Long-stay ICU patients with frailty: mortality and recovery outcomes at 6 months.

BACKGROUND: Prolonged intensive care unit (ICU) stay is associated with physical, cognitive, and psychological disabilities. The impact of baseline frailty on long-stay ICU patients remains uncertain. This study aims to investigate how baseline frailty influences mortality and post-ICU disability 6 months after critical illness in long-stay ICU patients. METHODS: In this retrospective cohort study, we assessed patients hospitalized for ≥ 7 days in the ICU between May 2018 and May 2021, following them for up to 6 months or until death. Based on the Clinical Frailty Scale (CFS) at ICU admissions, patients were categorized as frail (CFS ≥ 5), pre-frail (CFS 3-4) and non-frail (CFS 1-2). Kaplan-Meier curves and a multivariate Cox model were used to examine the association between frailty and mortality. At the 6 month follow-up, we assessed psychological, physical, cognitive outcomes, and health-related quality of life (QoL) using descriptive statistics and linear regressions. RESULTS: We enrolled 531 patients, of which 178 (33.6%) were frail, 200 (37.6%) pre-frail and 153 (28.8%) non-frail. Frail patients were older, had more comorbidities, and greater disease severity at ICU admission. At 6 months, frail patients presented higher mortality rates than pre-frail and non-frail patients (34.3% (61/178) vs. 21% (42/200) vs. 13.1% (20/153) respectively, p < 0.01). The rate of withdrawing or withholding of care did not differ significantly between the groups. Compared with CFS 1-2, the adjusted hazard ratios of death at 6 months were 1.7 (95% CI 0.9-2.9) for CFS 3-4 and 2.9 (95% CI 1.7-4.9) for CFS ≥ 5. At 6 months, 192 patients were seen at a follow-up consultation. In multivariate linear regressions, CFS ≥ 5 was associated with poorer physical health-related QoL, but not with poorer mental health-related QoL, compared with CFS 1-2. CONCLUSION: Frailty is associated with increased mortality and poorer physical health-related QoL in long-stay ICU patients at 6 months. The admission CFS can help inform patients and families about the complexities of survivorship during a prolonged ICU stay.

Expiratory high-frequency percussive ventilation: a novel concept for improving gas exchange.

BACKGROUND: Although high-frequency percussive ventilation (HFPV) improves gas exchange, concerns remain about tissue overdistension caused by the oscillations and consequent lung damage. We compared a modified percussive ventilation modality created by superimposing high-frequency oscillations to the conventional ventilation waveform during expiration only (eHFPV) with conventional mechanical ventilation (CMV) and standard HFPV. METHODS: Hypoxia and hypercapnia were induced by decreasing the frequency of CMV in New Zealand White rabbits (n = 10). Following steady-state CMV periods, percussive modalities with oscillations randomly introduced to the entire breathing cycle (HFPV) or to the expiratory phase alone (eHFPV) with varying amplitudes (2 or 4 cmH2O) and frequencies were used (5 or 10 Hz). The arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were determined. Volumetric capnography was used to evaluate the ventilation dead space fraction, phase 2 slope, and minute elimination of CO2. Respiratory mechanics were characterized by forced oscillations. RESULTS: The use of eHFPV with 5 Hz superimposed oscillation frequency and an amplitude of 4 cmH2O enhanced gas exchange similar to those observed after HFPV. These improvements in PaO2 (47.3 ± 5.5 vs. 58.6 ± 7.2 mmHg) and PaCO2 (54.7 ± 2.3 vs. 50.1 ± 2.9 mmHg) were associated with lower ventilation dead space and capnogram phase 2 slope, as well as enhanced minute CO2 elimination without altering respiratory mechanics. CONCLUSIONS: These findings demonstrated improved gas exchange using eHFPV as a novel mechanical ventilation modality that combines the benefits of conventional and small-amplitude high-frequency oscillatory ventilation, owing to improved longitudinal gas transport rather than increased lung surface area available for gas exchange.

Invasive and non-invasive assessment of macro- and micro-circulatory effects of vasopressors during sevoflurane anesthesia in a pediatric experimental model: A randomized trial.

