Intrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist as part of the normal pulmonary vasculature for over 50 years but have been underappreciated by physiologists and clinicians. Using a technique called saline contrast echocardiography we and others have demonstrated that during exercise or when breathing low oxygen gas mixtures IPAVA open, but breathing 100% oxygen during exercise prevents them from opening. However, the mechanism(s) for this dynamic regulation and the role IPAVA play in affecting pulmonary gas exchange efficiency remain unknown. In Chapter IV the infusion of epinephrine and dopamine into resting subjects opened IPAVA. While it is possible this opening was due to the direct vasoactive action of these catecholamines, the opening may simply be due to increases in cardiac output and pulmonary artery systolic pressure secondary to the cardiac effects of these drugs. In Chapter V I used Technetium-99m labeled macroaggregated albumin (99mTc-MAA) to quantify blood flow through IPAVA in exercising healthy humans. Initial attempts to correct for attenuation of the emitted signal were unsuccessful due to the time necessary for data acquisition and the resulting accumulation of free-99mTc. However, I used a blood sample to calculate freely circulating 99mTc which could be subtracted from the shunt fraction. Using this procedure I demonstrated for the first time using filtered solid particles that breathing 100% oxygen reduces blood flow through IPAVA during exercise. Finally, in Chapter VI I tackled the elephant in the room surrounding IPAVA in healthy humans: do these vessels play a role in pulmonary gas exchange efficiency? Our data suggest that the efficiency of pulmonary gas exchange is dependent on the driving pressure gradient for oxygen and the distance to blood flowing through the core of IPAVA. As such, with increases in exercise intensity the diffusion distance and transit time of blood at the core of IPAVA prevent complete gas exchange, thus blood flow through IPAVA acts as a shunt. This dissertation includes previously unpublished co-authored material.

The use of nebulization is becoming increasingly frequent in treatment of acute or chronic lung diseases for delivery of topically active drugs and is also an attractive way to deliver systemic drugs. A nebulizer can be defined by the aerodynamic properties of the emitted particles which are directly related to the lung deposition and the clinical response to a nebulized drug. New guidelines elaborated by an European norm (ENFR13544-1) aim to participate to a better control on quality and efficiency of existing devices and inspired the elaboration of the studies of this thesis. The aim of these works was to evaluate the nebulization function of a new kind of modality, the intrapulmonary percussive ventilation which contrarily to classical jet nebulizers nebulizes drugs under superimposed percussion conditions. In vitro measurements were realized by cascade impaction and laser diffraction. Lung deposition was investigated by imagery techniques and pharmacokinetic study. Aerodynamic properties were different between the in vitro methods. When measured by cascade impaction, MMAD and FPF were smaller for IPV comparatively to SST. By laser diffraction, FPF remained lower but MMAD was higher with IPV than with SST. The effect of percussions was greater on MMAD than on FPF. An irregular intrapulmonary deposition and a higher whole body deposition due to a higher extrapulmonary deposition with the IPV were measured by scintigraphy. The pharmacokinetic study highlighted that the drug output and the lung dose were lower when amikacin was delivered by IPV comparatively to SST. All results of these different studies seem unfavourable to the use of intrapulmonary percussive ventilation as modality of administration for nebulized drugs without further investigations. Results presented in this thesis concerning exclusively healthy subjects, we hope that they encouraged to perform complementary analysis and observations in different conditions such as patients with lung disease.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23100号 / 医博第4727号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 河本 宏, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No / The objective of this study was to develop SEDS-engineered budesonide particles suitable for dry powder inhalation delivery and to evaluate their aerosol performance across a range of passive dry powder inhalers (DPI). SEDS budesonide powders were manufactured in Nektar's SCF manufacturing plant and compared to the micronized drug and commercial powder (Pulmicort Turbuhaler, AstraZeneca). Aerosol performance was evaluated by determining emitted dose (ED) by a variation of the USP method and fine particle fraction (FPF) using Andersen cascade impaction. The SCF powder dispersed best in the Turbospin and Eclipse devices, exhibiting high EDs (70%-80%) and relatively low variability (RSD 8%-13%). Regardless of the device, the SEDS material outperformed both the micronized drug and the commercial powder, while exhibiting good batch-to-batch reproducibility (RSD <5%). All powders exhibited flow rate-dependent ED, albeit for the SEDS material it was minimized at reduced fill weights. This was attributed to inadequate and variable powder clearance from the capsules at low inspiratory flow rates, which was more pronounced in the Eclipse and Cyclohaler. The results demonstrate that SEDS is an attractive particle-engineering process that may enhance pulmonary performance of budesonide and possibly facilitate development of other small molecule pulmonary products in passive DPI.

