Implementing a bedside assessment of respiratory mechanics in patients with acute respiratory distress syndrome
- Lu Chen1, 2,
- Guang-Qiang Chen1, 2, 3,
- Kevin Shore1,
- Orest Shklar4,
- Concetta Martins4,
- Brian Devenyi4,
- Paul Lindsay4,
- Heather McPhail4,
- Ashley Lanys2,
- Ibrahim Soliman1,
- Mazin Tuma1,
- Michael Kim1,
- Kerri Porretta4,
- Pamela Greco4,
- Hilary Every4,
- Chris Hayes1, 2,
- Andrew Baker1, 2,
- Jan O. Friedrich1, 2 and
- Laurent Brochard1, 2Email author
© The Author(s). 2017
Received: 19 August 2016
Accepted: 17 March 2017
Published: 4 April 2017
Despite their potential interest for clinical management, measurements of respiratory mechanics in patients with acute respiratory distress syndrome (ARDS) are seldom performed in routine practice. We introduced a systematic assessment of respiratory mechanics in our clinical practice. After the first year of clinical use, we retrospectively assessed whether these measurements had any influence on clinical management and physiological parameters associated with clinical outcomes by comparing their value before and after performing the test.
The respiratory mechanics assessment constituted a set of bedside measurements to determine passive lung and chest wall mechanics, response to positive end-expiratory pressure, and alveolar derecruitment. It was obtained early after ARDS diagnosis. The results were provided to the clinical team to be used at their own discretion. We compared ventilator settings and physiological variables before and after the test. The physiological endpoints were oxygenation index, dead space, and plateau and driving pressures.
Sixty-one consecutive patients with ARDS were enrolled. Esophageal pressure was measured in 53 patients (86.9%). In 41 patients (67.2%), ventilator settings were changed after the measurements, often by reducing positive end-expiratory pressure or by switching pressure-targeted mode to volume-targeted mode. Following changes, the oxygenation index, airway plateau, and driving pressures were significantly improved, whereas the dead-space fraction remained unchanged. The oxygenation index continued to improve in the next 48 h.
Implementing a systematic respiratory mechanics test leads to frequent individual adaptations of ventilator settings and allows improvement in oxygenation indexes and reduction of the risk of overdistention at the same time.
The present study involves data from our ongoing registry for respiratory mechanics (ClinicalTrials.gov identifier: NCT02623192. Registered 30 July 2015).
KeywordsPulmonary function test Respiratory physiology Esophageal pressure Mechanical ventilation Quality improvement
Patients with acute respiratory distress syndrome (ARDS) present various degrees of impairment in respiratory mechanics and different physiological responses to a given level of positive end-expiratory pressure (PEEP). Applying the same ventilator regimen to every patient would be inadequate and at times can be potentially harmful. For example, the potential benefits of high PEEP in terms of oxygenation improvement and alveolar recruitment should be balanced against the risks induced by high pressures, such as hemodynamic impairment and overdistention. In other words, one needs to individualize the PEEP level by evaluating both its safety and its effectiveness for a specific patient . This requires the assessment of gas exchange, respiratory mechanics, and hemodynamic variables. Additionally, partitioning lung and chest wall mechanics can also help the individualization of ventilator settings.
Despite their potential interest for clinical management, neither airway pressure (Paw)-based respiratory mechanics nor esophageal pressure (Pes)-based lung and chest wall mechanics are systematically assessed in routine practice. This discrepancy can be explained by technical issues  in obtaining accurate transpulmonary pressure (PL), by a lack of standardized procedures, and by the challenges of integrating the results of these measurements into ventilatory management. Even worse, the most recent large observational studies on patients with ARDS showed that simple parameters such as plateau pressure (Pplat) were not measured in the majority of the patients .
To improve the integration of respiratory mechanics measurement in our clinical practice, a group of physicians and respiratory therapists (RTs) at our institution introduced a respiratory mechanics test to systematically assess respiratory mechanics (i.e., performing a pulmonary function test) for patients with ARDS and be implemented as a quality improvement (QI) program. The goal was to provide clinicians with relevant physiological assessment that could be helpful for clinical practice. Because the needs for adjusting ventilator settings can be very different, this program did not include clinical recommendations or specific guidelines associated with these measurements.
