High O2 Flow Rates Required to Achieve Acceptable FiO2 in CPAP-Treated Patients With Severe Covid-19: A Clinically Based Bench Study

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Axial slices are shown in the mediastinum window (left) and pulmonary parenchyma window (right) where heterogeneous consolidation is observed in the right lower lobe with hypodense areas (circle) and areas of ground glass and tree-in-bud pattern (arrow). Some bilateral solid pulmonary nodules (arrowhead) probably associated with metastases are also observed. (B) B-mode ultrasound performed in the same patient showing heterogeneous consolidation without air bronchogram and anechoic subpleural area (oval). (C–F) Ultrasound image after injection of contrast agent showing homogeneous but delayed enhancement (star) of the consolidated pulmonary parenchyma (pneumonia pattern). A subpleural triangular area is observed that shows more delayed enhancement than the surrounding consolidated parenchyma (oval). Moreover, washout of this area is rapid, suggesting malignancy. An ultrasound-guided biopsy of the suspicious area was subsequently performed with histological results confirming pancreatic adenocarcinoma metastases. Later, a fiberoptic bronchoscopy confirmed fungal superinfection in the surrounding parenchyma. (G) Large atypical and vacuolated epithelial cell groups associated with metastatic pancreatic adenocarcinoma. (H) Microbiological analysis of the bronchoalveolar lavage sample from the consolidation area showing branched structures corresponding to hyphae." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Gemma Isus Olivé, Alfredo Páez Carpio, Daniel Martínez, Ivan Vollmer" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Gemma" "apellidos" => "Isus Olivé" ] 1 => array:2 [ "nombre" => "Alfredo" "apellidos" => "Páez Carpio" ] 2 => array:2 [ "nombre" => "Daniel" "apellidos" => "Martínez" ] 3 => array:2 [ "nombre" => "Ivan" "apellidos" => "Vollmer" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0300289621000594" "doi" => "10.1016/j.arbres.2021.01.033" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289621000594?idApp=UINPBA00003Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212921002330?idApp=UINPBA00003Z" "url" => "/15792129/0000005700000009/v1_202109020614/S1579212921002330/v1_202109020614/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "cabecera" => "Scientific Letter" "titulo" => "High O2 Flow Rates Required to Achieve Acceptable FiO2 in CPAP-Treated Patients With Severe Covid-19: A Clinically Based Bench Study" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "607" "paginaFinal" => "610" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Marius Lebret, Emeline Fresnel, Guillaume Prieur, Jean Quieffin, Johan Dupuis, Bouchra Lamia, Yann Combret, Clément Medrinal" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Marius" "apellidos" => "Lebret" "email" => array:1 [ 0 => "mariuslebret@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Emeline" "apellidos" => "Fresnel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Guillaume" "apellidos" => "Prieur" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "Jean" "apellidos" => "Quieffin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Johan" "apellidos" => "Dupuis" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "Bouchra" "apellidos" => "Lamia" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 2 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] 6 => array:3 [ "nombre" => "Yann" "apellidos" => "Combret" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 7 => array:3 [ "nombre" => "Clément" "apellidos" => "Medrinal" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "h" "identificador" => "aff0040" ] 2 => array:2 [ "etiqueta" => "i" "identificador" => "aff0045" ] ] ] ] "afiliaciones" => array:9 [ 0 => array:3 [ "entidad" => "ERFPS, Rouen University Hospital, Physiotherapy School Rouen University, France" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "KerNel Biomedical, Bois-Guillaume, France" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Pulmonology Department, Le Havre Hospital, Avenue Pierre Mendes France, Montivilliers, France" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Research and Clinical Experimentation Institute (IREC), Pulmonology, ORL and Dermatology, Louvain Catholic University, Brussels, Brussels Capital Region, Belgium" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Asten Santé, Isneauville, France" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "UPRES EA3830 – GRHV, Institute for Research and Innovation in Biomedicine (IRIB), UNIROUEN, Rouen University Hospital, Rouen, Normandie, France" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Intensive Care Unit, Respiratory Section, Rouen University