**8. Treating the severe ARDS patient**

Ichikado [8] showed that fibroproliferation signs in high-resolution CT evaluation of early ARDS patients were correlated with higher mortality and ventilator dependency. The lung SAFE study [3], an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted in 459 ICUs from 50 countries across five continents showed that 2.377 out of 29.144 patients developed ARDS in the first 48 h and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2–31.9%); of moderate ARDS, 46.6% (95% CI, 44.5–48.6%); and of severe ARDS, 23.4% (95% CI, 21.7–25.2%). The cumulative frequency distribution of tidal volume was similar in patients in each severity category, with 65% of patients with acute respiratory distress syndrome (ARDS) receiving a tidal volume of 8 mL/kg of predicted body weight or less. In contrast, a right shift of the cumulative frequency distribution curves of plateau pressures was seen for increasing ARDS severity category, with pla-

There was a lower likelihood of survival to day 28 with increasing severity of acute respiratory distress syndrome (ARDS) at day 1. Patients with a driving pressure of greater than 14 cm

could argue that in the future tidal volume should be titrated according to the derived driving

Amato and colleagues [9] analyzed individual data from 3562 patients with ARDS enrolled in nine previously published randomized clinical trials of mechanical ventilation using a multilevel mediation analysis. They observed a strong association between driving pressure and ARDS survival even though all the ventilator settings that were used were lung protective (RR of death: 1.36, 95% CI 1.17–1.58, *P* < 0.001). These observations suggest that tidal volume might be adjusted to the resultant airway driving pressure in addition to the adjustment to the predicted body weight. They also observed that airway driving pressures higher than 15 cm

O were associated with increasing rates of mortality in ARDS patients. Recently, Villar and colleagues [10] analyzed the data from two observational studies enclosing 778 patients with moderate and severe ARDS. They assessed the risk of hospital death based on quantiles of tidal volume, positive end-expiratory pressure, plateau inspiratory pressure and airway driving pressure evaluated 24 h after ARDS diagnosis while the patients were ventilated with lung protective ventilation. The authors verified that positive end expiratory pressure and tidal volume that were set according to a protective lung ventilation strategy had no impact

As respiratory system driving pressure does not account for variable chest wall compliance or different degrees of intra-abdominal pressures or even more to the presence of inspiratory efforts or asynchrony, esophageal manometry can be used to measure transpulmonary pressure that represents the lungs parenchyma stress during tidal volume ventilation. Recently, Baedorf and colleagues examined the relationships between respiratory system and transpulmonary driving pressure measured at baseline, 5 min and 24 h after PEEP titration and

on mortality while a plateau pressure higher than 29 cm H2

O were associated with a higher hospital mortality.

O on day 1 of ARDS criteria had a higher mortality. Taking into consideration, these data that tidal volume ventilation was similar across the ARDS severity but inspiratory driving

O in 8.5% of patients for which these data were available.

O and a driving pressure higher

O was associated with decreased mortality of those patients one

teau pressure of more than 30 cm H2

52 Advances in Extra-corporeal Perfusion Therapies

pressure less than 14 cm H2

inspiratory pressure.

H2

H2

than 19 cm H2

Low-tidal ventilation (≤6 mL/kg of predicted body weight) must be initiated as soon as the ARDS patient is intubated and mechanically ventilated. The predicted body weight (PBW) can be calculated as follows: for women, PBW = 45.5 + 0.91 (height in centimeters—152.4) and for men, PBW = 50.0 + 0.91 (height in centimeters—152.4). It is well documented that lower tidal volumes (6 mL/kg of predicted body weight) compared to higher tidal volumes (12 mL/kg of predicted body weight) associated with PEEP levels titrated by a PEEP/FIO2 table reduced mortality in a randomized, clinical trial that analyzed 861 ARDS patients (ARMA trial) [12].

It is crucial to adjust tidal volume to lung size that depends of the height and sex, but more importantly is to adjust the tidal volume to functional lung size that depends on the ARDS severity (lung compliance), sex, height, and chest wall compliance. The patient with severe ARDS and a low compliance will be ventilated with high airway pressures if ventilated with 6 mL/predicted body weight. Amato and colleagues [9], in 2015, reported that driving pressure (ΔP), that can be also be represented by tidal volume (VT)/respiratory system compliance (CRS), in which VT is intrinsically normalized to functional lung size, was a ventilatory variable more strongly associated with survival than VT or PEEP in patients who are not actively breathing. Using a statistical tool known as multilevel mediation analysis to study individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, they examined ΔP as an independent variable associated with survival. In the mediation analysis, they estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. The authors observed that among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31–1.51; *P* < 0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17–1.58; *P* < 0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, *P* = 0.004 and *P* = 0.001, respectively). They concluded that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival.

metabolic acidosis. Efforts must be taken to decrease the pulmonary dead space by means of recruitment maneuvers and PEEP titration, tidal volume and respiratory rate adjustments or even the initiation of prone ventilation. In the most difficult cases, tracheal gas insufflation or

Permissive hypercapnia can carry potential harmful consequences including pulmonary vasoconstriction and pulmonary hypertension, proarrhythmic effects of increased discharge of catecholamines and cerebral vasodilation yielding increased intracranial pressure. When applying protective ventilation in patients with severe ARDS, special attention should be given to patients with pulmonary hypertension and right ventricular dysfunction that could

probably be used with caution in patients with heart disease and is relatively contraindicated in those with elevated intracranial pressure. In ARDS cases with pulmonary hypertension and

Recently, three large clinical trials [18–20], including acute lung injury/ARDS patients ventilated with low tidal-volume, have compared different PEEP strategies (high vs. low), but none of them could show a significant difference in mortality. Moreover, a recent meta-analysis [21] has pooled those trials, revealing some combined benefits of the high PEEP strategy; still, the survival benefit was modest and limited to the subgroup of ARDS patients with

/FIO2 < 200 (moderate and severe ARDS according to Berlin definition). Conceptually, one could argue that none of the "high-PEEP" strategies was designed to test the "open-lung hypothesis" postulated by Lachmann, that is, the hypothesis that most of the collapsed lung tissue observed in early ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection [22–24]. According to a recent study by Borges and colleagues [25], a straight test of the "open-lung hypothesis" would certainly require more aggressive recruiting maneuvers in association with individualized, decremental PEEP titration. Recently, de Matos and colleagues [26] reported the experience with maximal recruitment strategy (MRS) in 51 patients with ARDS. MRS consisted of 2-min steps of pressure-controlled

tory/expiratory ratio of 1:1, and stepwise increments in PEEP levels from 10 to 45 cm H2

tomography images. At each of the steps, computer tomography image sequences from the carina to the diaphragm were acquired during an expiratory pause of 6–10 s. Visual inspection of the images was performed during the tomographic examination in order to assess the lung collapse in the lungs bases for immediate clinical decision, and after an offline quantitative analysis was realized. Nonaerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5–62.4) to 12.7% (IQR: 4.9–24.2) (*P* < 0.0001) after MRS. The opening

from 125 (±43) to 300 (±103; *P* < 0.0001) after MRS and was sustained above 300 throughout 7 days. MRS showed a statistically significant decrease in nonaerated areas of the ARDS lungs that was accompanied by a significant increment in oxygenation. The potentially recruitable

plateau pressure observed during the recruitment protocol was 59.6 (±5.9 cm H2

right ventricular dysfunction, prone position ventilation should be preferred [17].

removal or extracorporeal oxygenation should be started in order to keep

Severe Acute Respiratory Distress Syndrome http://dx.doi.org/10.5772/intechopen.77071 55

and low pH levels. Nonetheless, permissive hypercapnia should

O, respiratory rate of 10 breaths/min, inspira-

O, each one lasting 4 min monitored by thoracic

O). The mean PaO2

O and, then, from 25 to 10 cm

/FiO2

O

O), and the

ratio increased

extracorporeal CO2

not tolerate high PaCO2

PaO2

H2

the protective low tidal volume ventilation [17].

