Correlation Between PaO2/FiO2 and Lung Ultrasound Score in the Intensive Care Unit (O2LUSSU)

"Correlation Between PaO2/FiO2 and Lung Ultrasound Score in Patients Admitted to an Intensive Care Unit With Interstitial Syndrome: A Prospective Physiological Study"

The goal of this physiological interventional prospective study is to evaluate the improvement of the previously demonstrated correlation between PaO2/ FiO2 and Lung Ultrasound score (LUSS) in patients admitted in the ICU with an intesrtitial syndrom (IS) on the ultrasound of all aetiologies at inclusion and at twenty four and forty eight hours. The main question it aims to answer is if the LUSS is a valid tool to evaluate the severity of the IS Participants will initially have an arterial blood gas to evaluate the PaO2/FiO2 and in the ten minutes a lung ultrasound to evaluate the LUSS. This will be repeated at twenty four and forty eight hours.

JUSTIFICATION FOR THE RESEARCH Interstitial Syndrome (IS) also known as alveolar-interstitial syndrome, is a diffuse affection of the lung interstitial tissue leading to decreased alveolo-capillary exchange and therefore hypoxemia. Acute conditions such as viral or bacterial pneumonia and pulmonary edema lead to IS. Pulmonary edema can either be haemodynamically induced in acute heart failure (AHF) or secondary to permeability impairment in Acute Respiratory Distress Syndrome (ARDS). In literature, Acute Lung Injury (ALI) is also used to refer to a condition similar to ARDS with less severe hypoxemia. Chronic pathologies as Diffuse Parenchymal Lung Disease (DPLD) also cause IS. Lung Ultrasound (LUS) is a useful tool to diagnose IS. Indeed, LUS is non-invasive, non-irradiating, low cost and easily available at the patient's bedside. The interest of LUS for critically ill patient has been demonstrated5. In ICU, it was shown that LUS reduces number of chest radiography, relative medical costs and radiation exposure without affecting patient outcome. Literature suggests that LUS diagnostic accuracy for IS is higher than the diagnostic accuracy of chest radiography. Chest Computed Tomography is the actual gold standard for IS diagnosis, however not available at patient bedside, irradiating and more expensive. LUS is mostly based on the detection of artefacts created by air-tissue interfaces5. In IS, artefacts have been shown to be related to the presence of extra-vascular water and the water-thickened of interlobular septa. Comet Tail Artefact (CTA) was originally described as dense tapering trail of echoes just distal to a strongly reflective surface whereas Ring Down Artefact (RDA) starts from the point of origin of the ultrasound waves and "ring-down" to the end of the screen without fading. CTA and RDA are created by different mechanisms. Liechtenstein's early work introduced the term CTA to describe artefacts found in IS4. He later introduced the alphabetic nomenclature and assign the term B-lines to those IS artefacts. According to Yue Lee and All, a confusion between CTA and RDA exist in the literature as B-Lines definition correspond to RDA rater then CTA. International recommendations later agreed on the use of the term B-line, to describe artefact found in IS. Presence of multiple B-lines is widely recognised to suggest the presence of IS. Despite poor literature on this topic, IS severity is represented by hypoxemia generally evaluated by the realization of an Arterial Blood Gase (ABG) to obtain Arterial Partial Pressure in Oxygen (PaO2). A study however supported the absence of correlation between PaO2 and long-term mortality for AHF. Another rather recent study, including one-hundred and sixty-five COVID-19 patients that underwent non-invasive ventilation, nevertheless showed a statistically significant difference in PaO2 between survivor and non-survivor at twenty-eight days. According to the Berlin definition, hypoxemia represented by the ratio between PaO2 and the fraction of inspired oxygen (FiO2) is a severity indicator in ARDS. LUS could be an alternative to evaluate severity of IS. The Lung Ultrasound Score (LUSS) was initially developed on an experimental model to assess lung aeration and is based on quantitative assessment of B-lines in six thoracic zones bilaterally. In each zone, a sonographic lung aeration status is determined scoring from zero to four to determine a total score over thirty-six. Literature findings are consistent with LUSS being an efficient tool to measure lung aeration in different intensive care situations: re-aeration antibiotics-induced in Ventilator Associated Pneumonia, assessment of PEEP-induced lung recruitment. LUSS realized during weaning trial has been showed to be able to predict of postextubation distress. In the Intensive Care Unit (ICU), LUSS is efficient to quantify lesions and predict mortality associated with ARDS. During the recent COVID-19 pandemic, numerous trials have demonstrated that LUSS is associated with disease severity and mortality in COVID-19 patients. Recently, a negative linear correlation between PaO2/FiO2 and LUSS was shown three series of patients admitted to Intensive Care Units (ICU) with different aetiologies of IS: one with thirty-three COVID-19 patients, one with thirty-seven ARDS patients and one with seventy-two ALI patients. Lately, this correlation was confirmed in larger series of one-hundred and sixty-two patients admitted the Emergency Departement (ED) suggesting that LUSS could be a tool to evaluate PaO2 and therefore evaluate IS severity regardless of IS' aetiology in patients admitted to ED. STUDY PROCEDURE A LUSS will be realized by an investigator trained for Lung UltraSound (LUS) and considering him/herself confident for its use. A five-point Likert scale will be filled. To the statement "I am qualified to realize a LUSS", only emergency doctors answering "I strongly agree" or "I agree" will be eligible for inclusion and added to investigators list using an amendment to this protocol. The ultrasound machines operated for LUS belong to each ED meaning the investigators are familiar to its use. To uniformize the results, settings of the ultrasound machines will be standardized. To allow the exploration of the pulmonary parenchyma a low frequency curvilinear transducer will be used, and evaluation of B-lines will be performed using a depth of