Having implemented this systematic test in our clinical practice for 1 year, we retrospectively tried to assess if it had any impact. We looked for whether any changes in ventilatory settings were performed. We also assessed whether the observed changes modified physiological variables known to be associated with mortality, and we tried to understand whether the observed changes were consistent with the measurements.
Design and settings
This is a retrospective study of the impact of a 1-year program (see below) with an aim of systematically evaluating respiratory mechanics in patients with ARDS by comparing the ventilator settings and relevant physiological variables before and after performing the measurements. The program was decided by the critical care department at a teaching hospital (St. Michael’s Hospital, Toronto, ON, Canada) and implemented in both the medical-surgical and the trauma-neurosurgical intensive care units (ICUs). Of note, the measurements are entered into a registry for future studies.
Implementing the respiratory mechanics test in clinical practice
To increase awareness and understanding of monitoring respiratory mechanics, education sessions consisting of lectures, bench and bedside hands-on sessions, and feedback rounds were provided to ICU clinicians. The education sessions were focused on explaining the importance of measuring respiratory mechanics, the technical approaches for measurements, the physiological and clinical meanings of the measured variables based on scientific evidence, and the limitations of those variables. We did not propose to use one single parameter on which to base changes of the ventilator settings; we proposed to incorporate multiple variables (e.g., airway pressure, Pplat, driving pressure [Pdriv], chest wall component, recruitability, oxygenation, and hemodynamic response to PEEP) into the global history of the patient and let the clinical team decide what was best for the patient.
To standardize the procedures, we developed written protocols to guide esophageal catheter placement and the associated systematic measurements.
To simplify the calculations, we developed a custom-programmed Portable Document Format form (PDF; Adobe Systems, San Jose, CA, USA) to automatically calculate physiological parameters and generate a clinical report (see Additional file 1: Appendixes S1 and S2).
This clinical report was delivered to the caregivers in charge of the patients.
Patient enrollment process for the test
All patients admitted to the ICUs meeting the Berlin definition of ARDS  and receiving invasive mechanical ventilation were eligible. A daily screening was done, mostly on the weekdays. It was left at the discretion of the clinical team to decide to perform measurements, place esophageal catheters, and accept possible transient changes in sedation or paralysis (Additional file 1: Figure S1). Esophageal catheter insertion was recommended when the ratio of partial pressure of arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) was ≤200 mmHg. In the group of patients with mild ARDS (i.e., PaO2/FiO2 > 200 mmHg), catheters were placed at the discretion of the clinical team. In the following cases, the clinical team discussed the benefits of doing the measurements on a case-by-case basis: (a) severe hemodynamic instability (i.e., >30% increase in the dose of vasopressors in the last 6 h or need for >0.5 μg/kg/minute of norepinephrine); or (b) a known esophageal problem, active upper gastrointestinal bleeding, or any other contraindication to the insertion of a gastric tube.
Paw-based respiratory mechanics were measured by using end-expiratory and end-inspiratory occlusions for 1–2 seconds. The absence of leakage during an end-inspiratory occlusion was confirmed by the equivalence of expiratory VT between the breaths with occlusion to the one without occlusion. Total positive end-expiratory pressure (PEEPtot), airway peak pressure (Ppeak), and airway Pplat were recorded. Intrinsic PEEP, Pdriv (Pplat − PEEPtot), respiratory system compliance, and resistance were then calculated automatically.
Pes-based lung and chest wall mechanics  were measured simultaneously using end-expiratory and end-inspiratory occlusions. Transpulmonary pressure at end expiration (PL,end-exp) and transpulmonary pressure at end inspiration (PL,end-insp), lung compliance, chest wall compliance, and the ratio of lung elastance to respiratory system elastance were calculated automatically. PL, unless specifically indicated such as elastance-derived transpulmonary plateau pressure, was calculated using direct measurement of Pes.
Oxygenation and hemodynamic responses to PEEP were assessed by increasing PEEP by 3–5 cmH2O (preferably 5 cmH2O) from the clinical PEEP level if the Pplat was <35 cmH2O (in the vast majority of the cases). PEEP was reduced by 3–5 cmH2O if the Pplat had reached 35 cmH2O or in the presence of poor hemodynamic tolerance. We report this procedure as an incremental PEEP trial. FiO2 was kept constant for comparing the change in PaO2/FiO2.