ventilation, fixed driving pressure of 15 cm H2

O (PEEP titration phase) in steps of 5 cm H2

mean PEEP titrated after MRS was 24.6 (±2.9 cm H2

(recruitment phase). After that, PEEP was decreased to 25 cm H2

Moreover, recent evidences [13] showed that in severe ARDS patients, inspiratory efforts during assisted ventilation could worsen ventilator lung injury induced by the mechanical ventilation during the ventilatory support of the ARDS patients. This associated and added injury could explain the results of a phase IV randomized controlled trial in moderate-severe ARDS patients (PaO2 /FIO2 < 150), comparing cisatracurium to placebo for 48 h showed an improved adjusted 90-day survival rate and increased ventilator-free in the cisatracurium group without a significant increase in muscle weakness. Short-term paralysis may facilitate patientventilator synchrony in the setting of lung protective ventilation. Short-term paralysis would eliminate patient triggering and expiratory muscle activity. In combination, these effects may serve to limit regional overdistention and cyclic alveolar collapse. Paralysis may also act to lower metabolism and overall ventilatory demand [14]. Recently, Sottile and colleagues [15] showed that the use of neuromuscular blockade in ARDS patients receiving low tidal volume ventilation and a PaO2 /FIO2 ratio less than 120 were associated with decreased biomarkers of epithelial (serum surfactant protein-D) and endothelial (serum Von Willebrand factor) lung injury and systemic inflammation (serum interleukin 8).

At the same time, that an adequate sedation, an adequate short-term paralysis and low tidal volume were set in severe ARDS patients [16], an adequate respiratory rate must be concurrently set in order to keep a minute ventilation around 7–8 L/min and a PaCO2 around 40–60 mm Hg and a pH above 7.2. In the more severe ARDS patients, sometimes after the adjustment of a minute ventilation around 7–8 L/min with tidal volumes lesser than 6 mL/kg of predicted body weight, the PaCO2 levels stay above 80 mm Hg and pH less than 7.2 (specially patients with septic shock and metabolic acidosis). In these cases, the VCO2 must be assessed and be kept as least as possible (fever control, low carbohydrate intake) and hemodialysis can be initiate (especially in ARDS patients with concomitant acute renal failure) in order to help control the metabolic acidosis. Efforts must be taken to decrease the pulmonary dead space by means of recruitment maneuvers and PEEP titration, tidal volume and respiratory rate adjustments or even the initiation of prone ventilation. In the most difficult cases, tracheal gas insufflation or extracorporeal CO2 removal or extracorporeal oxygenation should be started in order to keep the protective low tidal volume ventilation [17].

ARDS and a low compliance will be ventilated with high airway pressures if ventilated with 6 mL/predicted body weight. Amato and colleagues [9], in 2015, reported that driving pressure (ΔP), that can be also be represented by tidal volume (VT)/respiratory system compliance (CRS), in which VT is intrinsically normalized to functional lung size, was a ventilatory variable more strongly associated with survival than VT or PEEP in patients who are not actively breathing. Using a statistical tool known as multilevel mediation analysis to study individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, they examined ΔP as an independent variable associated with survival. In the mediation analysis, they estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. The authors observed that among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31–1.51; *P* < 0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17–1.58; *P* < 0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, *P* = 0.004 and *P* = 0.001, respectively). They concluded that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival.

Moreover, recent evidences [13] showed that in severe ARDS patients, inspiratory efforts during assisted ventilation could worsen ventilator lung injury induced by the mechanical ventilation during the ventilatory support of the ARDS patients. This associated and added injury could explain the results of a phase IV randomized controlled trial in moderate-severe ARDS

adjusted 90-day survival rate and increased ventilator-free in the cisatracurium group without a significant increase in muscle weakness. Short-term paralysis may facilitate patientventilator synchrony in the setting of lung protective ventilation. Short-term paralysis would eliminate patient triggering and expiratory muscle activity. In combination, these effects may serve to limit regional overdistention and cyclic alveolar collapse. Paralysis may also act to lower metabolism and overall ventilatory demand [14]. Recently, Sottile and colleagues [15] showed that the use of neuromuscular blockade in ARDS patients receiving low tidal volume

epithelial (serum surfactant protein-D) and endothelial (serum Von Willebrand factor) lung

At the same time, that an adequate sedation, an adequate short-term paralysis and low tidal volume were set in severe ARDS patients [16], an adequate respiratory rate must be concurrently

and a pH above 7.2. In the more severe ARDS patients, sometimes after the adjustment of a minute ventilation around 7–8 L/min with tidal volumes lesser than 6 mL/kg of predicted body

as least as possible (fever control, low carbohydrate intake) and hemodialysis can be initiate (especially in ARDS patients with concomitant acute renal failure) in order to help control the

/FIO2 < 150), comparing cisatracurium to placebo for 48 h showed an improved

ratio less than 120 were associated with decreased biomarkers of

levels stay above 80 mm Hg and pH less than 7.2 (specially patients with

around 40–60 mm Hg

must be assessed and be kept

patients (PaO2

54 Advances in Extra-corporeal Perfusion Therapies

ventilation and a PaO2

weight, the PaCO2

/FIO2

injury and systemic inflammation (serum interleukin 8).

set in order to keep a minute ventilation around 7–8 L/min and a PaCO2

septic shock and metabolic acidosis). In these cases, the VCO2

Permissive hypercapnia can carry potential harmful consequences including pulmonary vasoconstriction and pulmonary hypertension, proarrhythmic effects of increased discharge of catecholamines and cerebral vasodilation yielding increased intracranial pressure. When applying protective ventilation in patients with severe ARDS, special attention should be given to patients with pulmonary hypertension and right ventricular dysfunction that could not tolerate high PaCO2 and low pH levels. Nonetheless, permissive hypercapnia should probably be used with caution in patients with heart disease and is relatively contraindicated in those with elevated intracranial pressure. In ARDS cases with pulmonary hypertension and right ventricular dysfunction, prone position ventilation should be preferred [17].

Recently, three large clinical trials [18–20], including acute lung injury/ARDS patients ventilated with low tidal-volume, have compared different PEEP strategies (high vs. low), but none of them could show a significant difference in mortality. Moreover, a recent meta-analysis [21] has pooled those trials, revealing some combined benefits of the high PEEP strategy; still, the survival benefit was modest and limited to the subgroup of ARDS patients with PaO2 /FIO2 < 200 (moderate and severe ARDS according to Berlin definition). Conceptually, one could argue that none of the "high-PEEP" strategies was designed to test the "open-lung hypothesis" postulated by Lachmann, that is, the hypothesis that most of the collapsed lung tissue observed in early ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection [22–24]. According to a recent study by Borges and colleagues [25], a straight test of the "open-lung hypothesis" would certainly require more aggressive recruiting maneuvers in association with individualized, decremental PEEP titration. Recently, de Matos and colleagues [26] reported the experience with maximal recruitment strategy (MRS) in 51 patients with ARDS. MRS consisted of 2-min steps of pressure-controlled ventilation, fixed driving pressure of 15 cm H2 O, respiratory rate of 10 breaths/min, inspiratory/expiratory ratio of 1:1, and stepwise increments in PEEP levels from 10 to 45 cm H2 O (recruitment phase). After that, PEEP was decreased to 25 cm H2 O and, then, from 25 to 10 cm H2 O (PEEP titration phase) in steps of 5 cm H2 O, each one lasting 4 min monitored by thoracic tomography images. At each of the steps, computer tomography image sequences from the carina to the diaphragm were acquired during an expiratory pause of 6–10 s. Visual inspection of the images was performed during the tomographic examination in order to assess the lung collapse in the lungs bases for immediate clinical decision, and after an offline quantitative analysis was realized. Nonaerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5–62.4) to 12.7% (IQR: 4.9–24.2) (*P* < 0.0001) after MRS. The opening plateau pressure observed during the recruitment protocol was 59.6 (±5.9 cm H2 O), and the mean PEEP titrated after MRS was 24.6 (±2.9 cm H2 O). The mean PaO2 /FiO2 ratio increased from 125 (±43) to 300 (±103; *P* < 0.0001) after MRS and was sustained above 300 throughout 7 days. MRS showed a statistically significant decrease in nonaerated areas of the ARDS lungs that was accompanied by a significant increment in oxygenation. The potentially recruitable lung was estimated at 45% (IQR: 25–53). ICU mortality was 28% and hospital mortality was 32%. The independent risk factors associated with mortality were older age and higher driving pressures. There were no significant clinical complications with MRS or barotrauma. A better evolution of these ARDS patients with less necessity of oxygen supplementation in the recovery phase of the disease and a better quality of life were observed in these patients [26].