Hospital, Rouen, Normandie, France" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Université Paris-Saclay, UVSQ, Erphan, Versailles, France" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Saint Michel School of Physiotherapy, Paris-Saclay University, Paris, Île-de-France, France" "etiqueta" => "i" "identificador" => "aff0045" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Se requieren altos índices de flujo de O2 para alcanzar una FiO2 aceptable en los pacientes con covid-19 tratados con CPAP: un estudio experimental basado en la clínica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4016 "Ancho" => 2091 "Tamanyo" => 587332 ] ] "descripcion" => array:1 [ "en" => "Dose–response relationship between oxygen (O2) flow rates delivered into the circuit, and fraction of inspired oxygen (FiO2) as a function of respiratory rate, presence/absence of non-intentional leakage, lung mechanics and leak port locations. Each Plot represents the mean FiO2 of the 10 cycles analysed. For each FiO2, the standard deviation was systematically below 0.3 and is therefore not represented on the graph. Panel A displays the results for the conventional intentional leak model, in which the unintentional leakage port was placed in series between the exhalation valve (intentional leak port) and the ASL 5000. Panel B displays the results for the same model as in panel A, but with restrictive lung mechanics. Panel C displays the results for by-pass leakage ports using an antibacterial filter between the ASL 5000 and both intentional and non-intentional leak ports. The blue lines represent the relationship between O2 flow and FiO2 without unintentional leaks, and the green lines represent the relationship between O2 flow and Fi2O with unintentional leaks." ] ] ] "textoCompleto" => "During the Covid-19 pandemic, a lack of ventilatory equipment in intensive care units (ICU), or patient comorbidities meant that some patients received non invasive, continuous positive airway pressure (CPAP), with the highest fraction of inspired oxygen (FiO2) as a ceiling treatment.<a class="elsevierStyleCrossRefs" href="#bib0085">1–3</a> In Le Havre hospital (France), between September and December 2020, around 30 patients were treated with bilevel home devices in CPAP mode using vented oronasal masks. In contrast with bench studies that reported high FiO2 with oxygen flow rates<30L/min in optimal experimental conditions (i.e., low minute ventilation, good pulmonary compliance and no leakage),<a class="elsevierStyleCrossRefs" href="#bib0100">4,5</a> many patients required O2 flow rates>70L/min to maintain oxygen saturation (SpO2)≥90%. We hypothesised that due to the high respiratory demand of patients with severe Covid-19, a high O2 flow rate would be required to reach adequate pressure levels with CPAP, thereby substantially increasing the oxygen flow rate needed to achieve a high FiO2. We carried out a bench study to measure the oxygen flow rates needed to reach high FiO2 levels, using a pulmonary model that reproduced the characteristics of patients with severe Covid-19.First, we extracted clinical data from 10 consecutive patients who were included in an ongoing clinical trial (EURO-CPAP CT2220141 approved by our institutional review board) from the CPAP built-in software. This case series is presented for descriptive purposes to illustrate our hypothesis. Then, we performed several bench experiments. We used a CPAP device (AirSense 10 AutoSet, ResMed, San Diego, CA, USA) set at 10 cmH2O, connected to an artificial lung (ASL 5000, Ingmar Medical, Pittsburgh, PA, USA). A low-resistance antibacterial filter (Clear-Guard, Intersurgical, Wokingham, UK), an oxygen inlet connector, a 15mm single limb circuit, a Whisper Swivel II Exhalation port (Philips Respironics, Murrysville, PA, USA) that simulated intentional leaks, and the artificial lung were placed in series and connected to the CPAP device. A standard 4-mm diameter leak port was placed between the exhalation port and the artificial lung to mimic unintentional leakage. Oxygen was delivered into the system using two O2 flow meters (EASY MED-O2, Air Liquide Healthcare, Paris, France) that could both deliver up to 50L/min. Three different mechanical lung conditions were simulated by modulating the resistance (R) and the compliance (C) of the artificial lung, corresponding to the following experimental models:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">A.Normal: R=5cmH2O/ls and C=60ml/cmH2O.</li><li class="elsevierStyleListItem" id="lsti0010">B.Restrictive: R=5 cmH2O/ls and C=30ml/cmH2O.</li><li class="elsevierStyleListItem" id="lsti0015">C.Normal with by-pass leak using a T-connector as recommended to reduce the risk of droplet aerosolization.