Acute Respiratory Distress Syndrome (ARDS) is associated with lung inflammation and fluid filling, resulting in a stiffer lung with reduced intrapulmonary gas volume. ARDS patients are admitted to the Intensive Care Unit (ICU) and require Mechanical Ventilation (MV) for breathing support. Positive End Expiratory Pressure (PEEP) is applied to aid recovery by improving gas exchange and maintaining recruited lung volume. However, high PEEP risks further lung injury due to overstretching of healthy lung units, and low PEEP risks further lung injury due to the repetitive opening and closing of lung units. Thus, selecting PEEP is a balance between avoiding over-stretching and repetitive opening of alveoli. Furthermore, specific protocols to determine optimal PEEP do not currently exist, resulting in variable PEEP selection. Thus, ensuring an optimal PEEP would have significant impact on patient mortality, and the cost and duration of MV therapy. Two important metrics that can be used to aid MV therapy are the elastance of the lungs as a function of PEEP, and the quantity of recruited lung volume as a function of PEEP. This thesis describes several models and model-based methods that can be used to select optimal PEEP in the ICU. Firstly, a single compartment lung model is investigated for its ability to capture the respiratory mechanics of a mechanically ventilated ARDS patient. This model is then expanded upon, leading to a novel method of mapping and visualising dynamic respiratory system elastance. Considering how elastance changes, both within a breath and throughout the course of care, provides a new clinical perspective. Next, a model using only the expiratory portion of the breathing cycle is developed and presented, providing an alternative means to track changes in disease state throughout MV therapy. Finally, four model-based methods are compared based on their capability of estimating the quantity of recruited lung volume due to PEEP. The models and model-based methods described in this thesis enable rapid parameter identification from readily available clinical data, providing a means of tracking lung condition and selecting optimal patient-specific PEEP. Each model is validated using data from clinical ICU patients and/or experimental ARDS animal models.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Children with prolonged mechanical ventilation after cardiac surgery have a higher risk for poor outcome due to a variety of ventilator‐associated morbidities. It therefore becomes essential to identify these children at higher risk of prolonged mechanical ventilation as well as find methods to identify children ready to be extubated as early as possible to avoid these complications. One physiological variable, the pulmonary dead space fraction (VD/VT), has been suggested as a possible indicator of prolonged mechanical ventilation. VD/VT essentially measures the amount of ventilated air that is unable to participate in gas exchange. Can VD/VT be used successfully in children undergoing cardiac surgery to identify those at risk for prolonged mechanical ventilation and identify those ready for extubation? Retrospective chart review of 461 patients at Phoenix Children’s Hospital in the Pediatric Cardiac Intensive Care Unit since the initiation of standard application of the Philips NM3 monitors in October 2013 through December 2014. From the 461 patients screened, only 99 patients met all the inclusion criteria. These 99 patients consisted of 29 patients with balanced single ventricle physiology and 61 patients with two ventricle physiology. Initial postoperative and pre‐extubation VD/VT values correlated with length of mechanical ventilation for patients with two ventricle physiology but not for patients with single ventricle physiology. Additionally, pre‐extubation VD/VT values of greater than 0.5 indicated higher rates of extubation failure in two ventricle patients. Conclusion: For children with two ventricle physiology undergoing cardiac surgery, VD/VT should be used clinically to estimate the length of mechanical ventilation for these children. VD/VT should also be checked in these patients before attempting to extubate. If VD/VT is found to be higher than 0.5, extubation should not be attempted since the patient is at a much higher risk for extubation failure.

