Ultrasound diaphragm excursion and noninvasive ventilation in critically ill patients: a horse to bet on? CURRENT STATUS:

BACKGROUND Diaphragmatic dysfunction is seen in up to 60% of critically ill patients with respiratory failure, and it is associated with worse outcomes. The functionality of the diaphragm can be studied with simple and codified bedside ultrasound evaluation. Diaphragm excursion (echographic measurement of the inspiratory displacement of the hemidiaphragm) is one of the most studied parameters. The aim of this study was to assess the prevalence of diaphragmatic dysfunction in critically ill non-intubated patients admitted to a general intensive care unit with acute respiratory failure. Response to non-invasive ventilation (NIV) was evaluated in patients with diaphragm dysfunction, as was whether the ultrasound assessment of the diaphragm excursion may be employed as a predictor of NIV failure. METHODS We collected data, including ultrasound diaphragm excursion, at 2 time points: at T0 (at the time of recruitment, just before starting NIV) and at T1 (after one hour of NIV). RESULTS A total of 47 patients were enrolled. Prevalence of diaphragm dysfunction was 42.5% (95% CI 28, 3 - 57,8). Surgical patients showed a higher incidence (relative risk of 1.97) than medical patients. Mean DE was not significantly different between NIV responders (1,35 ± 0.78 cm) and non-responders (1.21 ± 0.85 cm, p 0,6). Patients with diaphragmatic dysfunction responded positively to NIV in 60% (95% CI 36.0 - 80.9%) of cases, while patients without diaphragmatic dysfunction responded positively to the NIV trial in 70.4% (95% CI 49.8 - 86.2%) of cases (p = 0.54). Taking the use of ultrasound diaphragm excursion as a potential predictor of NIV response, the corresponding ROC curve had an area under the curve of 0.53; the best balance between sensitivity (58.1%) and specificity (62.5%) was obtained with a cut-off diaphragm excursion of 1.37 cm.

Diaphragmatic dysfunction (DD) in patients with respiratory failure has often been neglected, and only in recent years has it become a well-regarded topic in the literature [1]. Its prevalence in critically ill patients requiring invasive mechanical ventilation has been proven to be up to 60%. DD is associated with failure of weaning from mechanical ventilation, prolonged length of intensive care unit (ICU) stay and increased mortality [1][2][3][4]. Several conditions have been associated with diaphragmatic weakness, such as sepsis, shock, hypoxia and post-surgical settings, creating a "multiple-hit mechanism", in which various factors are combined to induce changes in respiratory mechanics leading to respiratory failure [1,5,6].
Post-surgical patients seem to be at high risk of diaphragm dysfunction, especially after cardiothoracic or upper abdominal surgery [5]: up to 79% of liver transplant patients have shown DD [7,8].
Simple and fast diaphragmatic bedside ultrasound evaluation techniques have been codified, giving great impetus to the study of diaphragm function [9][10][11][12][13][14]. One of the most studied parameters is the diaphragm excursion (DE, cm), which is the echographic measurement of the inspiratory downward displacement of the hemidiaphragm [15]. Several studies have investigated the ability of DE, alone or in combination with other parameters, to predict successful weaning from mechanical ventilation, but its role is not fully understood [16].
Acute respiratory failure is a common cause of admission to the ICU, and DD may be a primary contributory cause. When patients do not require emergent intubation, a trial of non-invasive ventilation (NIV) is often considered [17]. Because of positive inspiratory pressure, diaphragm excursion is expected to be increased, but its behaviour has not been fully studied during noninvasive ventilation (a situation combining spontaneous breathing effort and positive inspiratory pressure) in patients with and without DD [18].
To the best of our knowledge, the prevalence of DD in patients with acute respiratory failure eligible for an NIV trial has been investigated by only a few studies [19], and the role of ultrasound assessment of DE as a predictor of NIV failure in this type of patient has not been researched.
The primary aim of this study was to assess the prevalence of DD in non-intubated patients affected by acute respiratory failure admitted to a general ICU. Subsequently, we evaluated the diaphragm response to NIV and whether the ultrasound assessment of diaphragm excursion may be employed as a predictor of NIV failure.