La circulation pulmonaire est un système à faible pression (entre 10 et 15 mmHg au repos). Son principal rôle est la ré-oxygénation du sang qui permet l’apport aux organes du dioxygène nécessaire à leur fonctionnement. L’hyperTension Pulmonaire (HTP) est l’une de ses principales pathologies. Il s’agit d’une maladie rare engageant le pronostic vital du patient, définie par une pression artérielle pulmonaire moyenne supérieure ou égale à 25 mmHg au repos. Elle s’explique par une augmentation des résistances vasculaires pulmonaires liée, entre autres, au remodelage artériel présent dans cette pathologie participant à la diminution de la lumière artérielle. En effet, chez les patients atteint d’HTP, les trois tuniques formant l’artère (intima-media-adventice) voient leur structure se modifier. La plupart des travaux portent sur le remodelage de la media, mais de plus en plus d’études montrent que les premières altérations observées se situent au niveau de l’adventice. Plus précisément, les fibroblastes, les cellules majoritaires de cette tunique, agiraient comme régulateur clé de la fonction vasculaire pulmonaire. En réponse à un stress extérieur tel que l’hypoxie (à l’origine de certaines formes d'HTP), elles seraient les premières cellules à s’activer d'où leur dénomination par certains de « cellules sentinelles ». Cette activation se manifeste entre autres par des changements phénotypiques (différenciation en myofibroblastes), leur prolifération, leur migration, et la surproduction de protéines de la matrice extracellulaire. Ainsi les fibroblastes participent directement au remodelage artériel global observé dans l’HTP. Le calcium est connu pour réguler un grand nombre de voies de signalisation cellulaire impliquées dans les phénomènes précédemment cités. Au laboratoire, l’implication du canal TRPV4 (Transient Receptor Potential Vanilloid 4), un canal non sélectif perméable aux ions Ca2+, a déjà été montré concernant le remodelage de la media. L’activation du canal, amplifiée en situations pathologiques, participe à la migration et à la prolifération des cellules musculaires lisses des artères pulmonaires. Aussi, des données de la littérature montrent que TRPV4 joue un rôle important dans l’activité délétère des fibroblastes dans les sclérodermies, les fibroses pulmonaire et cardiaque. Il nous a donc semblé intéressant d’étudier l’implication des fibroblastes et du canal TRPV4 dans le remodelage adventitiel artériel lors de l’hypertension pulmonaire. Pour ce faire, nous nous sommes intéressés, dans une première partie, à l’implication du canal TRPV4 dans ce remodelage au niveau tissulaire. Nous avons ainsi montré, à l’aide de deux modèles animaux hypertendus, un induit par l’injection de monocrotaline et l’autre induit par une exposition hypoxique chronique, que la protéine TRPV4 est surexprimée dans l’adventice alors que son remodelage est significativement atténué chez des souris invalidées pour le gène trpv4. Dans un second temps, nous avons alors étudié le rôle de ce canal dans les réponses cellulaires impliquées dans le remodelage adventitiel. Pour cela nous avons mis au point la culture de fibroblastes d'adventice d'artères intrapulmonaires de rats. Puis par une approche pharmacologique (activateurs et bloqueurs du canal) et à l’aide de siRNA, nous avons montré que l’activation du canal TRPV4 favorise la prolifération (par incorporation de BrdU) et la migration (par test de brèche) des fibroblastes, ainsi que leur activité profibrotique avec la surproduction de matrice extracellulaire (MEC) (par quantification de l’expression protéique par Western blot). Il serait désormais intéressant de cultiver les fibroblastes en mimant in vitro les conditions pathologiques, en les plaçant dans un environnement hypoxique et/ou en les soumettant à un étirement chronique, et d’évaluer l’impact de l’HTP sur le canal et ses actions cellulaires. / Pulmonary circulation is a low pressure system (between 10 and 15 mmHg at rest). Its first role is blood oxygenation which allows to carry dioxygen to the organs fontionnality. Pulmonary Hypertension (PH) is one of the main pulmonary diseases. It is a rare and potentially fatal disorder, defined by a high arterial pulmonary mean pressure (greater than or equal to 25 mmHg at rest). This high pressure can be explained by the elevation of pulmonary arterial resistance and related to narrowing of the lumen of the artery, induced, among other, by the arterial remodeling in this pathology. Indeed, during the pathology implementation, the structure of the all three layers constituting the artery wall (intima-media-adventitia) is altered. The media and intima have received much attention from vascular biologists, howewer an increasing volume of experimental data indicates that this third compartment undergoes earlier and dramatic remodeling during PH. More specifically, the fibroblasts, the most abundant cells in adventitia, may act as key regulator of pulmonary vascular wall structure and function from the "outside-in". The fibroblasts may play the role of “sentinel cell” in the vessel wall. In responding to various stimuli, these cells are the first artery wall cells to show evidence of “activation” as proliferation, myofibroblast differenciation, migrationand invasion in the other wall layer, and extracellular matrix production. That way, fibroblasts participate directly to the overall artery remodeling observed in