Alveolar derecruitment was estimated using a single-breath simplified decremental PEEP maneuver (Fig. 1) performed within 10–15 seconds from the high PEEP used in the preceding step. A prolonged expiration (6–9 seconds) maneuver was performed while abruptly decreasing PEEP by 10 cmH2O from a high to a low level for one breath. Because inspiratory VT was unchanged, the difference in expiratory VT values between the expired VT displayed immediately after decreasing PEEP and the breath before changing PEEP was referred to as the total change in lung volume from high to low PEEP. In parallel, the predicted change in lung volume was estimated by the product of respiratory system compliance at low PEEP (or zero PEEP) and the change in pressure (i.e., 10 cmH2O of change in PEEP). When the total change in lung volume was greater than this predicted value, the difference was taken as an estimate of derecruited lung volume (Vder). A high Vder (e.g., ≥150 ml) due to reducing PEEP suggested that the PEEP was effective in recruiting the lung (or in maintaining the lung recruited). The rationale for this approach was reported previously, although the current method was simplified to make its use feasible rapidly at the bedside . Of note, we reduced PEEP to estimate derecruitment instead of raising PEEP to estimate recruitment because we speculated that derecruitment may occur faster than recruitment and is easier to detect. These technical simplifications have not been fully validated, however, and this was made clear to the clinicians.
A clinical report (Additional file 1: Appendix S2) was then generated automatically with reference thresholds from the literature for diagnostic purposes. At the end of the measurements, initial ventilator settings were resumed, and the clinical report was given to the clinical team in charge of the patient. The clinicians then decided whether to change the ventilator settings if deemed necessary. There were no therapeutic recommendations attached to the report, and the clinical team was free to use and integrate the data into a more cohesive clinical decision-making process. The intention of this procedure was to provide intensivists with reliable information on the pulmonary function of patients with ARDS and possibly to allow clinicians to individualize ventilator settings.
Patient enrollment for the present analysis
Patients who had been enrolled in the program during its first year of implementation were eligible for the present study. Patients whose results of the respiratory mechanics were not provided to the clinical team after the measurements owing to technical problems (i.e., no clinical report was generated for reference) were excluded from the study.
Endpoints for the analysis
We designed a statistical plan to decide a priori which variables we wanted to test. The first question was to determine the proportion of patients in whom ventilatory settings were changed after the measurements. We also wanted to determine if the changes were consistent with the measurements. The relevant endpoints were the effects of these changes on physiological parameters known to be associated with mortality, namely the oxygenation index (OI = mean Paw × FiO2 × 100/PaO2) [7, 8], the estimated physiological dead-space fraction , Pplat, and Pdriv . The OI integrates the intensity of ventilator assistance in terms of delivered mean Paw and its arterial oxygenation output. A low OI means that a relatively small intensity of assistance is needed for each millimeter of mercury of PaO2, whereas a high OI means that high delivered pressure and/or FiO2 is needed for each millimeter of mercury of PaO2. The dead-space fraction was calculated using the Enghoff modification of the Bohr equation with an estimation of resting energy expenditure using the Harris-Benedict equation and an assumption that the respiratory quotient equals 0.8. It is noteworthy that these two parameters, OI and dead-space fraction, were not directly given to clinicians. The Pdriv, calculated as the difference in Paw between a 1- to 2-second end-inspiratory occlusion (i.e., Pplat) and an end-expiratory occlusion (i.e., PEEPtot), was referred to as Pdriv in this study. For the purpose of our retrospective study, however, we found that the PEEPtot was not always assessed and documented by clinicians before or after the measurements and that the Pplat was sometimes estimated from the Ppeak in patients receiving pressure-controlled ventilation (PCV). The estimated Pdriv before and after the measurements could therefore slightly differ from the Pdriv during the measurements, and it was calculated as the difference between estimated Pplat and PEEP (not PEEPtot) and referred to as ∆P .
The denominator can be referred to as the “cost” of mechanical ventilation, whereas the numerator is the “benefit.” Therefore, a low O/SI suggests a low “benefit-to-cost ratio” of mechanical ventilation; that is, the benefit was achieved by paying a relatively high cost, whereas a high O/SI suggests a high benefit-to-cost ratio. Both the corrected VE and the O/SI before and after the measurements were compared. The O/SI was not provided to clinicians but was calculated for the study.
