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.