BACKGROUND: While non-invasive assessment of macro- and micro-circulation has the promise to optimize anesthesia management, evidence is lacking for the relationship between invasive and non-invasive measurements of cardiac output and microcirculatory indices. AIMS: We aimed to compare the abilities of non-invasive techniques to detect changes in macro- and micro-circulation following deep anesthesia and subsequent restoration of the compromised hemodynamic by routinely used vasopressors in a randomized experimental study. METHODS: A 20%-25% drop in mean arterial pressure was induced by sevoflurane in anesthetized mechanically ventilated just-weaned piglets (n = 12) prior to the administration of vasopressors in random order (dopamine, ephedrine, noradrenaline, and phenylephrine). Simultaneous transpulmonary thermodilution cardiac output assessment with the invasive pulse index continuous contour (PiCCO) method was compared with non-invasive estimates obtained with electrical conductivity (ICON) and echo Doppler (Cardio Q). Changes in microcirculation were characterized by sublingual red blood cell velocity, jugular cerebral venous oxygen saturation, and arterial lactate. MAIN OUTCOME MEASURES: Cardiac output indices obtained by invasive and non-invasive methods. RESULTS: Changes in cardiac output measured invasively and non-invasively correlated significantly after sevoflurane (r = .78, p = .003 and r = .76, p = .006 between PiCCO and ICON or Cardio Q, respectively). Following the administration of vasopressors, invasive and non-invasive cardiac output assessments were unrelated with significant correlations observed only between PiCCO and ICON after dopamine and ephedrine. Sevoflurane-induced hypotension decreased jugular cerebral venous oxygen saturation significantly and was recovered by all vasopressors. Sevoflurane and vasopressors had no effect on red blood cell velocity, which increased only after dopamine. No consistent changes in lactate were observed during the study period. CONCLUSIONS: The results of this study suggest that non-invasive cardiac output measurements may not accurately reflect changes in macrocirculation after hemodynamic optimization by vasopressors. Due to the incoherence between macro- and micro-circulation, monitoring microcirculation is essential to guide patient management.

Effect of body position on the redistribution of regional lung aeration during invasive and non-invasive ventilation of COVID-19 patients.

Severe COVID-19-related acute respiratory distress syndrome (C-ARDS) requires mechanical ventilation. While this intervention is often performed in the prone position to improve oxygenation, the underlying mechanisms responsible for the improvement in respiratory function during invasive ventilation and awake prone positioning in C-ARDS have not yet been elucidated. In this prospective observational trial, we evaluated the respiratory function of C-ARDS patients while in the supine and prone positions during invasive (n = 13) or non-invasive ventilation (n = 15). The primary endpoint was the positional change in lung regional aeration, assessed with electrical impedance tomography. Secondary endpoints included parameters of ventilation and oxygenation, volumetric capnography, respiratory system mechanics and intrapulmonary shunt fraction. In comparison to the supine position, the prone position significantly increased ventilation distribution in dorsal lung zones for patients under invasive ventilation (53.3 ± 18.3% vs. 43.8 ± 12.3%, percentage of dorsal lung aeration ± standard deviation in prone and supine positions, respectively; p = 0.014); whereas, regional aeration in both positions did not change during non-invasive ventilation (36.4 ± 11.4% vs. 33.7 ± 10.1%; p = 0.43). Prone positioning significantly improved the oxygenation both during invasive and non-invasive ventilation. For invasively ventilated patients reduced intrapulmonary shunt fraction, ventilation dead space and respiratory resistance were observed in the prone position. Oxygenation is improved during non-invasive and invasive ventilation with prone positioning in patients with C-ARDS. Different mechanisms may underly this benefit during these two ventilation modalities, driven by improved distribution of lung regional aeration, intrapulmonary shunt fraction and ventilation-perfusion matching. However, the differences in the severity of C-ARDS may have biased the sensitivity of electrical impedance tomography when comparing positional changes between the protocol groups.Trial registration: ClinicalTrials.gov (NCT04359407) and Registered 24 April 2020, https://clinicaltrials.gov/ct2/show/NCT04359407 .

Sevoflurane and Hypercapnia Blunt the Physiological Variability of Spontaneous Breathing: A Comparative Interventional Study.