<a class="elsevierStyleCrossRef" href="#bib0110">6</a></li></ul>Each model was run at breathing frequencies of 22, 30 and 35 cycles per minute (cpm), associated with inspiratory airway pressure drops of 2.5–6cmH2O at 100ms (P0.1) to reach tidal volumes of around 600ml. The values of the inspiratory effort settings chosen for the simulation in the ASL5000 were based on published clinical values.<a class="elsevierStyleCrossRefs" href="#bib0115">7–11</a> Each condition was run with and without unintentional leakage. FiO2 was measured with 5, 15, 30, 50, 60 and 80L/min of O2, and the experiment was stopped when 100% FiO2 was reached. The sensor used was a paramagnetic oxygen transducer located in the ASL 5000 piston chamber which allowed a fast measurement with a response time below 350ms. Ten respiratory cycles were analysed after the FiO2 had reached an asymptote for each model at each O2 flow rate. Normality and homogeneity were assessed using Shapiro-Wilk and Levene tests, respectively. Welch's ANOVA was used to compare respiratory rates at each O2 flow rate. A Games-Howell post-hoc procedure was applied for multiple comparisons, with 22cpm as the reference condition. Significance was set at 0.05. Statistical analysis was performed using IBM SPSS Statistics V25.Data from 10 consecutive patients with Covid-19 treated with CPAP and O2 are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Six patients needed O2 flow rates≥50L/min to maintain SpO2>90%. Minimum O2 flow rate was 15L/min. All patients had severe infection (i.e., PaO2/FiO2 ratio≤150at CPAP initiation).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the relationship between the O2 flow rate delivered and the resulting FiO2 in the simulation. Without unintentional leaks, a flow rate of at least 30L/min was necessary to reach FiO2>95%. FiO2 differed significantly for each respiratory rate at each O2 flow rate with and without unintentional leaks (p<0.001). With unintentional leaks, O2 flow rates of up to 80l/min were required to reach 100% FiO2 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A–C).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The results of this experimental bench study confirmed our clinical observation that high O2 flow rates are required to achieve a high FiO2 in patients with severe Covid-19 using CPAP and vented masks. An O2 flow rate of at least 30L/min, and up to 80L/min, was required to achieve 100% FiO2 for all three experimental models. Reduced compliance and unintentional leakage dramatically reduced FiO2. The arbitrary compliance of 30ml/cmH2O used in model B is similar to that of patients with severe COVID-19.<a class="elsevierStyleCrossRef" href="#bib0140">12</a> Such a low level of compliance would reduce the FiO2 with home CPAP and a vented mask, further confirming the need for high O2 flow rates. In our clinical cohort, three patients required an O2 flow rate above 80L/min: this very high rate causes two concerns. Firstly, we did not know the lung compliance of these patients. Secondly, the O2 flow rate required to achieve a given FiO2 is likely to be underestimated with the experimental model compared to the clinical situation, since no gas exchange occurs with an artificial lung. For instance, in a patient, with a 21% FiO2, the partial pressure of O2 in the inspired air will be 160mm Hg, while in the expired air (at sea level) it will be 120mm Hg due to oxygen absorption. Thus, in in vivo conditions even higher O2 flows than those reported in this study may be required.<a class="elsevierStyleCrossRef" href="#bib0145">13</a>Another important point is that many teams use helmets to ventilate patients with Covid-19.<a class="elsevierStyleCrossRefs" href="#bib0090">2,14</a> Helmets could be more advantageous than oronasal masks because of the lower rate of unintentional leakage; this would allow lower oxygen flow rates to be used to achieve sufficient FiO2 levels for patients with severe hypoxemia.Studies have shown that patients who cannot be intubated require a high FiO2 to maintain their SpO2 above 92%,<a class="elsevierStyleCrossRefs" href="#bib0095">3,15</a> and that poor oxygenation is strongly associated with mortality.<a class="elsevierStyleCrossRefs" href="#bib0095">3,16</a> Our study provides valuable data to guide clinicians in the use of O2 when using home CPAP in patients with severe Covid-19 who cannot be intubated. The results showed that these patients can be successfully treated with home CPAP devices, or NIV devices in CPAP mode, with vented masks, if a high O2 flow rate is provided. However, close monitoring of unintentional leaks is crucial to ensure a sufficient FiO2 for the treatment of severe hypoxemia in these patients.Authors’ contributionAll authors participated in the study design, research, and manuscript preparation. Dr. Marius Lebret is the guarantor of the content of the manuscript, including the data and