A recent systematic review and meta-analysis [27] that analyzed the effects of recruitment maneuvers for adult patients with acute respiratory distress syndrome showed an overall pool effect of a significant decrease on mortality in these patients and no associated increase in barotrauma. However, soon after, a large prospective, multicenter and controlled trial (ART trial) [28] that compared recruitment maneuver and best-compliance PEEP titration in 501 ARDS patients with 509 ARDS patients ventilated with low PEEP showed an increased 6-month mortality in both groups, but higher in the recruitment and PEEP titration group (65.3 vs. 59.9%, respectively, *P* = 0.04). However, in our opinion, the recruitment maneuver tested in ART trial was abrupt and short (started at 25 cm H2 O PEEP, duration of 1 s and not imaging monitored) what could have contributed to the higher levels of observed barotrauma and mortality [29]. When we combined the results of the systematic review and meta-analysis with the ART results, we observed a total of 1144 patients undergoing recruitment maneuvers and PEEP titration and 1179 controls with standard ventilation with a final result of no significant differences in mortality relatite risk of 0.91 [95% CI, 0.74–1.13]. The most effective recruitment maneuver and PEEP titration in ARDS remain to be determined [29].

Recent evidence showed that prolonged prone position ventilation (16 h) must be used in

**Figure 1.** Chest X-ray showing bilateral pulmonary infiltrates that predominate in lower lungs fields.

significantly improved 90-day mortality compared to supine ventilation (PROSEVA trial) [30]. Recent meta-analysis also showed that in the era of low tidal ventilation, the prone position use improved mortality of moderate/severe ARDS patients that needed invasive mechanical ventilatory support [31]. If PEEP titration during prone position, ventilation should improve

For patients in whom gas exchange is refractory to conventional ventilation and other advanced therapies, extracorporeal membrane oxygenation (ECMO) may be appropriate as salvage therapy. Venovenous ECMO may be able to support refractory hypoxemia in the setting of severe ARDS. It may also be used for carbon dioxide removal when respiratory system compliance is severely compromised and efforts to maintain plateau airway pressures within acceptable parameters lead to unsustainable levels of hypercapnia and respiratory acidosis. Prospective randomized controlled trial of ECMO in severe ARDS, reported in 2009, was the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial [32], in which 180 subjects with severe ARDS were randomized to conventional mechanical ventilation or referral to a specialized center for consideration of ECMO. The United Kingdom randomized and prospective clinical trial (CESAR) revealed a survival advantage in the ECMO group; the ECMO group had a 63% survival after 6 months, while the control group had a 47% survival rate. The study was criticized because there was no standardized protocol management for the control group and some patients in the ECMO group did not receive the proposed treatment. The authors demonstrated that this strategy is also likely to be cost-effective in settings with similar services to those in the United Kingdom. Patients should be considered for weaning

survival of ARDS patients, which is still a matter of debate.

/FIO2 < than 150 with PEEP levels of or more than 5 cm H2

O in order to

Severe Acute Respiratory Distress Syndrome http://dx.doi.org/10.5772/intechopen.77071 57

early ARDS with PaO2

Our group is used to apply maximal recruitment strategy maneuvers in our severe ARDS patients with PEEP titration with thoracic tomography with good results. Here, we present a case of a 47-year-old man, previously asymptomatic, that started with cough, dyspnea, and an acute hypoxemic respiratory failure. The chest-X-ray showed a bilateral pulmonary infiltrate that predominates in the lower lungs fields (**Figure 1**). SpO2 in ambient air was 77% and after oxygen mask of 100% SpO2 was 88% and he needed intubation and mechanical ventilation. Arterial pressure is of 11 × 7 cm Hg and HR of 110 rpm. Hemocultures and tracheal secretion were collected as well as a nasopharyngeal swab for respiratory viruses. Oseltamivir, clarithromycin and ceftriaxone were initiated. A transthoracic echocardiogram showed normal right and left ventricular function and a normal arterial pulmonary pressure. A protective mechanical ventilation was initiated with tidal volume of 6 mL/kg/predicted body weight (420 mL), RR of 20 rpm, PEEP of 15 cm H2 O, FIO2 of 100%, SpO2 de 90% and an arterial blood gas analysis showed a pH of 7,35, PaCO2 of 50 mm Hg, PaO2 of 60 mm Hg, sodium bicarbonate of 23 and base excess of −1, lactate of 10 mg/dL, SvO2 of 70 mm Hg, Hb of 13 g/dL, 12,000 leucocytes, platelets of 250,000, reactive C-protein of 120 mg/L, BNP of 40 pg/mL. He was submitted to maximal recruitment strategy maneuvers and PEEP titration of 25 cm H2 O in the tomography room (**Figure 2**). The PaO2 /FIO2 ratio increased from 60 to 200, and after 3 days, he was with PEEP of 15 cm H2 O and a PaO2 /FIO2 of 300. After 10 days, he was extubated and presented in ambient air a SpO2 of 95% and an expressive improvement in chest X-ray (**Figure 3**). All the collect cultures and the nasopharyngeal swab for respiratory viruses were negative. The thoracic tomography performed 3 days after extubation showed an important improvement of the lungs infiltrates (**Figure 4**).

**Figure 1.** Chest X-ray showing bilateral pulmonary infiltrates that predominate in lower lungs fields.

lung was estimated at 45% (IQR: 25–53). ICU mortality was 28% and hospital mortality was 32%. The independent risk factors associated with mortality were older age and higher driving pressures. There were no significant clinical complications with MRS or barotrauma. A better evolution of these ARDS patients with less necessity of oxygen supplementation in the recovery phase of the disease and a better quality of life were observed in these patients [26]. A recent systematic review and meta-analysis [27] that analyzed the effects of recruitment maneuvers for adult patients with acute respiratory distress syndrome showed an overall pool effect of a significant decrease on mortality in these patients and no associated increase in barotrauma. However, soon after, a large prospective, multicenter and controlled trial (ART trial) [28] that compared recruitment maneuver and best-compliance PEEP titration in 501 ARDS patients with 509 ARDS patients ventilated with low PEEP showed an increased 6-month mortality in both groups, but higher in the recruitment and PEEP titration group (65.3 vs. 59.9%, respectively, *P* = 0.04). However, in our opinion, the recruitment maneuver

imaging monitored) what could have contributed to the higher levels of observed barotrauma and mortality [29]. When we combined the results of the systematic review and meta-analysis with the ART results, we observed a total of 1144 patients undergoing recruitment maneuvers and PEEP titration and 1179 controls with standard ventilation with a final result of no significant differences in mortality relatite risk of 0.91 [95% CI, 0.74–1.13]. The most effective

Our group is used to apply maximal recruitment strategy maneuvers in our severe ARDS patients with PEEP titration with thoracic tomography with good results. Here, we present a case of a 47-year-old man, previously asymptomatic, that started with cough, dyspnea, and an acute hypoxemic respiratory failure. The chest-X-ray showed a bilateral pulmonary infiltrate

Arterial pressure is of 11 × 7 cm Hg and HR of 110 rpm. Hemocultures and tracheal secretion were collected as well as a nasopharyngeal swab for respiratory viruses. Oseltamivir, clarithromycin and ceftriaxone were initiated. A transthoracic echocardiogram showed normal right and left ventricular function and a normal arterial pulmonary pressure. A protective mechanical ventilation was initiated with tidal volume of 6 mL/kg/predicted body weight

O, FIO2

leucocytes, platelets of 250,000, reactive C-protein of 120 mg/L, BNP of 40 pg/mL. He was

All the collect cultures and the nasopharyngeal swab for respiratory viruses were negative. The thoracic tomography performed 3 days after extubation showed an important improve-

submitted to maximal recruitment strategy maneuvers and PEEP titration of 25 cm H2

/FIO2

/FIO2

of 50 mm Hg, PaO2

recruitment maneuver and PEEP titration in ARDS remain to be determined [29].