Data collection and statistical analysis
We collected information by reviewing the clinical charts for patients’ demographic, physiological, and radiographic characteristics; ARDS risk factors; coexisting conditions; ventilator settings; arterial blood gas (ABG) analysis; and documented respiratory parameters (e.g., VE and Pplat) before and after measurements (i.e., premeasurement and postmeasurement). We used the ABGs that were closest to the time of measurements but at least 1 h away from the measurements, as well as the corresponding ventilator settings and respiratory parameters. (Also refer to the discussion.) Detailed physiological variables obtained during the measurements were also collected.
The details of statistical analysis are reported in the additional files. Statistical methods are also described in the notes of the tables. Notably, because we decided the variables to be tested a priori in the statistical plan, we decided against using a Bonferroni adjustment, which would have highly increased the risk of type II errors .
During the first year of implementation (August 2014 to August 2015), 62 patients were enrolled and had measurements performed (Additional file 1: Figure S1). One patient was excluded from the study because of obvious input errors in the measurements (data were not used by clinicians).
Characteristics of the patients (N = 61)
Male sex, n (%)
Predicted body weighta, kg
68 ± 11
Body mass index, kg/m2
29 ± 7
APACHE II score at admissionb
28 ± 10
SOFA score at inclusionc
12 ± 4
Days of NIV prior to intubation, n
Days of IMV at inclusiond, n
Days of ARDS at inclusiond, n
Risk factors of ARDSe, n (%)
No risk factor
Severity of ARDS, n (%)
Patients treated with ECMO
Patients with tracheostomy
Days of IMV after inclusion, n
Duration of IMV, days
Ventilator settings and physiological variables before and after measurements (N = 61)
146 ± 60
162 ± 69
Pplat a, cmH2O
30 ± 5
28 ± 5
15.2 ± 7.4
13.8 ± 8.3
0.63 ± 0.10
0.62 ± 0.12
VE, corr, L/minute
13.0 ± 3.2
12.8 ± 3.3
Comparing postmeasurement with premeasurement values (Table 2), both OI and distending pressures (i.e., Pplat and ∆P) were significantly reduced. Measured at the same level of FiO2, the PaO2/FiO2 and the O/SI were significantly increased. In patients in whom PEEP was increased, the PaO2/FiO2 increased from 124 ± 78 mmHg to 173 ± 89 mmHg (P = 0.010), whereas the mean Paw increased from 18 ± 3 cmH2O to 21 ± 3 cmH2O (P < 0.0005). In patients whose PEEP was decreased, the PaO2/FiO2 remained stable (150 ± 64 mmHg vs. 153 ± 70 mmHg; P = 0.772), whereas the mean Paw decreased from 20 ± 4 cmH2O to 16 ± 4 cmH2O (P < 0.0005) (Fig. 2). On average, for the whole group, PaO2/FiO2 improved, whereas mean Paw decreased.
The estimated physiological dead-space fraction and corrected VE remained unchanged (Table 2). Arterial pH, bicarbonate level, heart rate, and mean arterial pressure remained unchanged (Additional file 1: Table S3).
Changes in ventilator settings associated with measurements
Relationship between measurements and subsequent clinical adjustments of PEEP
PEEP at postmeasurement vs. at premeasurement
Decreased (n = 20)
Unchanged (n = 27)
Increased (n = 8)
Markers of overdistentiona
28 ± 5b
25 ± 4b
26 ± 2
Elastance-derived PL,plat, cmH2O
15 ± 5
12 ± 4
13 ± 3
12 ± 5
9 ± 4
9 ± 5
Risk of atelectasisa
−2 ± 5
−2 ± 5
−5 ± 5
Response to the incremental PEEP trialc
Changes in Pdriv, cmH2O
Changes in PL,driv, cmH2O
1.9 ± 2.5
0.7 ± 1.8
−0.3 ± 1.2
Changes in PaO2/FiO2, mmHg
−4 [−17 to 12]
0 [−18 to 14]
3 [−29 to 10]
Changes in MAP, mmHg
−2 [−10 to 3]
−3 [−8 to 0]
105 ± 61e
142 ± 106
208 ± 124e
To our knowledge, this may be the first demonstration that systematic respiratory mechanics testing can be implemented with adequate validity and timelines in ICUs as a monitoring tool used for ventilatory adjustments. This provided physiological parameters for clinicians and helped to define the ventilatory therapy in patients with ARDS, as indicated by the changes in ventilator settings and in physiological variables observed after the test. Indeed, oxygenation could be improved using lower airway and distending pressures, a result that was unexpected, as indicated by the changes in OI, O/SI, Pplat, and ∆P. Such modifications would not have been performed without a systematic assessment.