analysis.FundingFunding was provided by Asten Santé.Conflict of interestML reports receiving personal fees from Air Liquid Medical Systems and non-financial support from NOMICS over the past 3 years, for work unrelated to the work presented here. ML is a part-time employee of Air Liquide Medical System (Med2lab).YC, CM and GP work as consultants for Air Liquid Medical System." "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Authors’ contribution" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:2 [ "identificador" => "xack552801" "titulo" => "Acknowledgements" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4016 "Ancho" => 2091 "Tamanyo" => 587332 ] ] "descripcion" => array:1 [ "en" => "Dose–response relationship between oxygen (O2) flow rates delivered into the circuit, and fraction of inspired oxygen (FiO2) as a function of respiratory rate, presence/absence of non-intentional leakage, lung mechanics and leak port locations. Each Plot represents the mean FiO2 of the 10 cycles analysed. For each FiO2, the standard deviation was systematically below 0.3 and is therefore not represented on the graph. Panel A displays the results for the conventional intentional leak model, in which the unintentional leakage port was placed in series between the exhalation valve (intentional leak port) and the ASL 5000. Panel B displays the results for the same model as in panel A, but with restrictive lung mechanics. Panel C displays the results for by-pass leakage ports using an antibacterial filter between the ASL 5000 and both intentional and non-intentional leak ports. The blue lines represent the relationship between O2 flow and FiO2 without unintentional leaks, and the green lines represent the relationship between O2 flow and Fi2O with unintentional leaks." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Body mass index: BMI; chronic respiratory failure: CRF; cardiac failure: CF; arterial hypertension: AH; type 2 diabetes: DT2; continuous positive airway pressure: CPAP; partial O2 pressure in arterial blood: PaO2; fraction of inspired oxygen: FiO2." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">BMI (kg/m2) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CRF \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CF \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AH \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DT2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PAO2/FiO2 at CPAP initiation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPAP level (cmH2O) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median leakage (l/min) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean Vt (ml) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean RR (cycle per minute) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">O2 flow<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (l/min) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SpO2 (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">122 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.5<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">120 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">374.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">409.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">143 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">927 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">938 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">972.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">134 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.5<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">473 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">98 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n 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Leakage, Tidal Volume (Vt) and Respiratory Rate (RR) were collected from built-in CPAP software during the first 48h of CPAP treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous Positive Airway Pressure (CPAP) face-mask ventilation is an easy and cheap option to manage a massive influx of patients presenting acute respiratory failure during the SARS-CoV-2 outbreak: a retrospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Alviset" 1 => "Q. Riller" 2 => "J. Aboab" 3 => "K. Dilworth" 4 => "P-A. Billy" 5 => "Y. 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The authors would also like to thank Johanna Robertson for English editing." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005700000009/v1_202109020614/S1579212921002743/v1_202109020614/en/main.assets" "Apartado" => array:4 [ "identificador" => "49861" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005700000009/v1_202109020614/S1579212921002743/v1_202109020614/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212921002743?idApp=UINPBA00003Z"]