PH. Calcium is involved in numerous cellular signalling pathways such as those previously described. In the laboratory, we already proved that TRPV4 (Transient Receptor Potential Vanilloid) channel, a non-selective cationic channel calcium permeable, is involved in media remodeling. Moreover, several datas show that this channel play an important role in diseases in which we observe a negative role of fibroblast such as sclerodermia, cardiac and pulmonary fibrosis. Considering these results, we were interested in the role of TRPV4 in fibroblast during PH more precisely in the adventitial remodeling process observed in this pathology. We first demonstrated the involment of TRPV4 in the adventitia remodeling regarding the tissue. Using two different animal models of PH, chronic hypoxia and monocrotalin models, we identified that this protein was up-regulated in sick rats and the mouse knock-down for this gene developed attenuated PH and adventitia remodeling compare to the control. Then we studied the role of TRPV4 in the mechanism leading to the adventitia remodeling. Thanks to pharmacological molecule and siRNA we proved that activation of TRPV4 increased proliferation (BrdU assay), migration (wound assay) and fibrotic activity such as excessed production of extracellular matrix (using western blot analyse) of the fibroblasts. With all these results, it would be interested to culture fibroblasts in hypoxic conditions and/or subjecting themselves to chronicle stretch to imitate HTP pathology and evaluate TRPV4 role in these conditions

This study aimed at determining the prevalence of the hepatopulmonary syndrome (HPS) and intrapulmonary vascular dilation (IPVD), and how they relate to the arterial oxygenation, in schistosomotic patients with the hepatosplenic form (HSE). Method: Patients with HSE were submitted to arterial gasometry and contrast transthoracic echocardiogram (CTTE). Patients with IPVD were submitted to spirometry. The criteria to identify HSE patients were positive parasitological examination of feces and/or positive epidemiology and abdominal echography compatible with the hepatosplenic form of schistosomiasis, according to the Niamey criteria WHO. Patients with other liver diseases were excluded. Criterion for HPS: PaO2 < 80mmHg and/or AaPO2 ≥ 15 mmHg, IPVD diagnosed through CTEE, in adittion to schistosomotic portal hypertension. For the data analysis, the patients were classified under three groups: Group 1 Patients with HPS; Group 2 Patients with IPVD but no alterations in arterial oxygenation; Group 3 Patients without IPVD. Results: Seventeen out of forty patients (42.5%) presented IPVD, but only six met the criteria for HPS, showing a prevalence of 15%. Among those, only one HPS patient presented a level of PaO2 lower than 80 mmHg. The average age of the 40 schistosomotic patients was 48.6 years. No nail clubbing, spider nevi, or platypnea were observed. There was no relation between gender and presence of HPS or IPVD. PaO2 and AaPO2 medians differed significantly among the groups (P = 0.001 and P = 0.005, respectively). PaO2 was significantly higher in the group with IPVD while comparing to the group with no IPVD (P = 0.001). There was no significant difference while comparing the HPS group to the group with no IPVD (P = 0.957). AaPO2 was significantly lower in the group with IPVD while comparing to the group with no IPVD (P = 0.005). There was no significant difference while comparing the HPS group to the group with no IPVD (P = 0.381). Conclusion: The results indicate that the IPVD and PHS frequency in schistosomotic patients is similar to the one found in cirrhotic patients. The presence of IPVD does not correlate with alterations of the arterial oxygenation in patients with the hepatosplenic form of schistosomiasis. It is possible that changes in gas exchange are caused by other reasons unrelated to the presence of IPVD. / O objetivo deste estudo foi determinar a prevalência da síndrome hepatopulmonar (SHP) e dilatações vasculares intrapulmonares (DVIP) e suas relações com a oxigenação arterial em pacientes esquistossomóticos da forma hepatoesplênica (EHE). Métodos: Pacientes com EHE foram submetidos à gasometria arterial e ecocardiografia transtorácica com contraste (ETC). Espirometria foi realizada nos pacientes com DVIP. Os critérios para identificação dos pacientes com EHE foram parasitológico de fezes positivo e/ou epidemiologia positiva associada à ultrassonografia de abdome superior compatível com EHE, segundo critérios de Niamey OMS. Foram excluídos pacientes com outras doenças hepáticas. Critérios de SHP: PaO2 < 80mmHg e/ou AaPO2 ≥ 15 mm Hg, DVIP diagnosticado pelo ETC, além de hipertensão portal esquistossomótica. Para análise dos dados, os pacientes foram divididos em três grupos: Grupo 1 Pacientes com SHP; Grupo 2 Pacientes com DVIP sem alterações da oxigenação arterial; Grupo 3: Pacientes sem DVIP. Resultados: Dezessete/40 pacientes (42,5%) apresentaram DVIP, mas apenas 06 cumpriram critérios para SHP, demonstrando uma prevalência de 15%. Destes, apenas 01 paciente com SHP apresentou nível de PaO2 inferior a 80 mm Hg. A média da idade dos 40 pacientes com esquistossomose foi de 48,6 anos. Os pacientes não diferiram quanto aos critérios clínicos e bioquímicos. As médias da PaO2 e da AaPO2 diferiram significativamente entre os grupos (P= 0,001 e P = 0,005 respectivamente), sendo a PaO2 significativamente maior no grupo 2 quando comparado ao grupo 1 (p = 0.022) e ao grupo 3 (P = 0,001). Não houve diferença significativa na comparação entre grupo 01 x grupo 3 (P = 0,957). O AaPO2 foi significativamente menor para o grupo 2 quando comparado ao grupo 1 (p=0.01) e ao grupo 3 (P = 0,005). Não houve diferença significativa na comparação entre grupo 01 x grupo 3 (P = 0,381). Conclusão: Os resultados indicam que, em pacientes com EHE, ocorre DVIP e SHP em frequências semelhantes às encontradas em pacientes com cirrose. A presença de DVIP parece não levar a alterações da oxigenação arterial em pacientes com esquistossomose da forma hepatoesplênica, podendo as alterações de trocas gasosas serem causadas por outros motivos não relacionados à presença de DVIP