Mechanical ventilation is vital for the treatment of patients in respiratory intensive care and can be life saving. However, the risks of regional pressure gradients and over-distension must be balanced with the need to maintain function. For these reasons mechanical ventilation can benefit from the regional information provided by bedside imaging such as electrical impedance tomography (EIT). In this thesis we develop and test methods to retrieve clinically meaningful measures of lung function from EIT and examine the feasibility of closing the feedback loop to enable EIT-guided control of mechanical ventilation. Working towards this goal we develop a reconstruction algorithm capable of providing fast absolute values of conductivity from EIT measurements. We couple the resulting conductivity time series to a compartmental ordinary differential equation (ODE) model of lung function in order to recover regional parameters of elastance and airway resistance. We then demonstrate how these parameters may be used to generate optimised pressure controls for mechanical ventilation that expose the lungs to minimal gradients of pressure and are stable with respect to EIT measurement errors. The EIT reconstruction algorithm we develop is capable of producing low dimensional absolute values of conductivity in real time after a limited additional setup time. We show that this algorithm retains the ability to give fast feedback on regional lung changes. We also describe methods of improving computational efficiency for general Gauss-Newton type EIT algorithms. In order to couple reconstructed conductivity time series to our ODE model we describe and test the recovery of regional ventilation distributions through a process of regularised differentiation. We prove that the parameters of our ODE model are recoverable from these ventilation distributions apart from the degenerate case where all compartments have the same parameters. We then test this recovery process under varying levels of simulated EIT measurement and modelling errors. Finally we examine the ODE lung model using control theory. We prove that the ODE model is controllable for a wide range of parameter values and link controllability to observable ventilation patterns in the lungs. We demonstrate the generation and optimisation of pressure controls with minimal time gradients and provide a bound on the resulting magnitudes of these pressures. We then test the control generation process using ODE parameter values recovered through EIT simulations at varying levels of measurement noise. Through this work we have demonstrated that EIT reconstructions can be of benefit to the control of mechanical ventilation.

archives@tulane.edu / Acute respiratory distress syndrome (ARDS) is a life-threatening, non-carcinogenic inflammatory pulmonary conditions characterized by the collection of fluids in the air sacs of the lungs. When fluid-filled airways are ventilated, the stresses of repetitive recruitment-decruitment (Rec-Der) causes cellular damage to the epithelial surface, leading to ventilator induced lung injury (VILI). The objective of this study was to establish a foundation for use of electric cell-substance impedance sensing (ECIS) in real-time analysis of cell membrane morphology and RecDer-induced damage. NCI H441 papillary adenocarcinoma human pulmonary epithelial cells are cultured onto custom 1F8x10E PC Flow Array. 10mM cysteine and 1% gelatin surface treatments demonstrated strong results for improved cell-substrate adhesion strength. RecDer insults were introduced at a velocity of 0.5mm/s through FBS-enhanced RPMI164 growth media. Experimental trials for 0 (n=1), 1 (n=1), 5 (n=1), 10 (n=1), 20 (n=7), and 50 (n=1) RecDer insults were analyzed using Annexin-V/PI flow cytometry; results showed monolayer health of 97.76%, 93.152%, 91.801%, 72.495%, 66.88% and 60.812% respectively. Trials for 20 (n=1), 30 (n=1), and 40 (n=1) RecDer insults were analyzed using ECIS; Frequency-dependent impedance modeling of the acquired data suggested increased damage to both cell-cell junction health and cell membrane integrity with increased RecDer insults. Results established a strong foundation for ECIS analysis of RecDer-induced monolayer damage. / 1 / Joshua Erwa Yao

Syfte: Studiens syfte var att jämföra en ny extubationsalgoritm med sedvanligtextubationsförfarande. Gruppen som studerades var patienter som genomgått en HIPEC-operationoch vårdats på Centrala intensivvårdsavdelningen. Metod: I En randomiserad kontrollerad klinisk pilotstudie randomiserades patienterna till en av tvågrupper. Därefter extuberades patienten enligt en studiealgoritm eller post-operativ standard. Resultat: Syresättningen var väsentligen oförändrad för studiegruppen (37,5 kPa till 36,6 kPa)medan den sjönk för kontrollgruppen (50,1 kPa till 40,6 kPa) vid jämförelse mellan 10 minuter efterankomst och 15 minuter efter extubation. Efter 13 till 18 timmars kontroll strax innan patienternalämnade intensivvårdsavdelningen var syresättningen på samma nivå som 15 minuter efterextubation för både studiegruppen och kontrollgrupp. Således kvarstod en försämrad syresättninghos kontrollgruppen vid utskrivning jämfört med 10 minuter efter ankomst. Slutsats: Studien visar att det skulle kunna vara fördelaktigt att extubera patienter enligt denstudiealgoritm som testats jämfört med dagens kliniska standard. Genom att fokusera på hur och ejnär extubationen ska ske är förhoppningen att denna studie kan bidra till att förbättra en procedursom i princip saknar konsensus. Mer forskning krävs för att kunna dra några generella slutsatser omresultatet. / Aim: To compare a new method of extubation with present standard procedure at the Central ICUafter HIPEC surgery. Method: In a randomized controlled study patients were randomized into two groups. Patients wereeither extubated according to a study algorithm based on best current knowledge, or according tostandard procedure. Results: The oxygenation remained on the same level in the study group (37,5 kPa to 36,6 kPa) butdecreased in the control group from 50,1 kPa to 40,6 kPa from 10 minutes after arrival to 15minutes after extubation. After 13 to 18 hours, just before the discharge from the ICU theoxygenation in both groups was at the same level as 15 minutes after extubation. Thus a decrease inoxygenation in the control group was found at discharge compared to 10 minutes after arrival in theICU. Conclusion: The result of the study showed that it may be benificial to extubate according to thestudy algorithm compared to present standard procedure. By directing focus from when to how theextubation is made, this study may contribute to the improvement of a clinical procedure that iscurrently lacking in scientific consencus. Further studies are needed to confirm these findings.