Background: Although spontaneous breathing is known to exhibit substantial physiological fluctuation that contributes to alveolar recruitment, changes in the variability of the respiratory pattern following inhalation of carbon dioxide (CO2) and volatile anesthetics have not been characterized. Therefore, we aimed at comparing the indices of breathing variability under wakefulness, sleep, hypercapnia and sedative and anesthetic concentrations of sevoflurane. Methods: Spontaneous breathing pattern was recorded on two consecutive days in six rabbits using open whole-body plethysmography under wakefulness and spontaneous sleep and following inhalation of 5% CO2, 2% sevoflurane (0.5 MAC) and 4% (1 MAC) sevoflurane. Tidal volume (VT), respiratory rate (RR), minute ventilation (MV), inspiratory time (TI) and mean inspiratory flow (VT/TI) were calculated from the pressure fluctuations in the plethysmograph. Means and coefficients of variation were calculated for each measured variable. Autoregressive model fitting was applied to estimate the relative contributions of random, correlated, and oscillatory behavior to the total variance. Results: Physiological sleep decreased MV by lowering RR without affecting VT. Hypercapnia increased MV by elevating VT. Sedative and anesthetic concentrations of sevoflurane increased VT but decreased MV due to a decrease in RR. Compared to the awake stage, CO2 had no effect on VT/TI while sevoflurane depressed significantly the mean inspiratory flow. Compared to wakefulness, the variability in VT, RR, MV, TI and VT/TI were not affected by sleep but were all significantly decreased by CO2 and sevoflurane. The variance of TI originating from correlated behavior was significantly decreased by both concentrations of sevoflurane compared to the awake and asleep conditions. Conclusions: The variability of spontaneous breathing during physiological sleep and sevoflurane-induced anesthesia differed fundamentally, with the volatile agent diminishing markedly the fluctuations in respiratory volume, inspiratory airflow and breathing frequency. These findings may suggest the increased risk of lung derecruitment during procedures under sevoflurane in which spontaneous breathing is maintained.

Hypophosphatemia on ICU Admission Is Associated with an Increased Length of Stay in the ICU and Time under Mechanical Ventilation.

Hypophosphatemia is frequently observed in the ICU and is associated with several impairments such as respiratory failure or infections. We hypothesized that hypophosphatemia on ICU admission is associated with a prolonged duration of mechanical ventilation and ICU length of stay (LOS), particularly in COVID-19 patients. This cross-sectional study analyzed data from 1226 patients hospitalized in the ICU of the Geneva University Hospitals from August 2020 to April 2021. Patients were categorized as having hypophosphatemia (phosphatemia ≤ 0.8 mmol/L) or non-hypophosphatemia (phosphatemia > 0.8 mmol/L) on ICU admission. Linear regressions were performed to investigate the association between hypophosphatemia on ICU admission and ICU LOS and duration of mechanical ventilation. Overall, 250 (20%) patients presented hypophosphatemia on ICU admission. In the univariable analysis, hypophosphatemic patients had longer ICU LOS than non-hypophosphatemic patients, 7.4 days (±10.4) versus 5.6 days (±8.3), (p < 0.01). Hypophosphatemia on ICU admission was associated with a prolonged duration of mechanical ventilation, 7.4 days (±11.2) versus 5.6 days (±8.9), (p < 0.01). These associations were confirmed in the multivariable analysis (p < 0.01). In the subgroup of COVID-19 patients, a significant association between hypophosphatemia and ICU LOS and duration of mechanical ventilation was also observed. In conclusion, hypophosphatemia on ICU admission is associated with a longer ICU LOS and time under mechanical ventilation, both in the general ICU population and in COVID-19 patients.

Physiologically variable ventilation prevents lung function deterioration in a model of pulmonary fibrosis.

Positive pressure ventilation exerts an increased stress and strain in the presence of pulmonary fibrosis. Thus, ventilation strategies that avoid high pressures while maintaining lung aeration are of paramount importance. Although physiologically variable ventilation (PVV) has proven beneficial in various models of pulmonary disease, its potential advantages in pulmonary fibrosis have not been investigated. Therefore, we assessed the benefit of PVV over conventional pressure-controlled ventilation (PCV) in a model of pulmonary fibrosis. Lung fibrosis was induced with intratracheal bleomycin in rabbits. Fifty days later, the animals were randomized to receive 6 h of either PCV (n = 10) or PVV (n = 11). The PVV pattern was prerecorded in spontaneously breathing, healthy rabbits. Respiratory mechanics and gas exchange were assessed hourly; end-expiratory lung volume and intrapulmonary shunt fraction were measured at hours 0 and 6. Histological and cellular analyses were performed. Fifty days after bleomycin treatment, the rabbits presented elevated specific airway resistance [69 ± 26% (mean ± 95% confidence interval)], specific tissue damping (38 ± 15%), and specific elastance (47 ± 16%) along with histological evidence of fibrosis. Six hours of PCV led to increased respiratory airway resistance (Raw, 111 ± 30%), tissue damping (G, 36 ± 13%) and elastance (H, 58 ± 14%), and decreased end-expiratory lung volume (EELV, -26 ± 7%) and oxygenation ([Formula: see text]/[Formula: see text], -14 ± 5%). The time-matched changes in the PVV group were significantly lower for G (22 ± 9%), H (41 ± 6%), EELV (-13 ± 6%), and [Formula: see text]/[Formula: see text] ratio (-3 ± 5%, P < 0.05 for all). There was no difference in histopathology between the ventilation modes. Thus, prolonged application of PVV prevented the deterioration of gas exchange by reducing atelectasis development in bleomycin-induced lung fibrosis.NEW & NOTEWORTHY The superposition of physiological breathing variability onto a conventional pressure signal during prolonged mechanical ventilation prevents atelectasis development in bleomycin-induced lung fibrosis. This advantage is evidenced by reduced deterioration in tissue mechanics, end-expiratory lung volume, ventilation homogeneity, and gas exchange.