O PEEP, duration of 1 s and not

in ambient air was 77% and after

de 90% and an arterial blood

O in the

of 60 mm Hg, sodium bicarbon-

of 70 mm Hg, Hb of 13 g/dL, 12,000

ratio increased from 60 to 200, and after 3 days, he

of 300. After 10 days, he was extubated and pre-

was 88% and he needed intubation and mechanical ventilation.

of 95% and an expressive improvement in chest X-ray (**Figure 3**).

of 100%, SpO2

tested in ART trial was abrupt and short (started at 25 cm H2

that predominates in the lower lungs fields (**Figure 1**). SpO2

ate of 23 and base excess of −1, lactate of 10 mg/dL, SvO2

O and a PaO2

oxygen mask of 100% SpO2

56 Advances in Extra-corporeal Perfusion Therapies

(420 mL), RR of 20 rpm, PEEP of 15 cm H2

gas analysis showed a pH of 7,35, PaCO2

tomography room (**Figure 2**). The PaO2

ment of the lungs infiltrates (**Figure 4**).

was with PEEP of 15 cm H2

sented in ambient air a SpO2

Recent evidence showed that prolonged prone position ventilation (16 h) must be used in early ARDS with PaO2 /FIO2 < than 150 with PEEP levels of or more than 5 cm H2 O in order to significantly improved 90-day mortality compared to supine ventilation (PROSEVA trial) [30].

Recent meta-analysis also showed that in the era of low tidal ventilation, the prone position use improved mortality of moderate/severe ARDS patients that needed invasive mechanical ventilatory support [31]. If PEEP titration during prone position, ventilation should improve survival of ARDS patients, which is still a matter of debate.

For patients in whom gas exchange is refractory to conventional ventilation and other advanced therapies, extracorporeal membrane oxygenation (ECMO) may be appropriate as salvage therapy. Venovenous ECMO may be able to support refractory hypoxemia in the setting of severe ARDS. It may also be used for carbon dioxide removal when respiratory system compliance is severely compromised and efforts to maintain plateau airway pressures within acceptable parameters lead to unsustainable levels of hypercapnia and respiratory acidosis.

Prospective randomized controlled trial of ECMO in severe ARDS, reported in 2009, was the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial [32], in which 180 subjects with severe ARDS were randomized to conventional mechanical ventilation or referral to a specialized center for consideration of ECMO. The United Kingdom randomized and prospective clinical trial (CESAR) revealed a survival advantage in the ECMO group; the ECMO group had a 63% survival after 6 months, while the control group had a 47% survival rate. The study was criticized because there was no standardized protocol management for the control group and some patients in the ECMO group did not receive the proposed treatment. The authors demonstrated that this strategy is also likely to be cost-effective in settings with similar services to those in the United Kingdom. Patients should be considered for weaning

**Figure 2.** Thoracic tomography before and after maximal recruitment maneuvers and PEEP titration. Pre-recruitment PEEP of 10 cm H2 O. Pos-recruitment PEEP of 25 cm H2 O.

from venovenous ECMO once the underlying disease process for which ECMO was initiated has sufficiently resolved so that they can be safely and adequately supported by protective ventilatory strategy and oxygenation support without evidence of excessive respiratory work of breathing. Markers of sufficient native lung function recovery include adequate gas exchange reserve, acceptable respiratory system compliance, and improvement in chest images [32].

**Figure 4.** Thoracic tomography at first day after admission and thoracic tomography 3 days after extubation.

Another recent approach for application of extracorporeal carbon dioxide removal new devices (ECMO-R) in ARDS patients is the observation in thoracic tomography of ARDS patients that in severe ARDS, even the low tidal volume ventilation with 6 mL/kg of predicted body weight can cause tidal hyperdistension in the nondependent regions of the lungs accompanied by pla-

Application of ECMO-R in these severe ARDS patients could allow the authors to decrease the

associated with lower levels of lung-derived inflammatory cytokines and a lower radiographic

tidal volume to less than 6 mL/kg with a consequent plateau pressure less than 25 cm H2

O and elevated plasma markers of inflammation.

Severe Acute Respiratory Distress Syndrome http://dx.doi.org/10.5772/intechopen.77071 59

O that was

teau airway pressures greater than 28 cm H2

**Figure 3.** Chest-X-ray day 1, day 3, and day 10 after admission (day of extubation).

**Figure 4.** Thoracic tomography at first day after admission and thoracic tomography 3 days after extubation.

**Figure 2.** Thoracic tomography before and after maximal recruitment maneuvers and PEEP titration. Pre-recruitment

O.

O. Pos-recruitment PEEP of 25 cm H2

**Figure 3.** Chest-X-ray day 1, day 3, and day 10 after admission (day of extubation).

PEEP of 10 cm H2

58 Advances in Extra-corporeal Perfusion Therapies

from venovenous ECMO once the underlying disease process for which ECMO was initiated has sufficiently resolved so that they can be safely and adequately supported by protective ventilatory strategy and oxygenation support without evidence of excessive respiratory work of breathing. Markers of sufficient native lung function recovery include adequate gas exchange reserve, acceptable respiratory system compliance, and improvement in chest images [32].

Another recent approach for application of extracorporeal carbon dioxide removal new devices (ECMO-R) in ARDS patients is the observation in thoracic tomography of ARDS patients that in severe ARDS, even the low tidal volume ventilation with 6 mL/kg of predicted body weight can cause tidal hyperdistension in the nondependent regions of the lungs accompanied by plateau airway pressures greater than 28 cm H2 O and elevated plasma markers of inflammation. Application of ECMO-R in these severe ARDS patients could allow the authors to decrease the tidal volume to less than 6 mL/kg with a consequent plateau pressure less than 25 cm H2 O that was associated with lower levels of lung-derived inflammatory cytokines and a lower radiographic index of lung injury [33], but prognostic implications of ECMO-R devices application in clinical practice are still under investigation [34]. Pumpless interventional lung assist (iLA) is also used in patients with ARDS and is aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. iLA can be used in severe ARDS patients as an extracorporeal device to remove CO2 enabling low tidal volume and a reduced inspiratory plateau pressure in the mechanical ventilator in extremely severe ARDS patients. iLA device was used in 51 severe ARDS patients by Zimmermann and colleagues with a decrease in PaCO2 allowing the ultraprotective ventilation (lower tidal volume and plateau inspiratory pressures) with a hospital mortality of 49% [35]. More recently, the use of an ultraprotective strategy using 4 mL/kg of predicted body weight associated with low flow extracorporeal carbon removal in 15 moderate ARDS patients was described by Faneli and coworkers [36]. Additional data to the use of ECMO in ARDS patients will be added with the publication of EOLIA trial (ClinicalTrials.gov Identifier: NCT01470703), a prospective and randomized trial that evaluated the role of ECMO in severe ARDS that has finished but not published yet.