O presente estudo avaliou comparativamente o padrão hemodinâmico e a presença de vasodilatação intrapulmonar antes e após tratamento cirúrgico tardio (> 2 anos) da hipertensão portal através da desconexão ázigo portal com esplenectomia (DAPE) e anastomose esplenorenal distal (AERD) na esquistossomose mansônica forma hepatoesplênica. Foram estudados prospectivamente 37 pacientes portadores de hipertensão portal secundária a esquistossomose mansônica confirmada por biópsia hepática , sendo 21 pacientes do sexo masculino e 16 do sexo feminino, com idade média de 46,6 + 12 anos, no período de janeiro de 2007 a dezembro de 2008. A avaliação do padrão hemodinâmico sistêmico foi realizada através do Doppler transesofágico (Cardio QÒ) e da ecocardiografia bidimensional com Doppler nos pacientes dos grupos AERD (n=13) e DAPE (n=15) . Os resultados obtidos foram comparados com grupo controle constituído por 10 pacientes sem hipertensão portal submetidos à endoscopia digestiva alta para avaliação de dispepsia. A avaliação da presença de síndrome hepatopulmonar foi realizada em todos os pacientes através da ecocardiografia contrastada com infusão salina 0,9% nos grupos DAPE (n=15), AERD (n=13) e pré-operatório (n=9). Os pacientes que apresentavam vasodilatação intrapulmonar no período pré-operatório repetiram o exame após 30 dias do procedimento cirúrgico. Em relação ao padrão hemodinâmico sistêmico observou-se aumento significativo (p =0,001) do débito cardíaco no grupo AERD (5,08 ± 0,91 L/min) em relação ao controle (4,17 ± 0,52 L/min). Ao contrário, os pacientes submetidos à DAPE (4,36 ± 0,59 L/min) não apresentaram diferença estatística significante (p = 0,47) em relação ao controle (4,17 ± 0,52 L/min). Os pacientes do grupo AERD apresentaram aumento estatisticamente significante (p = 0,001) do volume sistólico (60,1 + 5,6 ml) em relação ao controle (53,2 + 5,6 ml), enquanto que não houve diferença significativa (p = 0,41) nos pacientes submetidos à DAPE (56 ± 9,4 ml) . Não houve diferença estatisticamente significante entre os valores médios da freqüência cardíaca e da pressão arterial sistêmica em relação ao controle (AERD, p= 0,22 , DAPE, p = 0,91), (AERD, p = 0,40, DAPE , p = 0,06), respectivamente. Em relação a ecocardiografia bidimensional com doppler observou-se aumento estatisticamente significante (p = 0,0001) do diâmetro diastólico do ventrículo esquerdo (DDVE) nos pacientes submetidos à AERD (55,4 ± xviii 4,25 mm) em relação ao período pré-operatório (48,4 ± 4,4 mm), fato este não observado nos pacientes submetidos à DAPE (50 ± 3,26 mm, p = 0,25). O volume diastólico final do ventrículo esquerdo (VDF) apresentou diferença estatisticamente significante (p = 0,00001) nos pacientes submetidos à AERD (172,7 ± 40,7 ml) em relação ao período pré-operatório (116,3 ± 31,3 ml). Não foi observada diferença estatisticamente significante do VDF dos pacientes submetidos à DAPE (126,9 ± 25,2 ml) em relação ao período pré-operatório (p = 0,31). Em relação ao diâmetro sistólico do ventrículo esquerdo (DSVE) observou-se aumento estatisticamente significante (p = 0,0004) nos pacientes submetidos à AERD (36 ± 3,8 mm) em relação ao período pré-operatório (30,6 ± 2,4 mm). Os pacientes do grupo DAPE (32,5 ± 3 mm) não apresentaram diferença estatisticamente significante em relação ao período pré-operatório (p = 0,06 ). O volume sistólico final do ventrículo esquerdo (VSF) apresentou diferença estatisticamente significante ( p = 0,001) e dentro do valores da normalidade nos pacientes submetidos à AERD (48,4 ± 16,1 ml) em relação ao período pré-operatório (29,1 ± 6,5 ml). Os pacientes do grupo DAPE (35 ±10,6 ml) não apresentaram diferença estatisticamente significante da média do VSF em relação ao período pré-operatório (p = 0,06). Observou-se diminuição estatisticamente significante (p = 0,006) e dentro dos valores da normalidade na média da fração de ejeção (FE) nos pacientes submetidos à AERD (70,9 ± 2,6%) em relação ao período pré-operatório (74,4± 3,6%). Os pacientes submetidos à DAPE (72 ± 3,5%) não apresentaram diferença estatisticamente significante (p = 0,06) em relação ao período pré-operatório. Em relação à fração de encurtamento da fibra miocárdica (Delta D%), observou-se diminuição estatisticamente significante (p = 0,03) e dentro dos valores da normalidade nos pacientes submetidos à AERD (34,5 ± 2,2%) em relação ao período pré-operatório (36,7± 3%). Os pacientes submetidos à DAPE (34,9 ± 2,7%) não apresentaram diferença estatisticamente significante na média do Delta D% em relação ao controle (p = 0,10). Em relação ao átrio esquerdo (AE), observou-se aumento estatisticamente significante (p = 0,002) nos pacientes submetidos