Novel ventilation techniques in children.

Extraordinary progress has been made during the past few decades in the development of anesthesia machines and ventilation techniques. With unprecedented precision and performance, modern machines for pediatric anesthesia can deliver appropriate mechanical ventilation for children and infants of all sizes and with ongoing respiratory diseases, ensuring very small volume delivery and compensating for circuit compliance. Along with highly accurate monitoring of the delivered ventilation, modern ventilators for pediatric anesthesia also have a broad choice of ventilation modalities, including synchronized and assisted ventilation modes, which were initially conceived for ventilation weaning in the intensive care setting. Despite these technical advances, there is still room for improvement in pediatric mechanical ventilation. There is a growing effort to minimize the harm of intraoperative mechanical ventilation of children by adopting the protective ventilation strategies that were previously employed only for prolonged mechanical ventilation. More than ever, the pediatric anesthesiologist should now recognize that positive-pressure ventilation is potentially a harmful procedure, even in healthy children, as it can contribute to both ventilator-induced lung injury and ventilator-induced diaphragmatic dysfunction. Therefore, careful choice of the ventilation modality and its parameters is of paramount importance to optimize gas exchange and to protect the lungs from injury during general anesthesia. The present report reviews the novel ventilation techniques used for children, discussing the advantages and pitfalls of the ventilation modalities available in modern anesthesia machines, as well as innovative ventilation modes currently under development or research. Several innovative strategies and devices are discussed. These novel modalities are likely to become part of the armamentarium of the pediatric anesthesiologist in the near future and are particularly relevant for challenging ventilation scenarios.

The MD-PhD program in Geneva: a 10-year analysis of graduate demographics and outcomes.

BACKGROUND: MD-PhD programs confer degrees that empower medical doctors with in-depth scientific skills to contribute to biomedical research and academic medicine, alongside clinical practice. Whilst the career options and research opportunities related to graduates following these programs in the US are well documented, little is known about their European counterparts. In this article, we studied graduates who had completed the MD-PhD program at the University of Geneva between 2010 and 2019. METHODS: A cross-sectional survey was performed in April 2019, targeting all medical doctors who had obtained the MD-PhD degree from the University of Geneva since 2010. Demographics, opinions, and career outcomes of the MD-PhD graduates were assessed through an online anonymous questionnaire. RESULTS: Twenty-one questionnaires were collected from 31 MD-PhD graduates (response rate 65.5%). Most respondents (57.1%) had performed an MD-PhD training in basic sciences; however, only 14.3% had pursued this type of research thereafter. Most of the respondents held a position at a University hospital (90.5%), although a significant number of them were no longer involved in research in their current position (28.6%). 85.7% mentioned obstacles and challenges in combining clinical duties with research. Despite this, the majority (85.7%) declared that the MD-PhD degree had given them advantages in their career path, granting access to clinical and academic positions, as well as funding. CONCLUSIONS: Graduates from the MD-PhD program in Geneva were for the most part, satisfied with their training. However, because of the challenges and obstacles in combining clinical duties with research, the implementation of research activities in their current position proved difficult.

Physiologically variable ventilation reduces regional lung inflammation in a pediatric model of acute respiratory distress syndrome.

