Papers by Federico Formenti
Annals of the American Thoracic Society, Jul 1, 2015
significant correlations among airway ADMA and FENO (4). We did not measure ADMA in our study. AD... more significant correlations among airway ADMA and FENO (4). We did not measure ADMA in our study. ADMA has been associated with changes in hemodynamic parameters that associate with cardiovascular risk (5, 6). To explore a possible link between PPI treatment and hemodynamic changes in a post hoc analysis, we determined the associations among PPI treatment status, metabolizer phenotype, and key hemodynamic measures before and after the intervention period. Using our original statistical approach, we found that increasing PPI exposure was not associated with changes in blood pressure, heart rate, pulse pressure, mean arterial pressure, mid blood pressure ([sytolic blood pressure 1 diastolic blood pressure]/2), pulse pressure index, or rate pressure product (data not shown). However, we did see a weak trend between PPI exposure group and changes from baseline in systolic blood pressure (placebo 0.0 vs. lansoprazole-treated poor metabolizer 13.5; P = 0.09). It is biologically plausible for excess PPI exposure to increase susceptibility to asthmagenic pathogens and increase ADMA, leading to altered NOS activity and airway inflammation. However, further research is needed to confirm these speculations. Despite the fact that long-term use of PPIs is common, current US Food and Drug Administration recommendations for dosing is limited to short-term use (up to 12 weeks). We very much agree with Sukhovershin and colleagues that considering PPIs' multiple known adverse effects and limited research into long-term effects, judicious use of PPIs is warranted and should be conducted with close guidance from a medical professional.
ISBS - Conference Proceedings Archive, 2002
PLOS ONE, Jul 31, 2013
The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important... more The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (PA CO2 ) and oxygen (PA O2 ) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of PA CO2 (+6, +1, 24 and 29 mmHg, relative to baseline) with four levels of PA O2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both PA CO2 and the calculated haemoglobin oxygen desaturation (1-SO 2 ). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, PA CO2 and SO 2 . No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p.0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.
Current Opinion in Critical Care, Dec 13, 2021
Purpose of review More than 230 million people have tested positive for severe acute respiratory ... more Purpose of review More than 230 million people have tested positive for severe acute respiratory syndrome-coronavirus-2 infection globally by September 2021. The infection affects primarily the function of the respiratory system, where ∼20% of infected individuals develop coronavirus-19 disease (COVID-19) pneumonia. This review provides an update on the pathophysiology of the COVID-19 acute lung injury. Recent findings In patients with COVID-19 pneumonia admitted to the intensive care unit, the PaO2/FiO2 ratio is typically <26.7 kPa (200 mmHg), whereas lung volume appears relatively unchanged. This hypoxaemia is likely determined by a heterogeneous mismatch of pulmonary ventilation and perfusion, mainly associated with immunothrombosis, endothelialitis and neovascularisation. During the disease, lung weight, elastance and dead space can increase, affecting respiratory drive, effort and dyspnoea. In some severe cases, COVID-19 pneumonia may lead to irreversible pulmonary fibrosis. Summary This review summarises the fundamental pathophysiological features of COVID-19 in the context of the respiratory system. It provides an overview of the key clinical manifestations of COVID-19 pneumonia, including gas exchange impairment, altered pulmonary mechanics and implications of abnormal chemical and mechanical stimuli. It also critically discusses the clinical implications for mechanical ventilation therapy.
Experimental Physiology, Sep 27, 2021
New Findings What is the topic of this review? This review presents the fundamental concepts of r... more New Findings What is the topic of this review? This review presents the fundamental concepts of respiratory physiology and pathophysiology, with particular reference to lung mechanics and the pulmonary phenotype associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and subsequent coronavirus disease 2019 (COVID‐19) pneumonia. What advances does it highlight? The review provides a critical summary of the main physiological aspects to be considered for safe and effective mechanical ventilation in patients with severe COVID‐19 in the intensive care unit. Severe respiratory failure from coronavirus disease 2019 (COVID‐19) pneumonia not responding to non‐invasive respiratory support requires mechanical ventilation. Although ventilation can be a life‐saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection can lead to a pattern of lung injury in patients with severe COVID‐19 pneumonia typically associated with two distinct phenotypes, along a temporal and pathophysiological continuum, characterized by different levels of elastance, ventilation‐to‐perfusion ratio, right‐to‐left shunt, lung weight and recruitability. Understanding the underlying pathophysiology, duration of symptoms, radiological characteristics and lung mechanics at the individual patient level is crucial for the appropriate choice of mechanical ventilation settings to optimize gas exchange and prevent further lung injury. By critical analysis of the literature, we propose fundamental physiological and mechanical criteria for the selection of ventilation settings for COVID‐19 patients in intensive care units. In particular, the choice of tidal volume should be based on obtaining a driving pressure < 14 cmH2O, ensuring the avoidance of hypoventilation in patients with preserved compliance and of excessive strain in patients with smaller lung volumes and lower lung compliance. The level of positive end‐expiratory pressure (PEEP) should be informed by the measurement of the potential for lung recruitability, where patients with greater recruitability potential may benefit from higher PEEP levels. Prone positioning is often beneficial and should be considered early. The rationale for the proposed mechanical ventilation settings criteria is presented and discussed.