Validity of the measurements
Measurements of Pes in routine clinical practice out of the field of research have often been considered to be a challenge . By implementing education sessions, standardized procedures, and an electronic form for automatic calculations, the measurements of Pes were conducted in our ICUs by a number of healthcare professionals (RTs, medical doctors) who were not experienced researchers. The ∆Pes/∆Paw ratio during the positive pressure occlusion test—a method used to validate appropriate positioning of the esophageal catheter and the Pes measurements—was consistent across our cohort and very close to unity, indicating that the obtained Pes was reliable and provided a valid measure of changes in pleural pressure. These ∆Pes/∆Paw ratios were also confirmed using occlusion tests against inspiratory effort  in six patients after resumption of spontaneous efforts.
Changes in mode
Strictly controlling the VT at a target value was proven beneficial for survival .
Volume control permits an easier approach to monitoring respiratory mechanics. By setting an inspiratory pause time of 0.3–0.5 seconds, one can monitor Pplat in real time for each breath as well as its trend, leading to easy estimation of essential parameters such as Pdriv, compliance, and resistance. Peak Paw set in PCV is often used as a surrogate of Pplat, which potentially provides a simple method to limit Pdriv. This approach can overestimate Pplat when inspiratory flow does not return to zero at the end of inspiration; however, it can underestimate Pplat in the presence of the patient’s inspiratory effort.
By using an inspiratory pause time with a high and constant inspiratory flow, VCV can improve the elimination of carbon dioxide .
Changes in PEEP
The changes in ventilator settings, especially a frequent reduction in PEEP level, eventually led to lower airway Pplat and Pdriv, and at the same time to improvements in oxygenation, OI, and O/SI (Table 2). This result was rather unexpected. We were surprised by the highly variable response to PEEP changes (Fig. 3). These results are different form the usual expectation of the effects of PEEP, but, in reality, they looked quite similar to recently published results of randomized clinical trials . Oxygenation was improved but was not a primary physiological endpoint in our study for several reasons. With high Paw, improvements in oxygenation can be achieved by a reduction in cardiac output and shunt, which may worsen oxygenation delivery . With high pressure, improvements in oxygenation have been associated with similar  or even worse mortality [14, 19]. OI takes into account both Paw and oxygenation, and it has been shown to be associated with survival as well as ∆P [8, 10, 20, 21]. We also found that the O/SI, as a new index to evaluate the benefit-to-cost ratio of mechanical ventilation, was significantly improved after the measurements. Although there are no data to support the possible association between O/SI and survival, we separated patients in our cohort by hospital outcome and found that O/SI (calculated using data from the measurements) in survivors was significantly higher than in nonsurvivors (14.6 [10.9-18.8] and 8.8 [6.0-12.6], respectively; P < 0.0005). We reasoned that the O/SI, similarly to OI, may be more meaningful than oxygenation itself regarding clinical outcome.
Time points for comparisons
We decided to focus our comparison of the physiological variables at 1 h after the measurements to better ensure that the adjustments of ventilator settings and the physiological impact were likely secondary to the measurements. Later, the ventilation mode can be switched to partial assist mode. Also, comparing mean Paw (required for calculating OI) or Pdriv in pressure-target mode becomes challenging once the patient recovers spontaneous breathing effort.
We, however, also reviewed data at 24 h and 48 h. The improvements in physiological variables were consistent, indicated by the progressively lower OI at 24 and 48 h (12.4 ± 7.1 and 10.2 ± 0.9, respectively; P = 0.016) than at 1 h after the measurements. Of note, 16 and 21 patients (26.2% and 34.4%, respectively) had spontaneous effort, defined as actual RR exceeding preset RR or receiving partial support mode, – at 24 and 48 h.