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Scientific Letter

High O2 Flow Rates Required to Achieve Acceptable FiO2 in CPAP-Treated Patients With Severe Covid-19: A Clinically Based Bench Study

Se requieren altos índices de flujo de O2 para alcanzar una FiO2 aceptable en los pacientes con covid-19 tratados con CPAP: un estudio experimental basado en la clínica

Marius Lebreta,

Corresponding author

mariuslebret@gmail.com

Corresponding author.

, Emeline Fresnelb, Guillaume Prieurc,d, Jean Quieffinc, Johan Dupuise, Bouchra Lamiac,f,g, Yann Combretc,d, Clément Medrinalc,h,i

a ERFPS, Rouen University Hospital, Physiotherapy School Rouen University, France

b KerNel Biomedical, Bois-Guillaume, France

c Pulmonology Department, Le Havre Hospital, Avenue Pierre Mendes France, Montivilliers, France

d Research and Clinical Experimentation Institute (IREC), Pulmonology, ORL and Dermatology, Louvain Catholic University, Brussels, Brussels Capital Region, Belgium

e Asten Santé, Isneauville, France

f UPRES EA3830 – GRHV, Institute for Research and Innovation in Biomedicine (IRIB), UNIROUEN, Rouen University Hospital, Rouen, Normandie, France

g Intensive Care Unit, Respiratory Section, Rouen University Hospital, Rouen, Normandie, France

h Université Paris-Saclay, UVSQ, Erphan, Versailles, France

i Saint Michel School of Physiotherapy, Paris-Saclay University, Paris, Île-de-France, France