BACKGROUND: Benefits of variable mechanical ventilation based on the physiological breathing pattern have been observed both in healthy and injured lungs. These benefits have not been characterized in pediatric models and the effect of this ventilation mode on regional distribution of lung inflammation also remains controversial. Here, we compare structural, molecular and functional outcomes reflecting regional inflammation between PVV and conventional pressure-controlled ventilation (PCV) in a pediatric model of healthy lungs and acute respiratory distress syndrome (ARDS). METHODS: New-Zealand White rabbit pups (n = 36, 670 ± 20 g [half-width 95% confidence interval]), with healthy lungs or after induction of ARDS, were randomized to five hours of mechanical ventilation with PCV or PVV. Regional lung aeration, inflammation and perfusion were assessed using x-ray computed tomography, positron-emission tomography and single-photon emission computed tomography, respectively. Ventilation parameters, blood gases and respiratory tissue elastance were recorded hourly. RESULTS: Mechanical ventilation worsened respiratory elastance in healthy and ARDS animals ventilated with PCV (11 ± 8%, 6 ± 3%, p < 0.04), however, this trend was improved by PVV (1 ± 4%, - 6 ± 2%). Animals receiving PVV presented reduced inflammation as assessed by lung normalized [18F]fluorodeoxyglucose uptake in healthy (1.49 ± 0.62 standardized uptake value, SUV) and ARDS animals (1.86 ± 0.47 SUV) compared to PCV (2.33 ± 0.775 and 2.28 ± 0.3 SUV, respectively, p < 0.05), particularly in the well and poorly aerated lung zones. No benefit of PVV could be detected on regional blood perfusion or blood gas parameters. CONCLUSIONS: Variable ventilation based on a physiological respiratory pattern, compared to conventional pressure-controlled ventilation, reduced global and regional inflammation in both healthy and injured lungs of juvenile rabbits.

Physiologically variable ventilation in a rabbit model of asthma exacerbation.

BACKGROUND: Mechanical ventilation during status asthmaticus is challenging and increases the risk of severe complications. We recently reported the value of physiologically variable ventilation (PVV) in healthy and acutely injured lungs. We investigated whether PVV provides benefits compared with pressure-controlled ventilation (PCV) in an experimental model of severe acute asthma. METHODS: Allergen-sensitised rabbits were anaesthetised and randomised to either PCV (n=10) or PVV (n=12) during sustained bronchoconstriction induced by allergen and cholinergic stimuli for 6 h. The PVV pattern was generated from pre-recorded spontaneous breathing. Ventilation parameters, oxygenation index (PaO2/FiO2), and respiratory mechanics were measured hourly. Histological injury and inflammation were quantified after 6 h of ventilation. RESULTS: PVV resulted in lower driving pressures (13.7 cm H2O [12.5-14.9], mean [95% confidence interval]), compared with pressure-controlled ventilation (17.6 cm H2O [15.4-19.8]; P=0.002). PVV improved PaO2/FiO2 (PVV: 55.1 kPa [52-58.2]; PCV: 45.6 kPa [39.3-51.9]; P=0.018) and maintained tissue elastance (PVV: +8.7% [-0.6 to 18]; PCV: -11.2% [-17.3 to -5.1]; P=0.03). PVV resulted in less lung injury as assessed by lower histological injury score (PVV: 0.65 [0.62-0.65]; PCV: 0.71 [0.69-0.73]; P=0.003), cell count (PVV: 247 104 ml-1 [189-305]; PCV: 447 104 ml-1 [324-570]; P=0.005), and protein concentration in bronchoalveolar lavage fluid (PVV: 0.14 µg ml-1 [0.10-0.18]; PCV: 0.21 µg ml-1 [0.15-0.27]; P=0.035). CONCLUSIONS: Applying physiological variable ventilation in a model of asthma exacerbation led to improvements in gas exchange, ventilatory pressures, and respiratory tissue mechanics, and reduced lung injury. A global reduction in lung shear stress and recruitment effects may explain the benefits of PVV in status asthmaticus.

Determination of adequate positive end-expiratory pressure level required for carbon dioxide homeostasis in an animal model of infant laparoscopy.