Study Design
This is a single-centre observational prospective study, approved by our Local Ethics Committee

Experimental protocol
We collected data at 2 time points: at T 0 (at the time of recruitment, just before starting NIV) and at T 1 (after one hour of NIV).
At T 0 , we collected demographic data (age, sex, BMI), medical history (reason for ICU admission, associated diseases, SAPS II score) and pre-NIV respiratory and echographic data (PaO 2 /FiO 2 ratio, respiratory rate, ultrasound diaphragmatic measurements) as described below.
After these measurements, patients were ventilated in NIV with BiPAP pressure support via the Dragër Evita 4® (Lübeck, Germany) ventilator and Respironics PerforMax® full face mask (Philips Respironics, Murrysville, PA, USA). A pressure support (PS) range of 5-7 cmH2O and a positive endexpiratory pressure (PEEP) of 5-10 cmH2O were used. In order to tolerate non-invasive ventilation, all patients were sedated if necessary with remifentanil up to a maximum dosage of 0.05 μg/kg/min continuous IV infusion to achieve a Ramsey score of 2, according to our internal ICU sedation protocol.
The following criteria were used to declare NIV failure at T 1 and requirement of endotracheal intubation: failure to increase PaO 2 > 50% compared to the pre-NIV value, increase of the PaCO 2 > 15% compared to the pre-NIV value, respiratory rate > 40 min-1.
We also collected outcome data at least 100 days after recruitment: subsequent need for tracheal intubation, duration (expressed in days) of intubation, length of intensive care stay, hospital LOS, and death.

Ultrasound diaphragmatic measurements
At both T 0 and T 1 , we conducted a thoracic ultrasound exam to evaluate diaphragm motility. All US exams were conducted by an expert echographer using a Philips EN Visor® C 1. reported for quantitative variables, absolute and relative frequencies for qualitative variables. To test for outliers, the robust regression outlier removal method (ROUT) was used. Fisher's exact test or the t/Kolmogorov-Smirnov test (for qualitative variables) were used to evaluate whether the observed differences between independent variables were not due to chance. The prevalence of DD was calculated, together with the respective 95% confidence interval. Sensitivity and specificity were used as indices of the accuracy of diaphragmatic dysfunction in predicting NIV success or failure. The ROC curve of DE compared to NIV outcome was used to identify the threshold of DE that guaranteed the best balance between different levels of sensitivity and specificity.
In the scientific literature, there are currently no other studies that have analysed the prevalence of diaphragmatic dysfunction in spontaneously breathing patients with respiratory failure admitted to intensive care; since there is no available estimate on which to base the calculation of the sample size required in our study, we assumed an a priori prevalence of diaphragmatic dysfunction of 50% to maximize the sample size.
To calculate the study prevalence with a 2-sided 95% confidence interval and a maximum accuracy error of 15% per queue, given an expected proportion of 50%, it was necessary to enrol 47 patients.

Results
A total of 47 patients were enrolled. Patient characteristics and demographics are shown in Table 1; no statistically significant differences were found between the two groups. Post-surgical patients accounted for 38%, and the majority of them underwent hepatic surgery or orthotopic liver transplant (OLTx). The most common comorbidities were arterial hypertension (43%), type 2 diabetes mellitus (32%) and renal failure (30%).

Diaphragm dysfunction
The prevalence of DD in our patient population was 42.5% (95% CI 28, 8). There were no differences in age, sex, BMI, SAPS II score (see Table 1 Effect of non-invasive ventilation NIV was generally well tolerated and efficacious, with a mean improvement in the PaO 2 /FiO 2 ratio of 64 ± 7 points (95% CI 42,97 − 85,20, p < 0.001; Fig. 1) and a decrease of 1.5 ± 5.5 in respiratory rate (95% CI -3,153-0,08887, p = 0.06). Tins did not significantly change from before to during NIV, while Tesp increased by 0.15 sec (95% CI 0,04 − 0,26, p = 0.007), together with total respiration time, which increased by 0.23 sec (95% CI 0,08 to 0,37, p = 0.002) -see Table 2. In our study, diaphragm excursion proved to be significantly increased during NIV (+ 0.2 cm, p = 0.001) due to mechanical pressure support, as expected (Table 2). Table 2 Oxygenation and ultrasonographic assessment of the diaphragmatic function before and after one hour of NIV.  (Table 3). Table 3 NIV non-responder and NIV responder data before starting NIV trial. Post-surgical patients responded to NIV in 55% of cases, while medical patients had a benefit in 72% of cases, but this difference did not reach statistical significance (p = 0.34).