Mechanically ventilated patients are at risk of developing Ventilator-Associated Lung Injury (VALI). Improved ventilation strategies by lung-protective settings may cause hypercapnia. This study investigated whether attenuation of VALI is attributed to protective ventilation with low tidal volume (VT) or hypercapnia. Lung injury was induced in rats by instillation of 1.25M HCl. Ten rats each were ventilated for 4 hours with: Conventional Normocapnia (highVT), Lung-Protective Ventilation (VT¬ 8mL/Kg), Injurious Normocapnia (highVT, added dead space), Conventional Hypercapnia (highVT, inhaled CO2), Protective Hypercapnia (VT 8mL/Kg, inhaled CO2) and Permissive Hypercapnia (VT 8mL/Kg, hypoventilation). Lung-Protective Ventilation reduced pulmonary edema compared to Conventional and Injurious Normocapnia. Therapeutic hypercapnia reduced alveolar damage and inflammation by reducing IL-6 and MCP-1 in the lung, and IL-1? and TNF-? systemically. Therapeutic hypercapnia may be more effective in attenuating some of the biomarkers of VALI and protecting the lung than protective ventilation alone.

Mechanical ventilation saves lives, but it is an intervention fraught with the potential for serious complications. Prevention of these complications has become the focus of research and critical care in the last twenty years. This thesis presents the first use, or the application under new conditions, of three technologies that could contribute to optimization of mechanical ventilation. Optoelectronic plethysmography was used in Papers I and II for continuous assessment of changes in chest wall volume, configuration, and motion in the perioperative period. A forced oscillation technique (FOT) was used in Paper III to evaluate a novel positive end-expiratory pressure (PEEP) optimization strategy. Finally, in Paper IV, FOT in conjunction with an optical sensor based on a self-mixing laser interferometer (LIR) was used to study the oscillatory mechanics of the respiratory system and to measure the chest wall displacement. In Paper I, propofol anesthesia decreased end-expiratory chest wall volume (VeeCW) during induction, with a more pronounced effect on the abdominal compartment than on the rib cage. The main novel findings were an increased relative contribution of the rib cage to ventilation after induction of anesthesia, and the fact that the rib cage initiates post-apneic ventilation. In Paper II, a combination of recruitment maneuvers, PEEP, and reduced fraction of inspired oxygen, was found to preserve lung volume during and after anesthesia. Furthermore, the decrease in VeeCW during emergence from anesthesia, associated with activation of the expiratory muscles, suggested that active expiration may contribute to decreased functional residual capacity, during emergence from anesthesia. In the lavage model of lung injury studied in Paper III, a PEEP optimization strategy based on maximizing oscillatory reactance measured by FOT resulted in improved lung mechanics, increased oxygenation, and reduced histopathologic evidence of ventilator-induced lung injury. Paper IV showed that it is possible to apply both FOT and LIR simultaneously in various conditions ranging from awake quiet breathing to general anesthesia with controlled mechanical ventilation. In the case of LIR, an impedance map representing different regions of the chest wall showed reproducible changes during the different stages that suggested a high sensitivity of the LIR-based measurements.