at least 12cm as commonly recommended. If patients are isolated for infectious reasons, special precautions will be applied following institutional procedures of ultrasound use on contagious patients. LUS will take place within 10 minutes of ABG analysis. LUS will be performed at the patient's bedside. The investigator will be blinded to any other procedure made by treating physician for diagnostic purposes. The treating physician will be allowed to perform a LUS on its own. The LUSS procedure will be used as validated in a larger number of studies. For that matter, the thorax is virtually divided in six thoracic zones bilaterally, comporting two anterior zones, two lateral zones and two posterior zones. The anterior and lateral zones will be evaluated in strict dorsal decubitus and the posterior zones will be evaluated with a light contro-lateral decubitus allowed, if necessary, because of patient morphotype. For each zone a score from zero to three will be determined as shown in figure 4: 0: A normal aeration of the lung with presence of A lines, persistent pleural sliding and less than three B-lines. 1: Interstitial syndrome, resulting in moderate loss of aeration with more than three spaced B-lines, 7mm apart, scores one point. 2: Alveolar-interstitial syndrome meaning a severe loss of aeration with coalescent B-lines, less then 3mm apart, scores two. 3: An alveolar consolidation leading to a complete loss of aeration with an ultrasonographic tissue like pattern. LUSS will be calculated by adding the score given to each 12 zones, with a maximum of thirty-six. Patients scoring less than two, will be considered empirically with no interstitial syndrome and will be excluded of the study. Investigators will also report the presence of pleural effusions and if present estimate their amount. If present, pleural effusions quantification will be realized at lung base. The maximal distance between parietal and visceral pleura (Dmax) in millimeter will be measured after freezing the image in end-expiration. If the ABG indication according to treating ICU physician persist, the complete intervention including calculation of LUSS, research and quantification of pleural effusions will be repeated at twenty-four and forty-eight hours. Result of LUSS, pleural effusions' presence and Dmax won't be communicated to the treating physician expect if the LUS results could influence patient prognosis. STUDY CONDUCTION Study Settings: Before the study launching, the investigator will be evaluated using a five-point Likert scale as previously described. A presentation of the study and the procedure will be organized by the coordinating investigators in each center. Patients' recruitment: The eligible patients will be identified by the treating ICU physician. Adult patients admitted to ICU with signs and symptoms of ARF and an indication of realization of ABG to evaluate PaO2 according to treating ICU physician will be considered for inclusion. ABG won't be considered as an intervention as the decision of the realization of an ABG is being left to the treating ICU physician. If those criteria are met, treating physician will contact an investigator. Inclusion: Investigator will be responsible to verify if patient meet all inclusion criteria. Consent will correspond to the signature of a paper consent form in duplicate after being informed over research modalities by the investigator. If the patient is unable to give his consent because of an acute condition and have no legal representative, a delayed consent will be authorized. One signed copy of the consent form will be returned to the patient or the legal representative. Intervention: All included patients will undergo a LUS, the calculation of a LUSS and search of pleural effusions and pleural effusions' quantification by Dmax measurement when pleural effusions are present. In Belgium, LUS isn't recognized as standard of care giving to this study an interventional character. Intervention will take place in a range of time of maximum then minutes before or after ABG realization. The result of the intervention will not be communicated to the treating physician except when LUS could influence patient's prognosis. Follow up: If ABG indication persists following treating ICU physician and if the patient is still present in the ICU, the intervention as described previously will be repeated at twenty-four and forty-eight hours. Data collection and Data treatment: After inclusion data will be reported in an informatized CRF using REDCap software by investigator and Pleural Effusion Volume (Vpe) in milliliter will be automatically calculated by multiplying Dmax per twenty according to Balik and all's formula. The SOFA score at inclusion, twenty-four and forty-eight hours will also be calculated and recorded. Name, first name, date of birth and hospital administrative number of the included patients will be recorded. Investigators will only access personal data of the patient they have personally included. Principal investigators will have access to all personal data to be able to collect missing data. After data completion, a neutral identifier composed by inclusion centre's number, number of inclusion and year of birth will be used. A correspondence list will be kept under the principal investigator responsibility. STATISTICS Data analysis was performed using JMP Pro 16.0.0 Software (SAS Institute). Continuous variables are expressed as mean values and standard deviations. Discrete variables are reported as categories and expressed as numbers and percentages. The Pearson correlation was used to measure the linear correlation between continuous variables, and correlations are expressed as correlation coefficient and 95% confidence interval. Comparisons between quantitative data were performed with a χ2 test, and between-group comparisons between continuous data with a Wilcoxon-Mann-Whitney test. The significance threshold was set with a P value of < 0.05. A one-sided hypothesis test will be use to show the improvement of the correlation between PaO2/FiO2 and LUSS. Pearson formula will be used to show correlation between PaO2/FiO2 and LUSS. Multiple linear regression will be used to test the effects of continuous variables such as presence of pleural effusions on the correlation between PaO2/FIO2 and LUSS.