à AERD (40,7 ± 4,6mm) em comparação ao pré-operatório (35,2 ± 4,3 mm). Não foi observada diferença estatisticamente significante no tamanho do AE nos pacientes submetidos à DAPE (37,4 ± 4,1 mm) em relação ao período pré-operatório (p = 0,16). A espessura do septo intraventricular nos grupos DAPE (8,64 ± 1,71 mm,) e AERD (8,84 ± 1,16 mm) não apresentou diferença estatisticamente significante quando comparados ao período pré-operatório (p = 0,81 , p = 0,78) respectivamente. A análise da parede posterior do ventrículo esquerdo (PP) dos grupos DAPE (8,50 ± 1,67mm) e AERD (8,38 ± 1mm) não apresentou diferença estatisticamente significativa quando comparado ao período pré-operatório (p = 0,83, p = 0,54) respectivamente. Em relação ao ecocardiograma contrastado observou-se a presença de vasodilatação intrapulmonar em 9 pacientes (60%) submetidos à DAPE, 9 pacientes (69%) submetidos à AERD e 5 pacientes (55%) no período préoperatório. Neste último grupo a repetição do exame 30 dias após tratamento cirúrgico com técnica de desconexão demonstrou desaparecimento da vasodilatação intrapulmonar em 3 de 4 pacientes, visto que um dos pacientes que apresentou VIP foi excluído após identificação de adenocarcinoma pela biópsia hepática realizada no intra-operatório. Observou-se em apenas um dos 23 pacientes portadores de vasodilatação intrapulmonar alargamento do gradiente alvéolo arterial de oxigênio > 15 mmHg, caracterizando a presença de síndrome hepatopulmonar. Em conclusão, os pacientes no pós-operatório tardio de AERD apresentam padrão hemodinâmico caracterizado por aumento do débito cardíaco e sobrecarga volumétrica com dilatação das cavidades ventriculares esquerdas ao contrário dos pacientes submetidos à DAPE, que mantém debito cardíaco similar à população normal e sem sobrecarga das cavidades esquerdas ou comprometimento funcional do miocárdio. Estas alterações são secundárias ao aumento do retorno venoso determinado pela manutenção do baço e da anastomose esplenorenal distal. Embora a vasodilatação intrapulmonar seja observada em 62 % (23 de 37 pacientes) dos pacientes com hipertensão portal secundária a forma hepatoesplênica da esquistossomose mansônica, independente da técnica cirúrgica utilizada para seu tratamento, a síndrome hepatopulmonar foi observada em apenas 2,7 % dos pacientes / This study is a comparative analysis of the hemodynamic pattern and presence of intrapulmonary vasodilatation in hepatoesplenic mansoni schistosomiasis before and after surgical treatment (> 2 years) of portal hypertension by esophagogastric devascularization with splenectomy (EGDS) and distal splenorenal shunt (DSRS). 37 patients with portal hypertension secondary to hepatosplenic mansoni schistosomiasis confirmed by liver biopsy were prospectively studied between January 2007 to December 2008. 21 patients were male and 16 were female, with an mean age of 46.6 +12 years. The hemodynamic evaluation was performed by transesophageal doppler (Cardio QÒ) and Doppler echocardiography in DSRS (n=13) and EGDS (n=15) patients. The results were compared with a control group of 10 patients without portal hypertension submitted to upper digestive endoscopy for dyspepsia evaluation The presence of pulmonary vasodilatation was evaluated in all patients by contrastenhanced echocardiography with saline solution 0,9% in DSRS (n=15), EGDS (n=13) and preoperative (n=9) groups. Patients with intrapulmonary vasodilation in the preoperative period repeated the exam 30 days after surgical treatment of portal hypertension by a devascularization procedure. Systemic hemodynamic evaluation by transesophageal Doppler revealed a significant increase in cardiac output (p =0.001) in the DSRS (5,08 ± 0,91 L/min) patients in relation to control group (4,17 ± 0,52 L/min). By contrast, patients submitted to EGDS (4,36 ± 0,59 L/min) present no increase in cardiac output (p = 0.47) when compared with control group (4,17 ± 0,52 L/min). The DSRS patients presented a statistically significant increase (p = 0.001) in systolic volume (60,1 + 5,6 ml) in relation to the control (53,2 + 5,6 ml), while no significant difference (p = 0.41) was observed in EGDS group (56 ± 9,4 ml). There was no statistically significant difference between heart rate and mean arterial pressure between groups (EGDS, p= 0,22, DSRS, p = 0,91), (EGDS, p = 0,40, DSRS, p = 0,06), respectively. The bidimensional Doppler echocardiography evaluation demonstrated a statistically significant increase (p = 0,0001) in left ventricular diastolic diameter (LVDD) in DSRS patients (55,4 ± 4,25 mm) in relation to the preoperative period (48,4 ± 4,4 mm) while there was no difference in patients submitted to EGDS (50 ± 3,26 mm, p = 0,25). Patients submitted to DSRS presented a statistically significant increase (p = 0,00001) in left ventricular end-diastolic volume (LVEDV) in (172,7 ± 40,7 ml) in relation to the preoperative period (116,3 ± 31,3 ml). No statistically significant difference was found in LVEDV in the patients submitted to DSRS (126,9 ± 25,2 ml; p = 0,31). Patients submitted to DSRS presented a statistically significant increase (p = 0,0004) in left ventricular systolic diameter (36 ± 3,8 mm) in relation to the preoperative period (30,6 ± 2,4 mm) while patients in the EGDS group (32,5mm ± 3) did not present any statistically significant difference (p = 0,06). There was also a statistically significant increase (p = 0,001), nevertheless