When spontaneous breathing (SB) is allowed during mechanical ventilation (MV), atelectatic lung areas are recruited and oxygenation improves thereby. Whether unsupported SB at its natural pattern (without PEEP and at low pressure/small tidal volume) equally recruits and improves oxygenation, and if so by which mechanism, has not been studied. A porcine lung collapse model was designed to study this question. The cardiac output dependency of the pulmonary shunt was investigated with healthy lungs and with major shunt (during one-lung ventilation) and with SB, MV and continuous positive airway pressure (CPAP). The hypoxic pulmonary vasoconstriction (HPV) was blocked with sodium nitroprusside (SNP) to see whether HPV is the only mechanism available for ventilation/perfusion (VA/Q) matching during MV and SB. In all experiments, respiratory rate and tidal volume during MV were matched to SB. Oxygenation was assessed by serial blood gas measurements, recruitment by thoracic CTs; pulmonary shunt was assessed by multiple inert gas elimination or venous admixture. SB attained better oxygenation and lower pulmonary shunt compared with MV, although it did not recruit collapsed lung. Pulmonary shunt did not correlate with cardiac output during SB, whereas a correlation was found during MV and CPAP. With blocked HPV, pulmonary shunt was considerably lower during SB than MV. In conclusion, SB improves VA/Q matching as compared with MV, even when no recruitment occurs. In contrast to MV and CPAP, cardiac output has no major effect on pulmonary shunt during SB. The improved VA/Q matching during SB despite a blocked HPV might indicate the presence of a SB-specific mechanism that improves pulmonary blood flow redistribution towards ventilated lung regions independent of or supplementary to HPV.

Introduction: Weaning from mechanical ventilation is defined as the gradual reduction of mechanical support, and replacing this support with spontaneous ventilation. It is a complex process involving assessing the patient's readiness to wean, optimising factors that can impede the process, selecting the most appropriate weaning mode and continually assessing the patient's progress. In paediatric intensive care the clinician must also account for the unique physiological and psychosocial needs of the child. Aim: The aim of the study was to explore the need for, and impact, of guidelines for weaning children from mechanical ventilation on patient outcomes and staff practice. Method: The study was multi-dimensional using the Model for Improvement as the conceptual framework and decided into four phases. Phase one: A survey of Australian PICUs in 2000 revealed that over 2500 children were ventilated over a 12 month-period, with a potential population of 625 children experiencing difficulties with weaning from mechanical ventilation. No guidelines for weaning children from mechanical ventilation were identified at the time. Standardising the approach to weaning had proven successful with the adult population. Phase two: Collaborative guidelines for weaning, based on available evidence and expert opinion, were drawn up, validated by a panel of experts and safely piloted. Phase three: The guidelines were then tested using a time series design over two years on a PICU at a tertiary referral children's facility. Results demonstrated that total ventilation time, weaning duration and length of stay were not significantly improved in the experimental group. However, quality indicators were slightly improved and a survival analysis also showed a slightly reduced probability of long term ventilated patients remaining ventilated. Results also demonstrated a reduction in the fluctuation of outcome variables over time indicating improved consistency in weaning due to the guidelines Phase four: A qualitative analysis of focus group interviews with staff about the impact of guidelines on their practice generated themes, centred on practice development, framework, relationships and challenges. Few previous studies have investigated the perceptions of staff regarding use of practice guidelines. This study identified that staff viewed the use of weaning guidelines favourably and perceived that their implementation improved patient outcomes. Weaning is a relatively neglected area of intensive care because much of the initial focus of management is resuscitation and stabilisation. This study has demonstrated the positive impact that standardised and collaborative practice can have on patient outcome and clinical practice.