All patients included in the study, meaning patients in the ICU presenting an interstitial syndrom no matter the aetiology

Evaluation of the Lung Ultrasound Score in patients presenting an interstitial syndrom on the lung ultrasound and to compare it with PaO2/FiO2

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS.

to assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS.

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS.

To to determine the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS.

To assess the correlation between the PaO2/FiO2 and the LUSS in patients admitted in an ICU with IS According to the aetiologic diagnosis attributed to the IS (pulmonary oedema, bacterial or viral infection, post operative reactionary hypoventilation) The end point of this secondary outcome considers the null hypothesis to be an improvement of 0,214 of the correlation between PaO2/FiO2 and LUSS

To assess the correlation between the PaO2/FiO2 and the LUSS in patients admitted in an ICU with IS according to admission diagnosis (cardiogenic shock, sepsis, infection, post operative)

To assess the correlation between the PaO2/FiO2 and the LUSS in patients admitted in an ICU with IS according to LUSS value (between two and six and between seven and thirty-six) The end point of this secondary outcome considers a negative linear distribution for PaO2/FiO2 and LUSS values

To assess the correlation between the PaO2/FiO2 and the LUSS in patients admitted in an ICU with IS acordiing on hypoxemia severity based on PaO2/FiO2 as defined for ARDS3 (mild hypoxemia with PaO2/FiO2 between three hundred and two hundred, moderate hypoxemia with PaO2/FiO2 between one hundred and two hundred and severe hypoxemia with a PaO2/FiO2 of less than one hundred)

To assess the correlation between the PaO2/FiO2 and the LUSS in patients admitted in an ICU with IS according to Respiratory Rate (RR) (low RR of less than twelve per minute, normal RR between twelve and twenty and elevated RR of more than twenty)

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS According to the aetiologic diagnosis attributed to the IS (pulmonary oedema, bacterial or viral infection, post operative reactionary hypoventilation) a negative linear distribution for PaO2/FiO2 and LUSS values

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS according to admission diagnosis (cardiogenic shock, sepsis, infection, post operative)

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS according to LUSS value (between two and six and between seven and thirty-six)

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS acordiing on hypoxemia severity based on PaO2/FiO2 as defined for ARDS3 (mild hypoxemia with PaO2/FiO2 between three hundred and two hundred, moderate hypoxemia with PaO2/FiO2 between one hundred and two hundred and severe hypoxemia with a PaO2/FiO2 of less than one hundred)