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using a pulmonary model that reproduced the characteristics of patients with severe Covid-19&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">First&#44; we extracted clinical data from 10 consecutive patients who were included in an ongoing clinical trial &#40;EURO-CPAP CT2220141 approved by our institutional review board&#41; from the CPAP built-in software&#46; This case series is presented for descriptive purposes to illustrate our hypothesis&#46; Then&#44; we performed several bench experiments&#46; We used a CPAP device &#40;AirSense 10 AutoSet&#44; ResMed&#44; San Diego&#44; CA&#44; USA&#41; set at 10 cmH<span class="elsevierStyleInf">2</span>O&#44; connected to an artificial lung &#40;ASL 5000&#44; Ingmar Medical&#44; Pittsburgh&#44; PA&#44; USA&#41;&#46; A low-resistance antibacterial filter &#40;Clear-Guard&#44; Intersurgical&#44; Wokingham&#44; UK&#41;&#44; an oxygen inlet connector&#44; a 15<span class="elsevierStyleHsp" style=""></span>mm single limb circuit&#44; a Whisper Swivel II Exhalation port &#40;Philips Respironics&#44; Murrysville&#44; PA&#44; USA&#41; that simulated intentional leaks&#44; and the artificial lung were placed in series and connected to the CPAP device&#46; A standard 4-mm diameter leak port was placed between the exhalation port and the artificial lung to mimic unintentional leakage&#46; Oxygen was delivered into the system using two O<span class="elsevierStyleInf">2</span> flow meters &#40;EASY MED-O<span class="elsevierStyleInf">2</span>&#44; Air Liquide Healthcare&#44; Paris&#44; France&#41; that could both deliver up to 50<span class="elsevierStyleHsp" style=""></span>L&#47;min&#46; Three different mechanical lung conditions were simulated by modulating the resistance &#40;<span class="elsevierStyleItalic">R</span>&#41; and the compliance &#40;<span class="elsevierStyleItalic">C</span>&#41; of the artificial lung&#44; corresponding to the following experimental models&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">A&#46;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Normal&#58; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#47;l<span class="elsevierStyleHsp" style=""></span>s and <span class="elsevierStyleItalic">C</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>ml&#47;cmH<span class="elsevierStyleInf">2</span>O&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">B&#46;</span><p id="par0020" class="elsevierStylePara elsevierViewall">Restrictive&#58; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5 cmH<span class="elsevierStyleInf">2</span>O&#47;l<span class="elsevierStyleHsp" style=""></span>s and <span class="elsevierStyleItalic">C</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;cmH<span class="elsevierStyleInf">2</span>O&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">C&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Normal with by-pass leak using a T-connector as recommended to reduce the risk of droplet aerosolization&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a></p></li></ul></p><p id="par0030" class="elsevierStylePara elsevierViewall">Each model was run at breathing frequencies of 22&#44; 30 and 35 cycles per minute &#40;cpm&#41;&#44; associated with inspiratory airway pressure drops of 2&#46;5&#8211;6<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O at 100<span class="elsevierStyleHsp" style=""></span>ms &#40;P0&#46;1&#41; to reach tidal volumes of around 600<span class="elsevierStyleHsp" style=""></span>ml&#46; The values of the inspiratory effort settings chosen for the simulation in the ASL5000 were based on published clinical values&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">7&#8211;11</span></a> Each condition was run with and without unintentional leakage&#46; FiO<span class="elsevierStyleInf">2</span> was measured with 5&#44; 15&#44; 30&#44; 50&#44; 60 and 80<span class="elsevierStyleHsp" style=""></span>L&#47;min of O<span class="elsevierStyleInf">2</span>&#44; and the experiment was stopped when 100&#37; FiO<span class="elsevierStyleInf">2</span> was reached&#46; The sensor used was a paramagnetic oxygen transducer located in the ASL 5000 piston chamber which allowed a fast measurement with a response time below 350<span class="elsevierStyleHsp" style=""></span>ms&#46; Ten respiratory cycles were analysed after the FiO<span class="elsevierStyleInf">2</span> had reached an asymptote for each model at each O<span class="elsevierStyleInf">2</span> flow rate&#46; Normality and homogeneity were assessed using Shapiro-Wilk and Levene tests&#44; respectively&#46; Welch&#39;s ANOVA was used to compare respiratory rates at each O<span class="elsevierStyleInf">2</span> flow rate&#46; A Games-Howell post-hoc procedure was applied for multiple comparisons&#44; with 22<span class="elsevierStyleHsp" style=""></span>cpm as the reference condition&#46; Significance was set at 0&#46;05&#46; Statistical analysis was performed using IBM SPSS Statistics V25&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Data from 10 consecutive patients with Covid-19 treated with CPAP and O<span class="elsevierStyleInf">2</span> are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Six patients needed O<span class="elsevierStyleInf">2</span> flow rates<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>L&#47;min to maintain SpO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>90&#37;&#46; Minimum O<span class="elsevierStyleInf">2</span> flow rate was 15<span class="elsevierStyleHsp" style=""></span>L&#47;min&#46; All patients had severe infection &#40;i&#46;e&#46;&#44; PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> ratio<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>at CPAP initiation&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the relationship between the O<span class="elsevierStyleInf">2</span> flow rate delivered and the resulting FiO<span class="elsevierStyleInf">2</span> in the simulation&#46; Without unintentional leaks&#44; a flow rate of at least 30<span class="elsevierStyleHsp" style=""></span>L&#47;min was necessary to reach