BACKGROUND: Capnoperitoneum provides a ventilatory challenge due to reduction in end-expiratory lung volume and peritoneal carbon dioxide absorption in both children and adults. The primary aim of this controlled interventional trial was to determine the positive end-expiratory pressure (PEEP) level needed to ensure for adequate carbon dioxide clearance and preservation of carbon dioxide homeostasis in an experimental model of infant laparoscopy. The secondary aim was to evaluate potential effects on cardiac output of PEEP and abdominal pressure level variations in the same setting. METHODS: Eight chinchilla bastard rabbits were anesthetized and mechanically ventilated. Intra-abdominal pressures were randomly set to 0, 6, and 12 mm Hg by carbon dioxide insufflation. Carbon dioxide clearance using volumetric capnography, arterial blood gas data, and cardiac output was recorded, while PEEP 3, 6, and 9 cmH2 O were applied in a random order. RESULTS: A PEEP of 9 cmH2 O showed restoration of carbon dioxide clearance without causing changes in arterial partial pressure of carbon dioxide and bicarbonate and with no associated deterioration in cardiac output. CONCLUSION: The results promote a PEEP level of 9 cmH2 O in this model of infant capnoperitoneum to allow for adequate carbon dioxide removal with subsequent preservation of carbon dioxide homeostasis. The use of high PEEP was not associated with any decrease in cardiac output.

End-expiratory lung volume assessment using helium and carbon dioxide in an experimental model of pediatric capnoperitoneum.

BACKGROUND: Capnoperitoneum during laparoscopy leads to cranial shift of the diaphragm, loss in lung volume, and risk of impaired gas exchange. Infants are susceptible to these changes and bedside assessment of lung volume during laparoscopy might assist with optimizing the ventilation. Thus, the primary aim was to investigate the monitoring value of a continuous end-expiratory lung volume (EELV) assessment method based on CO2 dynamics ( EELV CO 2 ) in a pediatric capnoperitoneum model by evaluating the correlation and trending ability against helium washout (EELVHe ). METHODS: Intra-abdominal pressure (IAP) was randomly varied between 0, 6, and 12 mm Hg with CO2 insufflation, while positive end-expiratory pressure (PEEP) levels of 3, 6, and 9 cm H2 O were randomly applied in eight anesthetized and mechanically ventilated chinchilla rabbits. Concomitant EELV CO 2 and EELVHe and lung clearance index (LCI) were obtained under each experimental condition. RESULTS: Significant correlations were found between EELV CO 2 and EELVHe before capnoperitoneum (r = .85, P < .001), although increased IAP distorted this relationship. The negative influence of IAP was counteracted by the application of PEEP 9, which restored the correlation between EELV CO 2 and EELVHe and resulted in 100% concordance rate between the methods regarding changes in lung volume. EELVHe and LCI showed a curvilinear relationship, and an EELVHe of approximately 20 mL kg-1 , determined with a receiver operating characteristic curve, was associated with near-normal LCI values. CONCLUSION: In this animal model of pediatric capnoperitoneum, reliable assessment of changes in EELV based on EELV CO 2 requires an open lung strategy, defined as EELV above approximately 20 mL kg-1 .

Characteristics and opinions of MD-PhD students and graduates from different European countries: a study from the European MD-PhD Association.

BACKGROUND: MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates. PURPOSE: This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe. METHODS: Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression. RESULTS: Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p <0.05) were observed for age group, resident status, clinical time allocation, duration of studies, sources of funding, publications, average impact factor of the journals in which the research was published, satisfaction with the duration of MD-PhD studies and future career choices of MD-PhD students. Responses related to self-perception about clinical and research competence and challenges faced during MD-PhD training did not show a significant country-wise difference. CONCLUSION: The MD-PhD workforce in Europe is highly diverse in their demographics, programme characteristics and career paths but does not differ in opinions related to the challenges faced. The results of this study may be helpful for implementation and improvement of MD-PhD programmes.

Benefit of Physiologically Variable Over Pressure-Controlled Ventilation in a Model of Chronic Obstructive Pulmonary Disease: A Randomized Study.