Our study has limitations. First, though we tried to ensure that measurements were likely based on reasonable physiological principles, what we established was an association between the measurements and the changes in settings, owing to the nature of an observational study. Second, with no control group, we are not able to describe any results on outcomes. Third, the results are limited to a single center. Fourth, there were some missing data in the assessment, such as the response to PEEP and the recruitability. Fifth, the simplified method for estimating derecruitment at the bedside requires further validation. Sixth, although we tried to minimize a direct influence of the initiators of the project (LC, LB) on the ventilator settings, interactions were frequent at the beginning of the project, and it is difficult to ascertain their exact influence. These interactions were meant to overcome the technical and knowledge barriers to measurement and interpretation of respiratory mechanics in clinical practice.
A respiratory mechanics test can be embedded in clinical practice and provides physiological parameters for clinicians. It leads to individualization of ventilator settings in patients with ARDS that improved physiological endpoints known to be associated with clinical outcomes, and it allowed reduction in the pressures needed to maintain oxygenation.
Arterial blood gas
Acute Physiology and Chronic Health Evaluation
Acute respiratory distress syndrome
Extracorporeal membrane oxygenation
- FiO2 :
Fraction of inspired oxygen
Intensive care unit
Invasive mechanical ventilation
Mean arterial pressure
- PaCO2 :
Partial pressure of arterial carbon dioxide
- PaO2/FiO2 ratio:
Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen
Predicted body weight
Driving pressure (Pplat − PEEPtot) or ∆P (Pplat − PEEP)
Positive end-expiratory pressure
Total positive end-expiratory pressure
Ratio of changes in Pes and Paw during end-expiratory occlusion
- PL :
- PL :
end-exp, Transpulmonary pressure at end expiration
- PL :
end-insp, Transpulmonary pressure at end inspiration
Airway peak pressure
Airway plateau pressure
Sepsis-related Organ Failure Assessment
- VD/VT,esti :
Estimated physiological dead-space fraction
- Vder :
Derecruited lung volume
- VE,corr :
Corrected expired volume per minute
- VE :
- VT :
We greatly appreciate the continuous support from the nurses and physicians in the Department of Critical Care, as well as the Department of Respiratory Therapy, for their support and involvement with this project, with special thanks to leadership members (Karen Wannamaker, Margaret Oddi). We are particularly grateful to the respiratory therapists for their noteworthy contributions, namely Erica Berridge, Kay Ching, Karima Dewji, Joana Ferreira, Stacey Halliday, Noreen Kassam, Lesia Kolwzan, Julia Lee, Jennifer Lim, Priya Patel, Rickey Russell, Carolins Sierra, Nicole Wailoo, and Tracy Walsh. We thank the physicians for their collaboration, including Dr. Karen Burns, Dr. Claudia Dos Santos, Dr. David Hall, Dr. David Klein, Dr. Natalie Wong, Dr. Sara Gray, Dr. John Laffey, Dr. Warren Lee, Dr. Simon Abrahamson, Dr. John Marshall, and Dr. Antoine Pronovost. We also thank Carolyn Campbell and Orla Smith for their continuous help with the research organization. We are greatly thankful to Jianing Gu for her hard work on data collection. We are full of gratitude to Dr. Jordi Mancebo for his helpful comments on the manuscript.
LB holds the Keenan Chair in Critical Care Medicine and Acute Respiratory Failure at St. Michael’s Hospital. No other funding was available.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
LC, GQC, OS, CM, BD, PL, HM, IS, MT, MK, KP, PG, and HE made substantial contributions to data acquisition and helped to revise the manuscript. LC, GQC, KS, AL, and LB participated in the design of the study, performed the statistical analysis, and helped to revise the manuscript. LC, GQC, OS, CM, PG, HE, CH, AB, JOF, and LB conceived of the study and participated in its design and coordination. LC and LB drafted the manuscript. GQC, OS, CM, PG, HE, CH, AB, and JOF helped to revise the draft of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the research ethics board (REB#16-095) of St. Michael’s Hospital (Toronto, ON, Canada). Informed consent was waived on the basis of the study’s retrospective observational design preserving confidentiality of personal information. Please refer to the REB approval letter (see Additional file 2 ).
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