**References**

[1] Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: The Berlin definition. ARDS defini-

Severe Acute Respiratory Distress Syndrome http://dx.doi.org/10.5772/intechopen.77071 61

[2] Caser EB, Zandonade E, Pereira E, Gama AM, Barbas CS. Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evalu-

[3] Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A, LUNG SAFE investigators; ESICM trials group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive

[4] Barbas CS, Isola AM, Caser EB. What is the future of acute respiratory distress syndrome

[5] Kushimoto S, Endo T, Yamanouchi S, Sakamoto T, Ishikura H, Kitazawa Y, Taira Y, Okuchi K, Tagami T, Watanabe A, Yamaguchi J, Yoshikawa K, Sugita M, Kase Y, Kanemura T, Takahashi H, Kuroki Y, Izumino H, Rinka H, Seo R, Takatori M, Kaneko T, Nakamura T, Irahara T, Saito N. The Picco Pulmonary Edema Study Group. Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome

[6] Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies

[7] Boissier F, Katsahian S, Razazi K, Thille AW, Roche-Campo F, Leon R, Vivier E, Brochard L, Vieillard-Baron A, Brun-Buisson C, Mekontso Dessap A. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome.

[8] Ichikado K. The Berlin definition and clinical significance of high resolution CT (HRCT)

[9] Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, Richard JC, Carvalho CR, Brower RG. Driving pressure and survival in the acute respiratory distress syndrome. The New England Journal of

[10] Villar J, Martín-Rodríguez C, Domínguez-Berrot AM, Fernández L, Ferrando C, Soler JA, Díaz-Lamas AM, González-Higueras E, Nogales L, Ambrós A, Carriedo D, Hernández M, Martínez D, Blanco J, Belda J, Parrilla D, Suárez-Sipmann F, Tarancón C, Mora-Ordoñez JM, Blanch L, Pérez-Méndez L, Fernández RL, Kacmarek RM. Spanish initiative for epidemiology, stratification and therapies for ARDS (SIESTA) investigators network. A quantile analysis of plateau and driving pressures: Effects on mortality in patients with acute respiratory distress syndrome receiving lung-protective ventilation.

imaging in acute respiratory distress syndrome. Masui. 2013;**62**(5):522-531

in acute lung injury. New England Journal of Medicine. 2006;**354**(24):2564-2575

after the Berlin definition? Current Opinion in Critical Care. 2014;**20**(1):10-16

ation of 7,133 patients. Critical Care Medicine. 2014;**42**(3):574-582

tion task force. JAMA. 2012;**307**(23):2526-2533

care units in 50 countries. JAMA. 2016;**315**(8):788-800

by the Berlin definition. Critical Care. 2013;**17**(4):R132

Intensive Care Medicine. 2013;**39**(10):1725-1733

Medicine. 2015;**372**(8):747-755

Critical Care Medicine. 2017;**45**(5):843-850

In conclusion, the severe ARDS is defined as an acute bilateral pulmonary infiltrate onset, in a patient with a PaO2 /FIO2 equal or less than 100 with a positive end expiratory pressure equal or more than 5 cm H2 O that have an ARDS risk factor with no signs of cardiac failure or hypervolemia. Thus, when an intensivist evaluates an ARDS patient severity, he/her has to take into consideration the patient's age, cause of ARDS, the PaO2 /FIO2 ratio, response to PEEP, prone position, PaCO2 with protective ventilation (6 mL/predicted body weight), right ventricular function and level of pulmonary artery pressure, presence of shock (and necessity of vasoactive drugs), APACHE II score, number of organ failures (specially renal failure). The severe ARDS patients present a higher mortality ratio and required an extremely careful and specialized treatment. The cause of ARDS initiation should be addressed and promptly treated. These patients present a more difficult mechanical ventilatory support (higher airway pressures with low tidal ventilation and higher PaCO2 levels). They should be adequately monitored (airway and esophageal pressure measurements, bedside echocardiography and lung ultrasound, if possible). Protective ventilatory strategy must be offered and monitored (low tidal volume (less than 6 mL/kg of predicted body weight) and low distending inspiratory driving pressures (less than 15 cm H2 O) with adequate PEEP levels, and early prone position applied for more than 16 h. The possible benefits for adjunctive ventilatory support therapy (higher PEEP, recruitment maneuvers, inhalatory nitric oxide, ECMO and continuous hemodialysis) in the refractory cases should be offered, observing and monitoring the cross-talking among the multiple organ dysfunctions and guiding and changing the treatment according to the patients' responses. The more difficult cases must be treated in specialized centers with expertise supervision [4, 17, 26, 37, 38].

## **Author details**

Carmen Silvia Valente Barbas1,2\*, Roberta Fittipaldi Palazo2 and Gustavo Faissol Janot de Matos2

\*Address all correspondence to<EMAIL_ADDRESS>
1 University of São Paulo, Brazil

2 Adult ICU, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil


**4. Discussion**

The results obtained with Test 2 allowed for concluding something already expected, namely, that by increasing the number of data provided to the ANN, the learning process leads to high accuracy results, and thus the amount of data introduced in the future should be even higher, allowing for more accurate predictions. This directly results from the observations of Table 4 and Figure 5. This trend was previously argued by Tay and Cao [56], namely, that ANN results depend to a large extent on the amount of data provided to the system, being a time-consuming task.

Based on the results previously described, it can be stated that many network architectures have provided very accurate results, with eight architectures showing errors lower than 3.15% (96.85% accuracy), which can be considered an excellent result in terms of machining cost prediction. This result is less than those previously obtained by other researchers [57], who reported average accuracies of about 98.5% using ANNs, which has been shown to be a more accurate method to detect the different blends of fuel than RSM (response surface methodology) methods. Moreover, another study [58] about predictions of AISI 1050 steel machining performance has shown that ANNs presented the most accurate prediction value (92.1%), which is below the accuracy provided by the eight different architectures used in this work. In that work [58], it remains clear that ANN can provide more accurate values than other prediction techniques, such as the adaptive neuro-fuzzy inference system (ANFIS), which provided an accuracy of 73% compared to the 92.1% achieved using ANN. Saric et al. [55] also claimed an error of 2.03% using back-propagation neural networks in the estimation of CNC machining times. However, using self-organizing map neural networks, the results are less accurate, showing errors of about 10.05%. Ning et al. [52] used as a training dataset 21,943 features, and 4338 for validation, obtaining an accuracy of 97.7%, which is very similar to that achieved through this work. Thus, it is expected that a higher number of features used for training of the model can contribute to a better accuracy of the predictions, but too much data cannot contribute to accuracy improvement and can cause higher computing time, which can be unnecessary.

Regarding Table 5, the best results were obtaining using as input variables the volume of removed materials (V) and the total number of elements of each feature (Q). Indeed, the second most accurate result was obtained using the same variables plus the machined

surface area (A). However, adding this variable, the results started to degrade. Among the other combinations considered in this work, only the Q + A combination presented acceptable results, together with the combination Q + At. Thus, it is possible to infer that the volume of removed materials plays an important role in terms of keeping the accuracy as high as possible, which can be combined with V for the best results and combined with A for close to the best results.


*6.3. Comparison of Di*ff*erent Methods*

In order to further evaluate the proposed local coding method, here we compare it with some common feature extraction methods (LBP [16], GLBP [20], LLBP [17], SLGS [23], and MOW-LGS [24]). The ROCs are plotted in Figure 15, and the simulation results are listed in Table 4.

**Figure 15.** Comparisons of different methods.

**Table 4.** Comparisons on EER (%) and time cost (single individual).

From Figure 15, we observe that the EER of the proposed approach is lowest among these feature extraction methods. Hence, feature expression based on the proposed coding approach can effectively address the problem of illumination and finger posture variation in finger trimodal fusion recognition.

From Table 4, we can clearly see that the proposed local coding algorithm not only produces the best recognition accuracy, and also that the computation cost of feature extraction is also lowest as compared with other methods. This shows that our method is more robust to finger feature representation.