INTRODUCTION: The advantages of physiologically variable ventilation (PVV) based on a spontaneous breathing pattern have been demonstrated in several respiratory conditions. However, its potential benefits in chronic obstructive pulmonary disease (COPD) have not yet been characterized. We used an experimental model of COPD to compare respiratory function outcomes after 6 h of PVV versus conventional pressure-controlled ventilation (PCV). MATERIALS AND METHODS: Rabbits received nebulized elastase and lipopolysaccharide throughout 4 weeks. After 30 days, animals were anesthetized, tracheotomized, and randomized to receive 6 h of physiologically variable (n = 8) or conventional PCV (n = 7). Blood gases, respiratory mechanics, and chest fluoroscopy were assessed hourly. RESULTS: After 6 h of ventilation, animals receiving variable ventilation demonstrated significantly higher oxygenation index (PaO2/FiO2 441 ± 37 (mean ± standard deviation) versus 354 ± 61 mmHg, p < 0.001) and lower respiratory elastance (359 ± 36 versus 463 ± 81 cmH2O/L, p < 0.01) than animals receiving PCV. Animals ventilated with the variable mode also presented less lung derecruitment (decrease in lung aerated area, -3.4 ± 9.9 versus -17.9 ± 6.7%, p < 0.01) and intrapulmonary shunt fraction (9.6 ± 4.1 versus 17.0 ± 5.8%, p < 0.01). CONCLUSION: PVV applied to a model of COPD improved oxygenation, respiratory mechanics, lung aeration, and intrapulmonary shunt fraction compared to conventional ventilation. A reduction in alveolar derecruitment and lung tissue stress leading to better aeration and gas exchange may explain the benefits of PVV.

Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia.

Critical limb ischemia (CLI) is a serious condition that entails a high risk of lower limb amputation. Despite revascularization being the gold-standard therapy, a considerable number of CLI patients are not suited for either surgical or endovascular revascularization. Angiogenic therapies are emerging as an option for these patients but are currently still under investigation. Before application in humans, those therapies must be tested in animal models and its mechanisms must be clearly understood. An animal model of hindlimb ischemia (HLI) has been developed by the ligation and excision of the distal external iliac and femoral arteries and veins in mice. A comprehensive panel of tests was assembled to assess the effects of ischemia and putative angiogenic therapies at functional, histologic and molecular levels. Laser Doppler was used for the flow measurement and functional assessment of perfusion. Tissue response was evaluated by the analysis of capillary density after staining with the anti-CD31 antibody on histological sections of gastrocnemius muscle and by measurement of collateral vessel density after diaphonization. Expression of angiogenic genes was quantified by RT-PCR targeting selected angiogenic factors exclusively in endothelial cells (ECs) after laser capture microdissection from mice gastrocnemius muscles. These methods were sensitive in identifying differences between ischemic and non-ischemic limbs and between treated and non-treated limbs. This protocol provides a reproducible model of CLI and a framework for testing angiogenic therapies.

Different contributions from lungs and chest wall to respiratory mechanics in mice, rats, and rabbits.

Changes in lung mechanics are frequently inferred from intact-chest measures of total respiratory system mechanics without consideration of the chest wall contribution. The participation of lungs and chest wall in respiratory mechanics has not been evaluated systematically in small animals commonly used in respiratory research. Thus, we compared these contributions in intact-chest mice, rats, and rabbits and further characterized the influence of positive end-expiratory pressure (PEEP). Forced oscillation technique was applied to anesthetized mechanically ventilated healthy animals to obtain total respiratory system impedance (Zrs) at 0, 3, and 6 cmH2O PEEP levels. Esophageal pressure was measured by a catheter-tip micromanometer to separate Zrs into pulmonary (ZL) and chest wall (Zcw) components. A model containing a frequency-independent Newtonian resistance (RN), inertance, and a constant-phase tissue damping (G) and elastance (H) was fitted to Zrs, ZL, and Zcw spectra. The contribution of Zcw to RN was negligible in all species and PEEP levels studied. However, the participation of Zcw in G and H was significant in all species and increased significantly with increasing PEEP and animal size (rabbit > rat > mice). Even in mice, the chest wall contribution to G and H was still considerable, reaching 47.0 ± 4.0(SE)% and 32.9 ± 5.9% for G and H, respectively. These findings demonstrate that airway parameters can be assessed from respiratory system mechanical measurements. However, the contribution from the chest wall should be considered when intact-chest measurements are used to estimate lung parenchymal mechanics in small laboratory models (even in mice), particularly at elevated PEEP levels. NEW & NOTEWORTHY In species commonly used in respiratory research (rabbits, rats, mice), esophageal pressure-based estimates revealed negligible contribution from the chest wall to the Newtonian resistance. Conversely, chest wall participation in the viscoelastic tissue mechanical parameters increased with body size (rabbit > rat > mice) and positive end-expiratory pressure, with contribution varying between 30 and 50%, even in mice. These findings demonstrate the potential biasing effects of the chest wall when lung tissue mechanics are inferred from intact-chest measurements in small laboratory animals.

Feasibility of forced oscillatory assessment of respiratory mechanics across a laryngeal mask airway in rabbits.