To assess the evolution of the correlation between the PaO2/FiO2 and the LUSS at inclusion, twenty-four hours, and forty-eight hours after inclusion in patients admitted in an ICU with IS according to Respiratory Rate (RR) (low RR of less than twelve per minute, normal RR between twelve and twenty and elevated RR of more than twenty)

To assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS According to the aetiologic diagnosis attributed to the IS (pulmonary oedema, bacterial or viral infection, post operative reactionary hypoventilation) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

to assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS according to admission diagnosis (cardiogenic shock, sepsis, infection, post operative) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

to assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS according to LUSS value (between two and six and between seven and thirty-six) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

to assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS acordiing on hypoxemia severity based on PaO2/FiO2 as defined for ARDS3 (mild hypoxemia with PaO2/FiO2 between three hundred and two hundred, moderate hypoxemia with PaO2/FiO2 between one hundred and two hundred and severe hypoxemia with a PaO2/FiO2 of less than one hundred) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

to assess the presence of a correlation between LUSS and the SOFA score at inclusion, twenty-four et forty-eight hours of inclusion in patient admitted to an ICU with IS according to Respiratory Rate (RR) (low RR of less than twelve per minute, normal RR between twelve and twenty and elevated RR of more than twenty) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS According to the aetiologic diagnosis attributed to the IS (pulmonary oedema, bacterial or viral infection, post operative reactionary hypoventilation) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

Influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS according to admission diagnosis

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with ISaccording to admission diagnosis (cardiogenic shock, sepsis, infection, post operative) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS according to LUSS value (between two and six and between seven and thirty-six) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

Influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS according to hypoxemia severity

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS acordiing on hypoxemia severity based on PaO2/FiO2 as defined for ARDS3 (mild hypoxemia with PaO2/FiO2 between three hundred and two hundred, moderate hypoxemia with PaO2/FiO2 between one hundred and two hundred and severe hypoxemia with a PaO2/FiO2 of less than one hundred) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

To determine the influence of the SOFA score on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS.according to Respiratory Rate (RR) (low RR of less than twelve per minute, normal RR between twelve and twenty and elevated RR of more than twenty) The end point of this secondary outcome considers a positive linear correlation between LUSS and SOFA score and a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the SOFA score

Influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS according to IS diagnosis

To determine the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS According to the aetiologic diagnosis attributed to the IS (pulmonary oedema, bacterial or viral infection, post operative reactionary hypoventilation) The end point of this secondary outcome considers a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the presence of pleural effusions and pleural effusions' size.

Influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS according to admission diagnosis

To determine the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS according to admission diagnosis (cardiogenic shock, sepsis, infection, post operative) The end point of this secondary outcome considers a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the presence of pleural effusions and pleural effusions' size.

Influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS according to LUSS value

To determine the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS according to LUSS value (between two and six and between seven and thirty-six) The end point of this secondary outcome considers a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the presence of pleural effusions and pleural effusions' size.

Influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS according to hypoxemia severity

To determine the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS acordiing to hypoxemia severity based on PaO2/FiO2 as defined for ARDS3 (mild hypoxemia with PaO2/FiO2 between three hundred and two hundred, moderate hypoxemia with PaO2/FiO2 between one hundred and two hundred and severe hypoxemia with a PaO2/FiO2 of less than one hundred) The end point of this secondary outcome considers a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the presence of pleural effusions and pleural effusions' size.

Influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS according to RR

To the influence of the presence and size of pleural effusions on the correlation between PaO2/FiO2 and LUSS at inclusion, twenty-four et forty-eight hours of inclusion in patients admitted to an ICU with IS according to Respiratory Rate (RR) (low RR of less than twelve per minute, normal RR between twelve and twenty and elevated RR of more than twenty) The end point of this secondary outcome considers a negative linear distribution for the correlation between PaO2/FiO2 and LUSS corrected by the presence of pleural effusions and pleural effusions' size.

Inclusion Criteria: - consent ->17 years old Exclusion Criteria: LUSS < 2 Non Inclusion Criteria: Patient with pathologies leading to chronic IS Chronic Obstructive Pulmonary Disease (COPD) or active asthma Patients under veino-veinous or veino-arterial " Extracorporeal Membrane Oxygenation " (ECMO) Severe trauma patients Less than twenty-four hours post operative patients LUS not feasible: prone position, pneumonectomy history, severe obesity

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