#### **7. Conclusions**

In this paper, a posture correction approach was first designed for reducing the finger pose variation. To solve the problem that the feature expression method was sensitive to illumination variation and posture rotation, a novel local coding algorithm was proposed for finger trimodal fusion recognition. On the one hand, the Gabor filter, to some extent, can effectively reduce the influence of illumination and noise in an image. On the other hand, the posture correction method and the local coding method were used to address the problem of finger posture variation. The proposed Gabor-GSLGS algorithm made full use of the texture features in multiple orientations between surrounding pixels. Furthermore, the proposed method assigned the same weights in symmetrical pixels, which improved the equilibrium

of the feature representation of the finger images. The experimental results showed that our method could improve the accuracy and computational efficiency of finger trimodal fusion recognition.

As part of our future work, we will apply the proposed local coding algorithm to other public biometric databases. Moreover, we will focus on reducing the dimensions of the feature vector and improving the efficiency of finger multimodal fusion recognition. At the same time, we will aim to exploit a more robust and effective fusion method which can integrate multiple modal features for personal identification.

**Author Contributions:** S.L. and H.Z. conceived and designed the experiments; S.L. performed the experiments and analyzed the data; S.L., H.Z., Y.S. and J.Y. wrote the paper.

**Funding:** This work is supported by the National Natural Science Foundation of China (No. 61806208, No. 61502498) and the Fundamental Research Funds for the Central Universities (NO.<PHONE_NUMBER>).

**Conflicts of Interest:** The authors declare no conflict of interest.


**5. PLM decision support tool for supply chain optimization**

#### **5.1. Functional specifications of the tool**

The proposed tool helps decision-makers with decisions about supply chain design in the product development phase [12].

We model the expected characteristics of the tool using the unified modeling language (UML) that allows the conceptualization, construction, and manipulation of data. The tool must maintain the PLM approach focused on the product; it must allow to:

We present in **Figure 2**, the flowchart of our methodology. As the digital mockup is the heart of PLM, it is the center of our proposed methodology flowchart, and all the operations are made around it. First, the designer receives constraints from the existing elements of the supply chain and from the customer specifications. The designer must also anticipate the constraints of the nonexisting elements (e.g., the designer should think about the transportability of the product by optimizing volume, shape, etc. even if the transporter is not yet determined). The purpose of the proposed methodology is to better adapt the product to the existing elements

The proposed tool helps decision-makers with decisions about supply chain design in the

We model the expected characteristics of the tool using the unified modeling language (UML) that allows the conceptualization, construction, and manipulation of data. The tool must

of the supply chain and design the rest of the supply chain optimally.

maintain the PLM approach focused on the product; it must allow to:

**5.1. Functional specifications of the tool**

**Figure 2.** Flowchart of the proposed methodology.

96 Product Lifecycle Management - Terminology and Applications

product development phase [12].

**5. PLM decision support tool for supply chain optimization**

The tool consists essentially of three modules that represent the main methodological steps proposed in the previous section (**Figure 3**).

Product design module: An interface must be implemented between the tool and computeraided design (CAD) software. The designer imports a CAD file to retrieve data relating to the digital model (product nomenclature, component characteristics (physical, geometrical, etc.)).

**Figure 3.** The three modules that make up our decision support tool.

The criteria for stopping the optimization process will be the cost of the product along the supply chain. A check with an objective cost will validate or not each design. This work is done by the decision-maker or the project manager. This person will feed the database and will be able to correctly fill in the information related to the product and the supply chain.

#### **5.2. UML modeling**

### *5.2.1. Use case diagrams*

The use case diagram for modeling the product architecture describes the procedure for introducing all product components and their properties (**Figure 4**).

During the design phase of the supply chain, the decision-maker identifies the existing links in the chain as well as the new links to be determined. It defines the link of succession of the different links which will make it possible to specify the order in which the optimization of the supply chain will be done point by point (**Figure 5**).

**Figure 5.** Use case diagram-Supply chain structure modeling.

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99

http://dx.doi.org/10.5772/intechopen.81272

**Figure 6.** Use case diagram—Supply chain optimization.

Optimizing the cost of each link in the supply chain involves introducing the data relating to each link, necessary for the mathematical resolution on the CPLEX software. Once the optimization results are obtained, the cost of the product throughout its supply chain is calculated and compared to an objective reference cost. Finally, the decision-maker validates the design of the product/supply chain pair or decides to modify some links in the supply chain or to act on the product design (digital model) as shown in **Figure 6**.

#### *5.2.2. Class diagram*

This class diagram is based on our proposed methodology for the simultaneous design of product and its supply chain; it integrates the variables of the optimization mathematical models relating to each link (ou element) of the supply chain [13] (**Figure 7**).

**Figure 4.** Use case diagram-Product architecture modeling.

**Figure 5.** Use case diagram-Supply chain structure modeling.

• Transport: transport cost and optimal quantity to transport (from the production site to the

The criteria for stopping the optimization process will be the cost of the product along the supply chain. A check with an objective cost will validate or not each design. This work is done by the decision-maker or the project manager. This person will feed the database and will be able to correctly fill in the information related to the product and the supply chain.

The use case diagram for modeling the product architecture describes the procedure for intro-

During the design phase of the supply chain, the decision-maker identifies the existing links in the chain as well as the new links to be determined. It defines the link of succession of the different links which will make it possible to specify the order in which the optimization of

Optimizing the cost of each link in the supply chain involves introducing the data relating to each link, necessary for the mathematical resolution on the CPLEX software. Once the optimization results are obtained, the cost of the product throughout its supply chain is calculated and compared to an objective reference cost. Finally, the decision-maker validates the design of the product/supply chain pair or decides to modify some links in the supply chain or to act

This class diagram is based on our proposed methodology for the simultaneous design of product and its supply chain; it integrates the variables of the optimization mathematical

models relating to each link (ou element) of the supply chain [13] (**Figure 7**).

• Warehouse: cost of storage and optimal quantity to store in each warehouse.

warehouse and from the warehouse to the customer).

98 Product Lifecycle Management - Terminology and Applications

ducing all product components and their properties (**Figure 4**).

the supply chain will be done point by point (**Figure 5**).

on the product design (digital model) as shown in **Figure 6**.

**Figure 4.** Use case diagram-Product architecture modeling.

**5.2. UML modeling**

*5.2.2. Class diagram*

*5.2.1. Use case diagrams*

**Figure 6.** Use case diagram—Supply chain optimization.

• Technological by bringing together all the actors around the digital mockup; it structures

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In our future work, we will implement the proposed methodology in two types of industries with different specifications: the agro-food packaging industry and the automotive industry.

[1] Barratt M, Barratt R. Exploring internal and external supply chain linkages: Evidence

[2] Zhu W, Gavirneni S, Kapuscinski R. Periodic flexibility, information sharing, and supply

[3] Kiritsis D, Bufardi A, Xirouchakis P. Research issues on product lifecycle management and information tracking using smart embedded systems. Advanced Engineering

[4] Tang D, Qian X. Product lifecycle management for automotive development focusing on

[6] Garetti M., Macchi M., and Van De Berg R. Digitally Supported Engineering of Industrial Systems in the Globally Scaled Manufacturing, IMS-NoE SIG White Paper, Milano; 2003

[7] Terzi S. Element of product lifecycle management: Definitions, open issues and refer-

[8] Sudarsan R, Fenes SJ, Sriran RD, Wang F. A product modeling framework for product

[9] Vezzetti E, Moos S, Kretli S. A product lifecycle management methodology for supporting knowledge reuse in the consumer packaged goods domain. Computer-Aided

[10] Paviot T. Methodology for Resolving Interoperability Issues in the Product Lifecycle

Management Domain [Thesis], Ecole Centrale de Paris (France); 2010

[5] CIMdata: Product Lifecycle Management. Empowering the Future of Business; 2003

from the field. Journal of Operations Management. 2011;**29**(5):514-528

chain performance. IIE Transactions. 2010;**42**(3):173-187

supplier integration. Computer in Industry. 2008;**59**:288-295

ence models, Phd thesis, University of Nancy I; 2005

lifecycle management. Computer-Aided Design. 2005;**37**

• Mathematical by optimizing the costs of the different supply chain partners.

the supply chain design.