OBJECTIVES: The forced oscillation technique (FOT) is the method of choice for assessment of respiratory tissue mechanics. A laryngeal mask airway (LMA) is increasingly used to secure the airways in subjects under sedation or general anesthesia. While FOT is routinely performed using an endotracheal tube (ETT), the accuracy of information about airway and tissue mechanics obtained with FOT using a LMA has not been characterized. Therefore, we compared the mechanical parameters obtained with FOT using LMA and ETT in rabbits. APPROACH: FOT was performed through a LMA at normal and reduced oscillatory amplitudes in anesthetized and mechanically ventilated rabbits (n = 9) at positive end-expiratory pressures (PEEP) of 3 and 6 cmH2O. These measurements were repeated at normal amplitude for the same animal using an ETT. Airway resistance, inertance, respiratory tissue damping (G) and elastance (H) were measured under each condition by FOT. The potential bias of the distensible upper airways when FOT was applied using LMA was assessed with a simulation study. MAIN RESULTS: Values of parameters reflecting airway mechanics were significantly higher when measured using LMA at both PEEPs and oscillatory amplitudes than with ETT. Conversely, regardless of the condition, there was a correlation (r = 0.89 both at normal and reduced amplitudes; p  < 0.0001) with good agreement (mean bias of 8.8 cmH2O/l and 11.3 cmH2O/l) in H, whereas G was systematically lower when obtained with LMA than with ETT at PEEP 3 (21.1% ± 7.2% and 9.6% ± 6.9% at normal and reduced oscillatory amplitudes, respectively) and 6 cmH2O (15.1% ± 8.2%, 1.6% ± 9.4%, p  < 0.05 for all). SIGNIFICANCE: Mechanical properties of the airways and the respiratory tissues, particularly for respiratory tissue stiffness, can be reliably assessed using LMA. However, the involvement of a longer laryngo-tracheo-bronchial pathway when using LMA should be considered for airway resistance and inertance, whereas upper airway shunting may affect the assessment of respiratory tissue damping.

Volumetric but Not Time Capnography Detects Ventilation/Perfusion Mismatch in Injured Rabbit Lung.

Whereas time capnography (Tcap) is routinely displayed during mechanical ventilation, the volumetric representation (Vcap) is seldom used. We compared the diagnostic value of indices derived from Tcap and Vcap following ventilation to perfusion ratio () mismatch subsequent to experimentally induced acute respiratory distress syndrome (ARDS), and alveolar recruitment by elevating the positive end-expiratory pressure (PEEP). Lung injury was induced by iv lipopolysaccharide, whole lung lavage and injurious ventilation in anesthetized, mechanically ventilated rabbits (n = 26). Mainstream Tcap and Vcap were performed to assess normalized phase 2 (Sn2T, Sn2V) and phase 3 slopes (Sn3T, Sn3V) in the time and volumetric domains. Vcap was also used to estimate Enghoff's physiological dead space (VDE). Lung oxygenation index (PaO2/FiO2) and intrapulmonary shunt (Qs/Qt) were derived from arterial and central venous blood gas samples. All measurements were made under baseline conditions, and, following lung injury, under moderate (6 cmH2O) and high PEEP levels (9 cmH2O). Lung injury deteriorated the PaO2/FiO2 (baseline vs. injured 466 ± 10.2 [95% confidence interval] vs. 77.3 ± 17.1 mmHg, p < 0.05) and compromised all mechanical parameters significantly, whereas Tcap parameters exhibited contradictory or inconsistent changes. Conversely, Vcap indices exhibited consistent changes and provided excellent diagnostic value in detecting lung-function deterioration subsequent to lung injury [area under the receiver operating characteristic (ROC) curve of 1.0 ± 0.0, 0.87 ± 0.22 and 0.86 ± 0.22 for VDE, Sn3V and Sn3V/Sn2V, respectively]. Elevated PEEP increased PaO2/FiO2 and decreased Qs/Qt, which was reflected only in the Vcap slope ratio (Sn3V/Sn2V, p < 0.05). Our findings demonstrate the limited value of Tcap to detect ventilation to perfusion ratio () mismatch, following severe lung injury. Conversely, indices derived from Vcap proved to be sensitive for detecting lung volume loss and alveolar recruitment. Therefore, promotion of Vcap is of paramount importance as a real-time, non-invasive, bedside monitoring modality to detect the development of and to follow-up the progression of lung injury in a model of ARDS.