FiO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>95&#37;&#46; FiO<span class="elsevierStyleInf">2</span> differed significantly for each respiratory rate at each O<span class="elsevierStyleInf">2</span> flow rate with and without unintentional leaks &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; With unintentional leaks&#44; O<span class="elsevierStyleInf">2</span> flow rates of up to 80<span class="elsevierStyleHsp" style=""></span>l&#47;min were required to reach 100&#37; FiO<span class="elsevierStyleInf">2</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The results of this experimental bench study confirmed our clinical observation that high O<span class="elsevierStyleInf">2</span> flow rates are required to achieve a high FiO<span class="elsevierStyleInf">2</span> in patients with severe Covid-19 using CPAP and vented masks&#46; An O2 flow rate of at least 30<span class="elsevierStyleHsp" style=""></span>L&#47;min&#44; and up to 80<span class="elsevierStyleHsp" style=""></span>L&#47;min&#44; was required to achieve 100&#37; FiO2 for all three experimental models&#46; Reduced compliance and unintentional leakage dramatically reduced FiO<span class="elsevierStyleInf">2</span>&#46; The arbitrary compliance of 30<span class="elsevierStyleHsp" style=""></span>ml&#47;cmH<span class="elsevierStyleInf">2</span>O used in model B is similar to that of patients with severe COVID-19&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> Such a low level of compliance would reduce the FiO<span class="elsevierStyleInf">2</span> with home CPAP and a vented mask&#44; further confirming the need for high O<span class="elsevierStyleInf">2</span> flow rates&#46; In our clinical cohort&#44; three patients required an O<span class="elsevierStyleInf">2</span> flow rate above 80<span class="elsevierStyleHsp" style=""></span>L&#47;min&#58; this very high rate causes two concerns&#46; Firstly&#44; we did not know the lung compliance of these patients&#46; Secondly&#44; the O<span class="elsevierStyleInf">2</span> flow rate required to achieve a given FiO<span class="elsevierStyleInf">2</span> is likely to be underestimated with the experimental model compared to the clinical situation&#44; since no gas exchange occurs with an artificial lung&#46; For instance&#44; in a patient&#44; with a 21&#37; FiO<span class="elsevierStyleInf">2</span>&#44; the partial pressure of O<span class="elsevierStyleInf">2</span> in the inspired air will be 160<span class="elsevierStyleHsp" style=""></span>mm Hg&#44; while in the expired air &#40;at sea level&#41; it will be 120<span class="elsevierStyleHsp" style=""></span>mm Hg due to oxygen absorption&#46; Thus&#44; in in vivo conditions even higher O<span class="elsevierStyleInf">2</span> flows than those reported in this study may be required&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Another important point is that many teams use helmets to ventilate patients with Covid-19&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">2&#44;14</span></a> Helmets could be more advantageous than oronasal masks because of the lower rate of unintentional leakage&#59; this would allow lower oxygen flow rates to be used to achieve sufficient FiO<span class="elsevierStyleInf">2</span> levels for patients with severe hypoxemia&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Studies have shown that patients who cannot be intubated require a high FiO<span class="elsevierStyleInf">2</span> to maintain their SpO<span class="elsevierStyleInf">2</span> above 92&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">3&#44;15</span></a> and that poor oxygenation is strongly associated with mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">3&#44;16</span></a> Our study provides valuable data to guide clinicians in the use of O<span class="elsevierStyleInf">2</span> when using home CPAP in patients with severe Covid-19 who cannot be intubated&#46; The results showed that these patients can be successfully treated with home CPAP devices&#44; or NIV devices in CPAP mode&#44; with vented masks&#44; if a high O<span class="elsevierStyleInf">2</span> flow rate is provided&#46; However&#44; close monitoring of unintentional leaks is crucial to ensure a sufficient FiO<span class="elsevierStyleInf">2</span> for the treatment of severe hypoxemia in these patients&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Authors&#8217; contribution</span><p id="par0060" class="elsevierStylePara elsevierViewall">All authors participated in the study design&#44; research&#44; and manuscript preparation&#46; Dr&#46; Marius Lebret is the guarantor of the content of the manuscript&#44; including the data and analysis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0065" class="elsevierStylePara elsevierViewall">Funding was provided by <span class="elsevierStyleGrantSponsor" id="gs1">Asten Sant&#233;</span>&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">ML reports receiving personal fees from Air Liquid Medical Systems and non-financial support from NOMICS over the past 3 years&#44; for work unrelated to the work presented here&#46; ML is a part-time employee of Air Liquide Medical System &#40;Med2lab&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">YC&#44; CM and GP work as consultants for Air Liquid Medical System&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Dose&#8211;response relationship between oxygen &#40;O<span class="elsevierStyleInf">2</span>&#41; flow rates delivered into the circuit&#44; and fraction of inspired oxygen &#40;FiO<span class="elsevierStyleInf">2</span>&#41; as a function of respiratory rate&#44; presence&#47;absence of non-intentional leakage&#44; lung mechanics and leak port locations&#46; Each Plot represents the mean FiO<span class="elsevierStyleInf">2</span> of the 10 cycles analysed&#46; For each FiO<span class="elsevierStyleInf">2</span>&#44; the standard deviation was systematically below 0&#46;3 and is therefore not represented on the graph&#46; Panel A displays the results for the conventional intentional leak model&#44; in which the unintentional leakage port was