**Author details**

Imane Bouhaddou

**References**

Address all correspondence to<EMAIL_ADDRESS>
Informatics. 2003;**17**(3/4):189-202

Design. 2011;**43**:1902-1911

National High School of Arts and Crafts, Meknes, Morocco

**Figure 7.** UML class diagram modeling the proposed methodology.


**2. Alternative Perspectives in Global Governance**

After the collapse of the bi-polar world in the 1990s, there was a tendency to a post-democratic era and the transformation of what we knew as liberal democracy. The ideological basis of this tendency is that all individuals in the planet possess human rights. Transnational frameworks, norms, international institutions and international NGOs, claiming to represent a global civil society, are anchoring on the human rights basis, questioning representative majority-rule democracy and the nation-state's credibility, sometimes reducing its sovereignty. Around this project of a global civil society, a new transnational elite has been built with "corporate" interests in its success.

At the same time, we experience the ascent of another tendency within mainly Muslim societies and Muslim communities in the West, which seeks a new post-democratic world based not on human rights but on "just order". This "just order" is not founded on ideological, egalitarian, class-structured premises but on absolute submission to God's sovereignty, transcending and sometimes questioning the nation-state's sovereignty or any other human-built structure. Around this project huge networks of violent and non-violent disposition have been built with millions of members, who also pursue an alternative global governance scheme, the global Ummah.

"Just order" in Islam means the merger of faith and law in the individual's life. According to Abdulaziz Sachedina, a rather modernist Muslim thinker, such a merger creates a sense of security and integrity in the individual and in the collective life of the community and leads to social harmony (Sachedina 2006, p. 8). The separation between law and faith results in chaos, confusion and violence and thus destroys the community of the faithful. Ultimately, submission to an all-encompassing God is the only condition for the creation and maintenance of justice in the society and equity on earth. Particularly for political Islam (Islamists), there is no other sovereignty than God's, and there is no di fferentiation between the public sphere and the individual. Islam is a religion first and foremost of the public realm.

What is more, contrary to the western liberal paradigm, Muslim just order reasons about political matters in religious terms, debating whether the Qur'an allows loyalty to the state, support for democratic institutions, political participation, equal rights for women or participation in a particular war. In these and other ways Islamists introduce a theological form of political reasoning in which others cannot participate but by whose outcome they are deeply a ffected. Some of them even consider democracy as a sort of polytheism since sovereignty rests on people and not on a unitary and all-encompassing God. This does not mean that the Islamists do not participate in electoral procedures and other functions of liberal democracies, but they are doing so on a contractual manner, or by using norms and institutions for promoting the Muslim community and faith.

For various reasons, and out of multiple developments, such views have a growing impact in Muslim communities. These now exceed 1.8 billion individuals, they have high birth rates and they are the majority in 55 states, one of them a nuclear power, with more than 60% of the planet's energy resources (SESRIC 2012) and, for the first time in history, large communities in non-Muslim states, particularly in Europe (Lipka and Hackett 2017).

As has been noted by Bikhu Parekh, "international events played an important part in reinforcing the consciousness of Islamic identity". The Iranian revolution, the Afghan Mujahidin resistance to Soviet occupation and the Muslim struggle against injustices and oppression in di fferent parts of the world gave Muslims common global causes and sharpened the awareness of the Ummah or the global Muslim community. The growing influence of religious institutions generously funded by the oil-rich Muslim countries, especially Saudi Arabia, reinforced this trend (Parekh 2008, pp. 8–9).

The Islamic Ummah can be seen as a macro level ideological structure, with geopolitical, institutional underpinnings and political structures comparable to the ideological structure of global liberalism, which today dominates notions of global governance (Adamson 2005, p. 548). In the field of finance and economy, there is a fast-growing development of an Islamic model, in compliance with Shari'a law entrepreneurship. Islamic financial and banking activities reached an impressive size of around USD 2 trillion in 2014 (The Economist 2014). During the last few years, expansion of Islamic financial instruments has also embraced a huge variety of modalities. The Islamic social finance o ffers an alternative view on finance which includes Zakat (almsgiving), Waqf (endowments), Sadaqah (charity) as well as Qardh al-hasan (interest-free loans) and focuses on socially beneficial activities. The total amount of Islamic social finance exceeded, in 2018, the USD 2.5 trillion assets of the commercial Islamic finance sector, with Zakat alone reaching USD 1 trillion per year (Rehman 2019).

A wide network of satellite TV and internet sites have been mushrooming, creating a sort of imagined Ummah, in a way parallel to that of publishing in the formation of modern European identities. Moreover, there is a growing number of varying organisations that promote the Islamic faith and Islamic way of living. Some analysts tend to admit that the Islamic organisations, be it political, educational, violent or non-violent, have used the internet and the information age more e fficiently than the political structures of global liberalism. Muslim youth in Britain and Muslim girls in France led the battle for Islam, quite often against the wishes of their parents, and demanded that the state should recognize, respect and make public space for it. By the late 1980s, Islam became a powerful political presence in Europe, its power deriving from its number, militancy, firm sense of identity, and global connections. Moreover, organisations of mixed political, social and preaching purposes are dominating Muslim communities and societies, and recruit thousands of members. Hizb-ut-Tahrir, perhaps the most globalised of them, is currently active in over forty countries. One of its main websites has seven languages listed: Arabic, Turkish, Russian, English, German, Urdu and Danish.

Features of Islamic Ummah can connect the local with the global, questioning at the same time the Western definitions for the state. Saudi authors of jihadist texts adopted the idea that the first state of Saudi Arabia in the late 18th century was "a political entity unbounded by defined territorial boundaries, unrecognized by the international community, and uncontaminated by international treaties and legal obligations. The first state is a local political configuration that defied regional and international contexts and promised to make true Islam hegemonic. They regard this state as a revival of the state of prophecy where the community was subject to divine law. Membership was determined not by recognized frontiers but by submission to the rightful Imam, whose authority over distant territory was recognized by paying zakat, receiving his judges, and performing jihad under his banner" (Al-Raseed 2008). Hence, since the present Saudi state cannot represent the model, as according to the same narrative it is corrupted and dependent on infidel powers, then the true Islamic identity should be sought not in local concepts but in global ones, in a reterritorialized utopia, which is again unbound by external constraints, the global Muslim Ummah.

### **3. The Challenges to the Global and Regional Order**

In the dawn of the third decade of the 21st century, there are three challenges that transform the global order and regional politics in the Middle East. First, there is a serious challenge to the nation-state. The formation of nation-states in the Middle East was based on the uprooting of local cognitive traditions and the imposition of western secular "rational" norms and bureaucratic frameworks. They exerted high pressure on religion in order to move it to the private sphere and placed religious institutions under strict state control. National liberation movements tried to reconstruct religious traditions in order to fit to their secular ideology instead of enriching their ideological repertoire with these traditions. The failure of these states to establish a credible social contract, their rampant corruption, cruel coercive mechanisms and inability to solve chronic socio-economic problems and their failure, particularly in Syria and Iraq, to unite di fferent ethnoreligious groups under the banner of a cohesive national project led to a complete de-legitimization of the secular nation-state and its "rational" underpinnings. As a result, various Islamic movements and hybrid political entities tried to resist against or substitute for the failed secular model.

The conflicts of Syria, Iraq, Yemen and Libya led to the fragmentation of these countries to alternate layers of hybrid politico-military entities which connect to each other by religious, ethnic/tribal or local bonds. The challenge in these cases is much more intense, more so since Syria and Iraq belonged to the core of the Arab order and were characterized by an almighty and ideologically consolidated domestic sovereignty. Even Egypt faced a threatening jihadist insurgency in the Sinai, something rather unimaginable for the strong Egyptian state two decades ago.