Intensive Care Medicine, Jul 31, 2020
Intensive Care Medicine Experimental
Background Within-breath oscillations in arterial oxygen tension (PaO2) can be detected using fas... more Background Within-breath oscillations in arterial oxygen tension (PaO2) can be detected using fast responding intra-arterial oxygen sensors in animal models. These PaO2 signals, which rise in inspiration and fall in expiration, may represent cyclical recruitment/derecruitment and, therefore, a potential clinical monitor to allow titration of ventilator settings in lung injury. However, in hypovolaemia models, these oscillations have the potential to become inverted, such that they decline, rather than rise, in inspiration. This inversion suggests multiple aetiologies may underlie these oscillations. A correct interpretation of the various PaO2 oscillation morphologies is essential to translate this signal into a monitoring tool for clinical practice. We present a pilot study to demonstrate the feasibility of a new analysis method to identify these morphologies. Methods Seven domestic pigs (average weight 31.1 kg) were studied under general anaesthesia with muscle relaxation and mech...
British Journal of Anaesthesia, 2022
British Journal of Anaesthesia, 2021
British Journal of Anaesthesia, 2021
BACKGROUND Artificial intelligence (AI) has the potential to personalise mechanical ventilation s... more BACKGROUND Artificial intelligence (AI) has the potential to personalise mechanical ventilation strategies for patients with respiratory failure. However, current methodological deficiencies could limit clinical impact. We identified common limitations and propose potential solutions to facilitate translation of AI to mechanical ventilation of patients. METHODS A systematic review was conducted in MEDLINE, Embase, and PubMed Central to February 2021. Studies investigating the application of AI to patients undergoing mechanical ventilation were included. Algorithm design and adherence to reporting standards were assessed with a rubric combining published guidelines, satisfying the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis [TRIPOD] statement. Risk of bias was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST), and correspondence with authors to assess data and code availability. RESULTS Our search identified 1,342 studies, of which 95 were included: 84 had single-centre, retrospective study design, with only one randomised controlled trial. Access to data sets and code was severely limited (unavailable in 85% and 87% of studies, respectively). On request, data and code were made available from 12 and 10 authors, respectively, from a list of 54 studies published in the last 5 yr. Ethnicity was frequently under-reported 18/95 (19%), as was model calibration 17/95 (18%). The risk of bias was high in 89% (85/95) of the studies, especially because of analysis bias. CONCLUSIONS Development of algorithms should involve prospective and external validation, with greater code and data availability to improve confidence in and translation of this promising approach. TRIAL REGISTRATION NUMBER PROSPERO - CRD42021225918.
Clinical Nutrition, 2020
We read with interest the study Modulation of Hb-O 2 affinity to improve hypoxemia in COVID-19 pa... more We read with interest the study Modulation of Hb-O 2 affinity to improve hypoxemia in COVID-19 patients, by Woyke et al. . The opinion paper discussed the potential impact of a nutritional intervention in patients with , where supplementing 5-Hydroxymethylfurfural (5-HMF) could increase haemoglobin-oxygen (Hb-O 2 ) affinity. Typically, hypercapnia, acidosis and hyperthermia shift the oxygen dissociation curve (ODC) to the right, reducing Hb-O 2 affinity and worsening hypoxaemia. This scenario could justify the rationale for the conclusion that a nutritional intervention shifting the ODC to the left could improve oxygenation in hypoxaemic respiratory failure , such as in COVID-19 patients. The scenario presented is physiologically sound and based on evidence available at the time of publication. However, a recent study showed that Hb-O 2 affinity was actually higher in mechanically ventilated COVID-19 patients [average(SD); p 50 23.4 (3.1) mmHg) compared to the normal value for p 50 of 26.7 mmHg, as well as compared to a control group of critically ill patients [p 50 24.6 (5.4) mmHg] [3]. In addition, COVID-19 is characterised by shunt and dead space e across the severity of oxygenation -that differ from the typical acute respiratory distress syndrome . This observed left-shift of the ODC may be a compensatory mechanism that, while facilitating oxygen uptake in the pulmonary circulation and arterial oxygenation, could reduce the rate of peripheral oxygen unloading, although the rate of oxygen unloading may be increased if/when peripheral carbon dioxide and temperature are elevated. The proposed nutritional intervention remains a potentially effective approach, especially in the absence of significant side effects, pending some important considerations. An optimum degree of ODC left-shift needs to be identified in terms of balancing the benefits of more rapid pulmonary oxygen uptake and arterial oxygenation with the associated reduced rate of peripheral oxygen unloading e therefore the modulation of other factors such as pH may be relevant. The nutritional intervention modality and timing needs to be determined: it may be beneficial only to a subset of COVID-19 patients with a defined clinical phenotype or perhaps earlier in the disease. Here lies the difficulty particularly if patients are asymptomatic or do not perceive hypoxaemia. Finally, the overall outcome of interest and the effect size need to be defined, particularly with reference to the efficacy in the reduction of p 50 . Despite the complexity of the proposed therapeutic nutritional intervention and the characterisation of the associated physiological responses, its implementation might be worth investigating.