within normal values, in left ventricular end-systolic volume (LVESV) in patients submitted to DSRS (48,4 ± 16,1 ml) in relation to the preoperative period (29,1 ± 6,5 ml). In contrast, EGDS patients (35 ± 10,6 ml) presented no significant difference in LVSV in relation to the preoperative group (p = 0,06). A statistically significant decrease within normal values was observed (p = 0,006) for mean ejection fraction (FE) in patients submitted to DSRS (70,9 ± 2,6%) in relation to the preoperative period (74,4± 3,6%) while EGDS group (72 ± 3,5%) did not present any statistically difference (p = 0,06) . Patients submitted to DSRS also presented a significant decrease (p = 0,03), within the normal values in myocardial fibers shortening fraction (34,5 ± 2,2%) in relation to the preoperative period (36,7± 3%) while no significant difference (p = 0.10) was observed in patients submitted to EGDS (34,9 ± 2,7%). A statistically significant increase in left atrium (LA) was observed (p = 0,002) in the patients submitted to DSRS (40,7 ± 4,6mm) in relation to the preoperative period (35,2 ± 4,3 mm). No statistically significant difference (p = 0,16) was observed in LA diameter in the patients submitted to EGDS (37,4 ± 4,1mm) in relation to the preoperative period. There was no statistically significant difference in intraventricular septum thickness in both DSRS (8,64 ± 1,71mm,) and EGDS (8,84 ± 1,16mm) groups when compared to the preoperative period (p = 0,81; p = 0,78, respectively.) Also, there was no statistically significant difference in left ventricular posterior wall (PW) in both DSRS (8,50 ± 1,67mm) and EGDS (8,38 ± 1mm) groups when compared with the preoperative period (p = 0,83; p = 0,54, respectively). Intrapulmonary vasodilation was observed in 9 patients (69%) submitted to DSRS, 9 patients (60%) submitted to EGDS, and 5 patients (55%) in the preoperative period by contrast-enhanced echocardiography. The same exam, repeated In the latter group 30 days after surgical treatment of schistosomal portal hypertension with a disconnection procedure, showed disappearance of the intrapulmonary vasodilatation in 3 out of 4 patients. In spite of great prevalence of intrapulmonary vasodilatation in all groups, widening of the arterial oxygen gradient > 15 mmHg, characterizing the hepatopulmonary syndrome, was observed in only one patient. In conclusion, patients submitted to DSRS presented systemic hemodynamics characterized by an increase in cardiac output and left ventricular dilatation secondary to volemic overload unlike patients submitted to EGDS, which maintained cardiac output similar to control patients without overload or functional myocardial impairment of left ventricle. These hemodynamics differences may be due to the presence of the spleen and the distal splenorenal anastomosis. Intrapulmonary vasodilation was observed xxv in 62% of the patients with portal hypertension secondary to the hepatosplenic mansonic schistosomiasis, irrespective of the surgical technique. Nevertheless, hepatopulmonary syndrome was observed in just 2.7% of the patients

O presente estudo avaliou comparativamente o padrão hemodinâmico e a presença de vasodilatação intrapulmonar antes e após tratamento cirúrgico tardio (> 2 anos) da hipertensão portal através da desconexão ázigo portal com esplenectomia (DAPE) e anastomose esplenorenal distal (AERD) na esquistossomose mansônica forma hepatoesplênica. Foram estudados prospectivamente 37 pacientes portadores de hipertensão portal secundária a esquistossomose mansônica confirmada por biópsia hepática , sendo 21 pacientes do sexo masculino e 16 do sexo feminino, com idade média de 46,6 + 12 anos, no período de janeiro de 2007 a dezembro de 2008. A avaliação do padrão hemodinâmico sistêmico foi realizada através do Doppler transesofágico (Cardio QÒ) e da ecocardiografia bidimensional com Doppler nos pacientes dos grupos AERD (n=13) e DAPE (n=15) . Os resultados obtidos foram comparados com grupo controle constituído por 10 pacientes sem hipertensão portal submetidos à endoscopia digestiva alta para avaliação de dispepsia. A avaliação da presença de síndrome hepatopulmonar foi realizada em todos os pacientes através da ecocardiografia contrastada com infusão salina 0,9% nos grupos DAPE (n=15), AERD (n=13) e pré-operatório (n=9). Os pacientes que apresentavam vasodilatação intrapulmonar no período pré-operatório repetiram o exame após 30 dias do procedimento cirúrgico. Em relação ao padrão hemodinâmico sistêmico observou-se aumento significativo (p =0,001) do débito cardíaco no grupo AERD (5,08 ± 0,91 L/min) em relação ao controle (4,17 ± 0,52 L/min). Ao contrário, os pacientes submetidos à DAPE (4,36 ± 0,59 L/min) não apresentaram diferença estatística significante (p = 0,47) em relação ao controle (4,17 ± 0,52 L/min). Os pacientes do grupo AERD apresentaram aumento estatisticamente significante (p = 0,001) do volume sistólico (60,1 + 5,6 ml) em relação ao controle (53,2 + 5,6 ml), enquanto que não houve diferença significativa (p = 0,41) nos pacientes submetidos à DAPE (56 ± 9,4 ml) . Não houve diferença estatisticamente significante entre os valores médios da freqüência cardíaca e da pressão arterial sistêmica em relação ao controle (AERD, p= 0,22 , DAPE, p = 0,91), (AERD, p = 0,40, DAPE , p = 0,06), respectivamente. Em relação a ecocardiografia bidimensional com doppler observou-se aumento estatisticamente significante (p = 