Submitted by EVELINE SIMÕES AZENHA AIDAR null (eveline.azenha@gmail.com) on 2017-08-31T15:48:33Z No. of bitstreams: 1 DISSERTAÇÃO FINAL.pdf: 1678448 bytes, checksum: 4637f30d94f03091ad67296304a35e14 (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-09-01T13:59:08Z (GMT) No. of bitstreams: 1 aidar_esa_me_jabo.pdf: 1678448 bytes, checksum: 4637f30d94f03091ad67296304a35e14 (MD5) / Made available in DSpace on 2017-09-01T13:59:08Z (GMT). No. of bitstreams: 1 aidar_esa_me_jabo.pdf: 1678448 bytes, checksum: 4637f30d94f03091ad67296304a35e14 (MD5) Previous issue date: 2017-07-20 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A manutenção da função respiratória adequada é essencial para realização de anestesia segura e eficiente. Sendo assim, são necessários estudos que avaliam métodos ventilatórios e seus empregos na rotina clínica. Neste estudo, foram comparadas a ventilação espontânea (VE), ventilação pressão controlada, ventilação pressão controlada associada à pressão positiva expiratória final e ventilação mandatória intermitente sincronizada (SIMV). As modalidades foram comparadas em quatro grupos de oito animais cada. Os coelhos foram anestesiados com isofluorano durante duas horas e posicionados em decúbito lateral direito, totalizando 32 animais. Variáveis cardiovasculares, ventilatórias e hemogasométricas foram registradas em cinco diferentes momentos, com intervalo de 30 minutos. Após, os resultados foram avaliados estatisticamente pelo método dos quadrados mínimos, seguido pelo teste Tukey – Kramer (p≤0,05). Com relação às variáveis cardiovasculares, as médias de pressão arterial média (PAM) e pressão arterial sistólica (PAS) permaneceram discretamente abaixo dos valores de normalidade em todos os grupos. Houve diminuição significativa da PAM e PAS no grupo ventilação ciclada à pressão associada à pressão positiva no final da expiração (GPP) ao longo do tempo anestésico. Quanto aos gases sanguíneos, a pressão parcial de dióxido de carbono arterial (PaCO2) foi maior no GPP quando comparado aos outros grupos, gerando acidemia respiratória após uma hora de procedimento. As médias altas de pressão parcial de oxigênio no sangue venoso sugerem maior oferta associada a menor consumo de O2 em todos os grupos. A concentração de dióxido de carbono ao final da expiração (ETCO2) apresentou médias discretamente elevadas no grupo ventilação ciclada a pressão e grupo ventilação espontânea (GE), enquanto que o GPP apresentou maiores médias que, possivelmente, estão relacionadas à diminuição do volume corrente deste grupo. O grupo ventilação mandatória intermitente sincronizada (GM) foi o único a apresentar normocapnia. Os desequilíbrios hemodinâmicos e ventilatórios registrados se agravaram ou se iniciaram após uma hora de procedimento anestésico. Pode-se então concluir que uso da SIMV proporcionou melhor estabilidade hemodinâmica e ventilatória. / Maintaining adequate respiratory function is essential for safe and efficient anesthesia. Therefore, studies evaluating ventilatory methods and their use in the clinical routine are necessary. In this study, spontaneous ventilation, pressurecontrolled ventilation, pressure-controlled ventilation associated with positive endexpiratory pressure, and synchronized intermittent mandatory ventilation were compared. The modalities were compared in four groups of eight rabbits each. The rabbits were anesthetized with isofluorane for two hours and placed in the right lateral recumbency, totaling 32 animals. Cardiovascular, ventilatory and hemogasometric variables were recorded at five different moments, with an interval of 30 minutes each. Afterwards, the results were statistically evaluated by the least squares method, followed by the Tukey - Kramer test (p≤0.05). Regarding the cardiovascular variables, mean values of mean arterial pressure (MAP) and systolic blood pressure (SBP) remained slightly below normal values in all groups. There was a significant decrease in MAP and PAS in the group under pressure controlled ventilation associated with positive end-expiratory pressure (GPP) throughout the anesthetic time. As for blood gases, the partial pressure of arterial carbon dioxide was higher in GPP when compared to other groups, generating respiratory acidosis after one hour of procedure. High partial pressure of venous oxygen means suggest a higher supply associated with lower O2 consumption in all groups. End-tidal carbon dioxide presented mildly elevated in pressure controlled ventilation group (GP) and spontaneous ventilation group (GE), whereas GPP presented higher averages that, possibly, are related to the decrease of the tidal volume in this group. Synchronized intermittent mandatory ventilation group (GM) was the only one to present normocapnia. The registered hemodynamic and ventilatory imbalances were aggravated or initiated after one hour of anesthetic procedure. It can be concluded that the use of synchronized intermittent mandatory ventilation provided better hemodynamic and ventilatory stability. / FAPESP: 2015/26543-6