Diaphragmatic dysfunction and NIV failure
The mean T 0 diaphragm excursion was slightly larger in NIV-responder patients Given the above differences, assuming the use of ultrasound diaphragm excursion as a potential predictor of NIV response, the corresponding ROC curve (Fig. 2)

Outcome
The mean length of stay in the ICU was shorter in patients with normal diaphragm function (11 ± 9 days), compared to patients with DD (14 ± 13 days), but this difference did not reach statistical significance (p = 0.297). See Fig. 3A.

Discussion
The main result of this study is that, in accordance with the literature, the prevalence of DD in patients admitted to the ICU with acute respiratory failure was high, being present in almost half of the patients enrolled in this study (42.5%). Surgical patients were most affected (prevalence of DD 61%), and this was expected, as it is known that surgical manipulation (especially heart, thorax and upper abdominal surgery) can impair diaphragmatic muscle function [5]. We should not overlook, however, that even in the non-surgical population, acute respiratory failure was accompanied by DD in almost 1 in 3 patients (31%) in this study.
We used DE, or diaphragm displacement, as the ultrasonographic parameter of diaphragmatic function, as it is the simplest and fastest method in spontaneous breathing patients. DE is associated with lung volume during the inspiratory phase [20] but does not correlate with inspiratory muscular effort [21] in patients undergoing assisted mechanical ventilation, and it is influenced by several factors [1,22]. Since DE may be the result of the sum of the patient's inspiratory activity and mechanical ventilatory support, DE has true value only when assessed during spontaneous breathing.
In our study, DE proved to be significantly increased during NIV (p = 0.001) due to mechanical pressure support, as expected.
NIV may have physiologic benefits with an improvement in respiratory mechanics, such as decreased respiratory rate and unloading of the respiratory muscle and increased tidal volume and minute ventilation [23]. In our study, those benefits were echographically represented by an increase in diaphragm excursion (+ 0.2 cm), a decreased respiratory rate (-1.54 min-1), and a prolonged Ttot (+ 0.23") and Tesp (+ 0.15"), all statistically significant measures. Inspiratory time, however, was not significantly changed by NIV.
In our opinion, NIV allowed the unloading of the respiratory muscles (the patient made less effort and decreased the respiratory rate) without changing the inspiratory time decided by the respiratory centres, and through PEEP/CPAP, it led to a prolonged expiration time (likely to determine alveolar recruitment).
Similarly, NIV responder patients demonstrated longer respiratory times at T 0 (Tins 0.86" vs 0.75", Tesp 0.91" vs 0.64", Ttot 1.78 vs 1.39") than NIV non-responders, despite having the same initial mean respiratory rate as non-responder patients (21.2 vs 21.4 min-1) -see Table 3. We believe that We also evaluated the same predictive capacity of the slope of the DE curve (pend, cm/s), which corresponds to the speed of diaphragm contraction, and found no significant differences between responders and non-responders (p = 0.37). A cut-off value of 1.64 cm/s of the slope of the DE curve had a sensitivity of 56.2% and specificity of 29.6% to identify a NIV responder subject (AUC-ROC 0.50).
Overall, our results point towards the only tentative evidence of a non-statistically significant trend of a different response to NIV among respiratory patients with and without DD. Further studies with larger sample sizes are necessary to confirm or refute this hypothesis definitively.
In the current state of the research, DE seems not to be an appropriate a priori predictor of NIV failure.
The same was true of the outcome measures: both the ICU length of stay and the 100-day mortality showed a non-statistically significant trend towards a worse outcome for patients with DD, in accordance with what is reported in the literature [3]. This also leads to an increase in patient management costs.
The main limitations of our study consist of the small sample size and the fact that the diaphragm thickening fraction was not acquired. In addition, no obese patients were recruited in the present study.

Conclusions
In conclusion, DD is a frequent occurrence in critically ill patients with respiratory failure, whether they are surgical or medical patients. DD is associated with various comorbidities and disease severity, but it is not only a condition that identifies the most serious patients; it may represent another form of organ failure [3]. The functionality of the diaphragm can be effectively and easily tested by bedside ultrasound examination, and its measurement should be considered in every patient with respiratory failure [3].
Further studies with larger sample sizes are necessary to confirm or refute the hypothesis that the presence of DD can modify the patient's response to NIV.