0,0001) do diâmetro diastólico do ventrículo esquerdo (DDVE) nos pacientes submetidos à AERD (55,4 ± xviii 4,25 mm) em relação ao período pré-operatório (48,4 ± 4,4 mm), fato este não observado nos pacientes submetidos à DAPE (50 ± 3,26 mm, p = 0,25). O volume diastólico final do ventrículo esquerdo (VDF) apresentou diferença estatisticamente significante (p = 0,00001) nos pacientes submetidos à AERD (172,7 ± 40,7 ml) em relação ao período pré-operatório (116,3 ± 31,3 ml). Não foi observada diferença estatisticamente significante do VDF dos pacientes submetidos à DAPE (126,9 ± 25,2 ml) em relação ao período pré-operatório (p = 0,31). Em relação ao diâmetro sistólico do ventrículo esquerdo (DSVE) observou-se aumento estatisticamente significante (p = 0,0004) nos pacientes submetidos à AERD (36 ± 3,8 mm) em relação ao período pré-operatório (30,6 ± 2,4 mm). Os pacientes do grupo DAPE (32,5 ± 3 mm) não apresentaram diferença estatisticamente significante em relação ao período pré-operatório (p = 0,06 ). O volume sistólico final do ventrículo esquerdo (VSF) apresentou diferença estatisticamente significante ( p = 0,001) e dentro do valores da normalidade nos pacientes submetidos à AERD (48,4 ± 16,1 ml) em relação ao período pré-operatório (29,1 ± 6,5 ml). Os pacientes do grupo DAPE (35 ±10,6 ml) não apresentaram diferença estatisticamente significante da média do VSF em relação ao período pré-operatório (p = 0,06). Observou-se diminuição estatisticamente significante (p = 0,006) e dentro dos valores da normalidade na média da fração de ejeção (FE) nos pacientes submetidos à AERD (70,9 ± 2,6%) em relação ao período pré-operatório (74,4± 3,6%). Os pacientes submetidos à DAPE (72 ± 3,5%) não apresentaram diferença estatisticamente significante (p = 0,06) em relação ao período pré-operatório. Em relação à fração de encurtamento da fibra miocárdica (Delta D%), observou-se diminuição estatisticamente significante (p = 0,03) e dentro dos valores da normalidade nos pacientes submetidos à AERD (34,5 ± 2,2%) em relação ao período pré-operatório (36,7± 3%). Os pacientes submetidos à DAPE (34,9 ± 2,7%) não apresentaram diferença estatisticamente significante na média do Delta D% em relação ao controle (p = 0,10). Em relação ao átrio esquerdo (AE), observou-se aumento estatisticamente significante (p = 0,002) nos pacientes submetidos à AERD (40,7 ± 4,6mm) em comparação ao pré-operatório (35,2 ± 4,3 mm). Não foi observada diferença estatisticamente significante no tamanho do AE nos pacientes submetidos à DAPE (37,4 ± 4,1 mm) em relação ao período pré-operatório (p = 0,16). A espessura do septo intraventricular nos grupos DAPE (8,64 ± 1,71 mm,) e AERD (8,84 ± 1,16 mm) não apresentou diferença estatisticamente significante quando comparados ao período pré-operatório (p = 0,81 , p = 0,78) respectivamente. A análise da parede posterior do ventrículo esquerdo (PP) dos grupos DAPE (8,50 ± 1,67mm) e AERD (8,38 ± 1mm) não apresentou diferença estatisticamente significativa quando comparado ao período pré-operatório (p = 0,83, p = 0,54) respectivamente. Em relação ao ecocardiograma contrastado observou-se a presença de vasodilatação intrapulmonar em 9 pacientes (60%) submetidos à DAPE, 9 pacientes (69%) submetidos à AERD e 5 pacientes (55%) no período préoperatório. Neste último grupo a repetição do exame 30 dias após tratamento cirúrgico com técnica de desconexão demonstrou desaparecimento da vasodilatação intrapulmonar em 3 de 4 pacientes, visto que um dos pacientes que apresentou VIP foi excluído após identificação de adenocarcinoma pela biópsia hepática realizada no intra-operatório. Observou-se em apenas um dos 23 pacientes portadores de vasodilatação intrapulmonar alargamento do gradiente alvéolo arterial de oxigênio > 15 mmHg, caracterizando a presença de síndrome hepatopulmonar. Em conclusão, os pacientes no pós-operatório tardio de AERD apresentam padrão hemodinâmico caracterizado por aumento do débito cardíaco e sobrecarga volumétrica com dilatação das cavidades ventriculares esquerdas ao contrário dos pacientes submetidos à DAPE, que mantém debito cardíaco similar à população normal e sem sobrecarga das cavidades esquerdas ou comprometimento funcional do miocárdio. Estas alterações são secundárias ao aumento do retorno venoso determinado pela manutenção do baço e da anastomose esplenorenal distal. Embora a vasodilatação intrapulmonar seja observada em 62 % (23 de 37 pacientes) dos pacientes com hipertensão portal secundária a forma hepatoesplênica da esquistossomose mansônica, independente da técnica cirúrgica utilizada para seu tratamento, a síndrome hepatopulmonar foi observada em apenas 2,7 % dos pacientes / This study is a comparative analysis of the hemodynamic pattern and presence of intrapulmonary vasodilatation in hepatoesplenic mansoni schistosomiasis before and after surgical treatment (> 2 years) of portal hypertension by esophagogastric devascularization with splenectomy (EGDS) and distal splenorenal shunt (DSRS). 37 patients with portal hypertension secondary to hepatosplenic mansoni schistosomiasis confirmed by liver biopsy were prospectively studied between January 2007 to December 2008. 