Experimental Physiology, 2021
New Findings What is the topic of this review? This review presents the fundamental concepts of r... more New Findings What is the topic of this review? This review presents the fundamental concepts of respiratory physiology and pathophysiology, with particular reference to lung mechanics and the pulmonary phenotype associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and subsequent coronavirus disease 2019 (COVID‐19) pneumonia. What advances does it highlight? The review provides a critical summary of the main physiological aspects to be considered for safe and effective mechanical ventilation in patients with severe COVID‐19 in the intensive care unit. Severe respiratory failure from coronavirus disease 2019 (COVID‐19) pneumonia not responding to non‐invasive respiratory support requires mechanical ventilation. Although ventilation can be a life‐saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The pathophysiology of severe acute...
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2021
Intensive Care Medicine, 2020
PLoS ONE, 2013
The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important... more The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (PA CO2 ) and oxygen (PA O2 ) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of PA CO2 (+6, +1, 24 and 29 mmHg, relative to baseline) with four levels of PA O2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both PA CO2 and the calculated haemoglobin oxygen desaturation (1-SO 2 ). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, PA CO2 and SO 2 . No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p.0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.
International Journal of Sports Medicine, Feb 8, 2019
The aim of this study was to assess the changes determined by increased cadence on skeletal muscl... more The aim of this study was to assess the changes determined by increased cadence on skeletal muscle oxygenation during cycling at exercise intensity equal to the ventilatory threshold (Tvent). Nine healthy, active individuals, with different levels of cycling experience, exercised at a power output equal to Tvent, pedalling at cadences of 40, 50, 60, 70, 80 and 90 rpm, each for 4 minutes. Cadences were tested in a randomized counterbalanced sequence. Cardiopulmonary and metabolic responses were studied using an ECG for heart rate, and gas calorimetry for pulmonary oxygen uptake and carbon dioxide production. NIRS was used to determine the tissue saturation index (TSI), a measure of vastus lateralis oxygenation. TSI decreased from rest to exercise; the magnitude of this TSI reduction was significantly greater when pedalling at 90rpm (-14±4%), compared to pedalling at 40 (-12±3%) and 50 (-12±3%) rpm (P=0.027 and 0.017, respectively). Albeit small, the significant decrease in ΔTSI at increased cadence recorded in this study suggests that skeletal muscle oxygenation is relatively more affected by high cadence when exercise intensity is close to Tvent.
Experimental Physiology, Mar 19, 2020
This review focuses on recent discoveries in skeletal and cardiac muscles indicating that mitocho... more This review focuses on recent discoveries in skeletal and cardiac muscles indicating that mitochondria behave as an interactive cohort with inter-organelle communication and specific reactions to stress signals. Our new finding is that intermitochondrial communications in cardiac and skeletal muscles rely on two distinct methods. In cardiac muscle, mitochondria are discrete entities and are fairly well immobilized in a structural context. The organelles have developed a unique method of communication, via nanotunnels, that allow temporary connection from one mitochondrion to another over distance of up to several microns, without overall movement of the individual organelles and loss of their identity. Skeletal muscle mitochondria, on the other hand, are quite dynamic. Through fusion, fission and elongation they form connections that include constrictions and connecting ducts (quite distinct from nanotunnels) and loose individual identity in the formation of extensive networks. Connecting elements in skeletal muscle are distinct from nanotunnels in Disclaimer: This is a confidential document.
Experimental Physiology, 2020
New Findings What is the topic for this review? This review summarizes recent discoveries in mito... more New Findings What is the topic for this review? This review summarizes recent discoveries in mitochondrial development and morphology studied with electron microscopy. What advances does it highlight? Although mitochondria are generally considered to be isolated from each other, this review highlights recently discovered evidence for the presence of intermitochondrial communication structures in cardiac and skeletal muscle, in animal models and humans. Within striated muscles, the means of intermitochondrial exchange and the reaction of mitochondria to external stimuli are uniquely dependent on the tissue, and we clearly differentiate between nanotunnels, the active protrusion of cardiac mitochondria, and the connecting ducts of skeletal muscle derived from fusion–fission and elongation events. This review focuses on recent discoveries in skeletal and cardiac muscles indicating that mitochondria behave as an interactive cohort with inter‐organelle communication and specific reaction...
physiological responses to hypoxia hypoxia-inducible factor system and blunted Tibetans living at... more physiological responses to hypoxia hypoxia-inducible factor system and blunted Tibetans living at sea level have a hyporesponsive You might find this additional info useful... 45 articles, 26 of which can be accessed free at:This article cites
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Papers by Federico Formenti