placed in series between the exhalation valve &#40;intentional leak port&#41; and the ASL 5000&#46; Panel B displays the results for the same model as in panel A&#44; but with restrictive lung mechanics&#46; Panel C displays the results for by-pass leakage ports using an antibacterial filter between the ASL 5000 and both intentional and non-intentional leak ports&#46; The blue lines represent the relationship between O<span class="elsevierStyleInf">2</span> flow and FiO<span class="elsevierStyleInf">2</span> without unintentional leaks&#44; and the green lines represent the relationship between O<span class="elsevierStyleInf">2</span> flow and Fi<span class="elsevierStyleInf">2</span>O with unintentional leaks&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Body mass index&#58; BMI&#59; chronic respiratory failure&#58; CRF&#59; cardiac failure&#58; CF&#59; arterial hypertension&#58; AH&#59; type 2 diabetes&#58; DT2&#59; continuous positive airway pressure&#58; CPAP&#59; partial O<span class="elsevierStyleInf">2</span> pressure in arterial blood&#58; PaO<span class="elsevierStyleInf">2</span>&#59; fraction of inspired oxygen&#58; FiO<span class="elsevierStyleInf">2</span>&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CRF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AH&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DT2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PAO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> at CPAP initiation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPAP level &#40;cm<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleInf">2</span>O&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median leakage &#40;l&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean Vt &#40;ml&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean RR &#40;cycle per minute&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">O<span class="elsevierStyleInf">2</span> flow<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;l&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SpO<span class="elsevierStyleInf">2</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">87&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">122&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">43&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">490&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2684899.png"
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Total leakage&#46;</p>"
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              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Unintentional leakage&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Descriptive data from 10 consecutive patients treated with CPAP and O<span class="elsevierStyleInf">2</span>&#46; Leakage&#44; Tidal Volume &#40;Vt&#41; and Respiratory Rate &#40;RR&#41; were collected from built-in CPAP software during the first 48<span class="elsevierStyleHsp" style=""></span>h of CPAP treatment&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
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            0 => array:3 [
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              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Continuous Positive Airway Pressure &#40;CPAP&#41; face-mask ventilation is an easy and cheap option to manage a massive influx of patients presenting acute respiratory failure during the SARS-CoV-2 outbreak&#58; a retrospective cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Alviset"
                            1 => "Q&#46; Riller"
                            2 => "J&#46; Aboab"
                            3 => "K&#46; Dilworth"
                            4 => "P-A&#46; Billy"
                            5 => "Y&#46; Lombardi"
                          ]
                        ]
                      ]
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                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0240645"
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                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2020"
                        "volumen" => "15"
                        "paginaInicial" => "e0240645"
                      ]
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              "identificador" => "bib0090"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Helmet CPAP treatment in patients with COVID-19 pneumonia&#58; a multicentre cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Aliberti"
                            1 => "D&#46; Radovanovic"
                            2 => "F&#46; Billi"
                            3 => "G&#46; Sotgiu"
                            4 => "M&#46; Costanzo"
                            5 => "T&#46; Pilocane"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/13993003.01935-2020"
                      "Revista" => array:4 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2020"
                        "paginaInicial" => "56"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17301091"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Noninvasive ventilatory support of covid-19 patients outside the intensive care units &#40;WARd-COVID&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Bellani"
                            1 => "G&#46; Grasselli"
                            2 => "M&#46; Cecconi"
                            3 => "L&#46; Antolini"
                            4 => "M&#46; Borelli"
                            5 => "F&#46; Giacomi"
                          ]
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        "texto" => "<p id="par0080" class="elsevierStylePara elsevierViewall">Dr&#46; Marius Lebret is the guarantor of the content of the manuscript&#44; including the data and analysis&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The authors would like to thank Asten Sant&#233; for providing funding the trial&#46; The authors would also like to thank Johanna Robertson for English editing&#46;</p>"
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2021.04.013

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