21 patients were male and 16 were female, with an mean age of 46.6 +12 years. The hemodynamic evaluation was performed by transesophageal doppler (Cardio QÒ) and Doppler echocardiography in DSRS (n=13) and EGDS (n=15) patients. The results were compared with a control group of 10 patients without portal hypertension submitted to upper digestive endoscopy for dyspepsia evaluation The presence of pulmonary vasodilatation was evaluated in all patients by contrastenhanced echocardiography with saline solution 0,9% in DSRS (n=15), EGDS (n=13) and preoperative (n=9) groups. Patients with intrapulmonary vasodilation in the preoperative period repeated the exam 30 days after surgical treatment of portal hypertension by a devascularization procedure. Systemic hemodynamic evaluation by transesophageal Doppler revealed a significant increase in cardiac output (p =0.001) in the DSRS (5,08 ± 0,91 L/min) patients in relation to control group (4,17 ± 0,52 L/min). By contrast, patients submitted to EGDS (4,36 ± 0,59 L/min) present no increase in cardiac output (p = 0.47) when compared with control group (4,17 ± 0,52 L/min). The DSRS patients presented a statistically significant increase (p = 0.001) in systolic volume (60,1 + 5,6 ml) in relation to the control (53,2 + 5,6 ml), while no significant difference (p = 0.41) was observed in EGDS group (56 ± 9,4 ml). There was no statistically significant difference between heart rate and mean arterial pressure between groups (EGDS, p= 0,22, DSRS, p = 0,91), (EGDS, p = 0,40, DSRS, p = 0,06), respectively. The bidimensional Doppler echocardiography evaluation demonstrated a statistically significant increase (p = 0,0001) in left ventricular diastolic diameter (LVDD) in DSRS patients (55,4 ± 4,25 mm) in relation to the preoperative period (48,4 ± 4,4 mm) while there was no difference in patients submitted to EGDS (50 ± 3,26 mm, p = 0,25). Patients submitted to DSRS presented a statistically significant increase (p = 0,00001) in left ventricular end-diastolic volume (LVEDV) in (172,7 ± 40,7 ml) in relation to the preoperative period (116,3 ± 31,3 ml). No statistically significant difference was found in LVEDV in the patients submitted to DSRS (126,9 ± 25,2 ml; p = 0,31). Patients submitted to DSRS presented a statistically significant increase (p = 0,0004) in left ventricular systolic diameter (36 ± 3,8 mm) in relation to the preoperative period (30,6 ± 2,4 mm) while patients in the EGDS group (32,5mm ± 3) did not present any statistically significant difference (p = 0,06). There was also a statistically significant increase (p = 0,001), nevertheless within normal values, in left ventricular end-systolic volume (LVESV) in patients submitted to DSRS (48,4 ± 16,1 ml) in relation to the preoperative period (29,1 ± 6,5 ml). In contrast, EGDS patients (35 ± 10,6 ml) presented no significant difference in LVSV in relation to the preoperative group (p = 0,06). A statistically significant decrease within normal values was observed (p = 0,006) for mean ejection fraction (FE) in patients submitted to DSRS (70,9 ± 2,6%) in relation to the preoperative period (74,4± 3,6%) while EGDS group (72 ± 3,5%) did not present any statistically difference (p = 0,06) . Patients submitted to DSRS also presented a significant decrease (p = 0,03), within the normal values in myocardial fibers shortening fraction (34,5 ± 2,2%) in relation to the preoperative period (36,7± 3%) while no significant difference (p = 0.10) was observed in patients submitted to EGDS (34,9 ± 2,7%). A statistically significant increase in left atrium (LA) was observed (p = 0,002) in the patients submitted to DSRS (40,7 ± 4,6mm) in relation to the preoperative period (35,2 ± 4,3 mm). No statistically significant difference (p = 0,16) was observed in LA diameter in the patients submitted to EGDS (37,4 ± 4,1mm) in relation to the preoperative period. There was no statistically significant difference in intraventricular septum thickness in both DSRS (8,64 ± 1,71mm,) and EGDS (8,84 ± 1,16mm) groups when compared to the preoperative period (p = 0,81; p = 0,78, respectively.) Also, there was no statistically significant difference in left ventricular posterior wall (PW) in both DSRS (8,50 ± 1,67mm) and EGDS (8,38 ± 1mm) groups when compared with the preoperative period (p = 0,83; p = 0,54, respectively). Intrapulmonary vasodilation was observed in 9 patients (69%) submitted to DSRS, 9 patients (60%) submitted to EGDS, and 5 patients (55%) in the preoperative period by contrast-enhanced echocardiography. The same exam, repeated In the latter group 30 days after surgical treatment of schistosomal portal hypertension with a disconnection procedure, showed disappearance of the intrapulmonary vasodilatation in 3 out of 4 patients. In spite of great prevalence of intrapulmonary vasodilatation in all groups, widening of the arterial oxygen gradient > 15 mmHg, characterizing the hepatopulmonary syndrome, was observed in only one patient. In conclusion, patients submitted to DSRS presented systemic hemodynamics characterized by an increase in cardiac output and left ventricular dilatation secondary to volemic overload unlike patients submitted to EGDS, which maintained cardiac output similar to control patients without overload or functional myocardial impairment of left ventricle. These hemodynamics differences may be due to the presence of the spleen and the distal splenorenal anastomosis. Intrapulmonary vasodilation was observed xxv in 62% of the patients with portal hypertension secondary to the hepatosplenic mansonic schistosomiasis, irrespective of the surgical technique. Nevertheless, hepatopulmonary syndrome was observed in just 2.7% of the patients