicações irrefutáveis no manejo de crianças criticamente doentes. Entretanto, o contato do tubo endotraqueal com a laringe pode gerar lesões graves, especialmente estenose subglótica (ESG). A incidência descrita destas lesões varia entre 1,5% e 32%, dependendo do delineamento do estudo. Diversos fatores são citados como de risco para lesão de laringe por intubação, entretanto poucas são as evidências a este respeito, dificultando a promoção de atitudes preventivas. Objetivos: Determinar a incidência de lesões de laringe por intubação na Unidade de Terapia Intensiva Pediátrica (UTIP) do Hospital de Clínicas de Porto Alegre (HCPA) e estudar os fatores de risco associados, além de avaliar a factibilidade e segurança da realização de fibronasolaringoscopia (FNL) nas primeiras horas após a extubação. Pacientes e Métodos: Foram incluídos pacientes entre zero e quatro anos de idade intubados por mais de 24 horas na UTIP do HCPA entre dezembro de 2005 e novembro de 2006. Foram excluídos pacientes com sintomas laríngeos, intubação ou traqueostomia prévios. Durante o período de intubação foram coletados os dados referentes a fatores de risco. Foi realizada FNL nas primeiras 8 horas após a extubação, no leito da UTIP. As imagens obtidas das regiões supraglótica, glótica e subglótica foram gravadas e avaliadas posteriormente por examinador cegado, sendo os pacientes classificados em Grupo 1 (exames normais ou com alterações leves) ou Grupo 2 (alterações moderadas ou graves). Os pacientes do Grupo 1 foram acompanhados clinicamente e os do Grupo 2 submetidos a FNL após 7 a 10 dias de extubação. Os resultados foram apresentados em médias e desvio padrão (DP) quando a variável apresentava distribuição normal e em mediana e intervalos interquartil 25%-75% (IIQ25-75) quando não se apresentava dessa forma. Para análise estatística foram utilizados os testes do qui-quadrado, Exato de Fischer e de Man-Whitney. Para determinação dos pontos de corte para sensibilidade e especificidade, foi utilizada a curva ROC. Resultados: Foram incluídos 35 pacientes com mediana (IIQ25-75) de idade de 11,14 (6,14 e 26,26) semanas. A mediana (IIQ25-75) do tempo de intubação foi oito (6–12) dias. O tempo decorrido entre a extubação e a realização da FNL apresentou média (±DP) de 5,15 (±2,18) horas, sendo o índice de complicações menores de 2,85%. Foram identificados 21(60%) os casos correspondendo ao Grupo 1 e 14 (40%) ao Grupo 2. Quatro pacientes (11,4%) desenvolveram ESG, todos provenientes do Grupo 2. Não houve diferença quanto ao surgimento de sintomas respiratórios entre os pacientes com desenvolvimento de ESG e os demais. O maior uso de sedação extra e a percentagem de dias com reposicionamento do tubo endotraqueal foram as variáveis de risco com diferença estatisticamente significativa entre os grupos 1 e 2. O uso de 6,78 doses de sedação extra por dia intubado apresenta sensibilidade de 93% e especificidade de 81% para lesão moderada ou grave de laringe na extubação.Conclusões: A FNL é segura quando realizada nas primeiras horas após a extubação e fornece informações precisas sobre as condições da laringe. A incidência encontrada de ESG (11,4%) é comparável à descrita na literatura e os pacientes com esta complicação apresentam sintomas tardiamente. O percentual de dias com necessidade de reposicionamento do TET e o maior uso de sedação extra estão relacionados ao desenvolvimento de lesões de laringe. Considerando este último fator como medida indireta de agitação podemos inferir que esta está relacionada a lesão de laringe. / Irrefutable evidence exists showing that endotracheal intubation is recommended for the management of critically ill children. However, the contact of the endotracheal tube with the larynx may cause severe injury, especially subglottic stenosis (SGS). The incidence of these lesions ranges from 1.5% to 32%, depending on the study design. Several factors have been regarded as risk for laryngeal lesions following intubation, but there is scant evidence supporting this finding, which negatively interferes with the adoption of preventive measures. Objectives: To determine the incidence of laryngeal lesions during intubation in the pediatric intensive care unit (PICU) of Hospital de Clínicas de Porto Alegre (HCPA), Brazil, and to assess the risk factors involved, in addition to determining the feasibility and safety of flexible nasolaryngoscopy (FNL) within the first hours of extubation. Patients and Methods: Patients aged 0 to 4 years and intubated for more than 24 hours, between December 2005 and November 2006, were included in the study. Patients with laryngeal symptoms or previous intubation or tracheostomy were excluded. The data about risk factors were collected during the intubation period. FNL was performed within the first 8 hours after extubation, in the PICU. The images of the supraglottic, glottic and subglottic regions were recorded and later analyzed by a blinded investigator, and the patients were then classified into Group 1 (normal results or mild lesions) or Group 2 (moderate or severe lesions). Group 1 patients were clinically followed whereas Group 2 patients were submitted to FNL after 7 to 10 days of extubation. The results were presented as means and standard deviations (SD) when the variable was normally distributed and as median and 25%- 75% interquartile ranges (25-75 IQR) otherwise. The statistical analysis included the chisquare test, Fischer’s exact test and the Mann-Whitney test. The ROC curve was used to establish the cutoff points for sensitivity and specificity. Results: Thirty-five patients with median (25-75 IQR) age of 11.14 (6.14 and 26.26) weeks were included. Median (25-75 IQR) intubation time corresponded to eight (6–12) days. The time elapsed between extubation and FNL corresponded to a mean (±SD) of 5.15 (±2.18) hours, with a complication rate less than 2.85%. Twenty-one (60%) cases were classified into Group 1 and 14 (40%) into Group 2. Four patients (11.4%) developed SGS, and all of them belonged to Group 2. There was no statistical difference regarding the development of respiratory symptoms between SGS patients and other patients. The larger use of additional sedation and the percentage of days with repositioning of the endotracheal tube constituted the risk variables with statistically significant difference between Groups 1 and 2. The use of 6.78 doses of additional sedation per day of intubation had a sensitivity of 93% and specificity of 81% for moderate or severe laryngeal lesion at the time of extubation.FNL is safe when performed within the first hours after extubation and provides accurate information about the larynx. The incidence of SGS (11.4%) observed is comparable to the one described in the literature and the patients with this complication develop symptoms only later. The percentage of days with necessity for endotracheal tube repositioning and larger use of additional sedation are related to the development of laryngeal lesions. If we regard the latter factor as indirect measure of agitation, we may infer that it is related to laryngeal injury.