Second, there is a challenge to global order. We are in the midst of widespread "disruption" or incoherence of what we know as global order. Hardt and Negri have argued that the "planetary networks of social production and reproduction and the constitution of global governance are increasingly out of sync." (Hardt and Negri 2019, pp. 68–69). Regional powers are not ready to acquiesce to the hegemonic role of the superpower in their region. Powers such as China, Russia, India, Iran, and Turkey act with a large degree of autonomy, without, however, challenging the superpower's preponderance in the global scale.

There was a sharp increase of the occurrences of civil war in the last two decades, reaching fifty-two instances in 2015, the highest number of civil conflicts in the modern era. These conflicts have a high degree of internationalization as they are transformed into regional conflicts with the participation of regional and global powers. At the same time these conflicts are not waged in delimited areas as it was the case with national liberation movements, but they are scattered in many areas beyond certain borders (Fearon 2004). In such fragmented international and regional environments politico-military, non-state actors have become the third challenge to global and regional order. State-like actors like the Kurdish entities in Iraq and Syria and Hamas in Gaza, states-within-states like Hezbollah and hybrid states such as the "Islamic State" have been shaping regional order in the last decade. Particularly religious politico-military non state actors have worked as mechanisms of inclusion into a privileged collective self and of the exclusion of "others".

The ascent of the "Islamic State" and its consolidation through hybrid state structures for a considerable period of time has been the most serious challenge to the Middle East nation-state. It is the first time that a state was set up by a multiethnic body politic without a dominant ethnic group. The "Islamic State" fostered a neo-medieval global order regarding borders and divine sovereignty and it transcended nation-state's constants, appropriating at the same time functions of the secular state (Eleftheriadou and Roussos 2018). The "Islamic State" was fast to outline what it has to o ffer to its "citizens", reminiscing and echoing previous social contracts (employment, welfare and health services) between the regimes and their citizens in the 20th century. These benefits and services provided an attractive alternative to the Sunni communities under "Islamic State's" control, especially in Iraq, given their marginalization and absence from the political and military scene as well as unemployment. The insecure Sunni communities that demonstrate a regression in human development had not any choice to opt out of its "benefits and services".

After the eruption of civil strife in Syria and Iraq, widespread violence and harassment, mainly by jihadist groups, came to substantiate fears for extinction of the Christians and other minorities in the region (CRPME 2016). Various jihadist groups have perpetrated ongoing ethnic cleansing. Regional antagonism in both Syria and Iraq has further exacerbated the conflicts, ignoring the dangers for non-Muslim communities. The churches' leadership initially tried to balance between its past co-optation policy with the regime and the growing instability and insecurity on the ground, more so since their faithful is territorially dispersed and the control on the ground is shifting. Middle Eastern churches are becoming increasingly diasporic instead of regional. Large numbers of Middle Eastern migrants and exiles in the Americas, Europe and Australia have been the basis of flourishing Eastern churches' parishes and bishoprics overseas. This means that Middle Eastern Christianity is linked to a world religious tradition.

Regional and global upheavals brought serious changes in the survival strategies of the Christian communities in the Middle East. First, Christians in the Middle East, particularly in Syria and Iraq, are facing a great danger of extinction resembling the genocides and mass exodus of Christians in the region during the First World War, and are bound to radically re-consider their survival strategies. Second, this might be the time the state in both Syria and Iraq is to rebuild in a federal and decentralized form. Third, the role and position of minorities, of the Christians in particular, in this state-rebuilding process would be the real test on what direction this process would take: towards a more decentralized and open to the world state, or towards autocratic federal states, where strong ethno-religious communities would reign over smaller groups. These questions will certainly be at the center of the debates for the future Middle East in the coming decade and attract the interest of global church actors, the Catholic and the Russian Orthodox Church.

### **4. Studying Religion and International Relations in the Middle East**

This Special Issue falls into the fields of "Area Studies" and of "Religion and Politics". As A. Acharya and B. Buzan pointed out "Area Studies should be a main location for sub-systemic theorizing", that is, to produce new knowledge (Acharya and Buzan 2007, p. 291). Today's Area Studies should produce patterns of theorization that consider non-Western International Relations perspectives (Katzenstein 2001, pp. 789–91).

The chapters are divided into three parts. The first includes two articles that deal with the contribution of religion to a post-Western turn in international relations in the Middle East and beyond. Mariano Barbato argues that an expansion of the post secular approach to a power politics of becoming would allow to grasp important trends that strive to integrate the plurality of the region beyond the exclusivist closures of secularist Pan-Arabism or religious Political Islam. The article discusses the post secular conceptual framework of Jürgen Habermas and William Connolly in order to expand their approaches to the analysis of the Middle East. Anna Solarz addresses the search for religion's "suitable place" within IR, taking as a starting point the social changes in the world and the postulated "Mesopotamian turn" in IR. She suggests that, through comparison and contrast with life in societies of the Middle East as it is in practice, religion has been incorporated quite naturally into IR, undermining, at the same time, the "Westphalian presumption".

The second part focuses on the role of state-like non-state actors (ISIS). Marina Eleftheriadou explores the implications of 'Islamic State's' (IS) rise on the international order and the salafi-jihadi movement. She argues that, in its capacity as a de facto revolutionary state, IS challenged the international order because, contrary to revolutionary states in the past, it negates the foundations of the Westphalian system. At the same time, the rise of IS had a tremendous impact on the jihadi (sub)system, as it initiated a period of fragmentation and alliance-building.

The third part focuses on the impact of religion on foreign and security policy (Israel, UAE, UK, Saudi Arabia). Panos Kourgiotis studies the ideological use of religion in the international relations of the United Arab Emirates during the Arab Spring and beyond. His essay examines the politics of 'moderate Islam' and argues that even though 'moderate Islam' has been devised for creating 'soft power', it serves 'sharp power' as well. Moria Bar-Maoz explores how religion has been shaping each of the stages of the decision-making process in which Israeli decision makers have been formulating national security policies since the beginning of the 21st century, focusing on two security issues:

terrorism and nuclear weapons. The paper argues that the stage in which decision makers identify and assess a threat to national interest has been greatly influenced by Israeli policymakers' operational perceptions on the relations between religion and security. Ihab Shabana studies Britain's encounter with the rise of political Islam in the Middle East and North Africa region and the way(s) that this phenomenon was (were) deciphered. He argues that British o fficials adopted four analytical schemas that concentrated on the rise of sectarian politics in MENA, the gradual accommodation of non-state actors and organizations in the political analysis, the prospect of an alliance between Islamist and communist forces and last, the prevalence of the idea of Islamic solidarity and Islamic exceptionalism in exerting international politics. Stella Athanassoulia explores the position that religion holds in the Saudi perceptions of stability in the post-2011 era, where safeguarding the status quo remained the priority, while the new administration responded to pressure by shifting towards a 'hard power' foreign policy with questionable results. At a second stage, the paper explores the links between foreign policy choices and internal challenges, namely the promotion of a new, modern image for the kingdom where the notion of 'moderate Islam' has been instrumentalized in order to support the 'Vision 2030' reform program.

This Special Issue explores the contribution of religion in reshaping modernity's contour of International Relations theories in the Middle East and beyond. Hence, it has a twofold purpose: first, to question main presuppositions and perceptions regarding religion and international politics in the Middle East and, second, to reflect on the role(s) of religion in the regional order.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The author declares no conflict of interest.


**3.3 ALK translocations**

ALK gene mutations, copy number changes, or fusion with other genes have oncogenic effects. Similar to EGFR mutations, translocations of ALK are predictive of response to Tyrosine Kinase Inhibitors (TKIs) [54]. ALK testing is mostly recommended for non-squamous cell lung cancers lacking EGFR mutations. The fusion between ALK and EML4 (echinoderm microtubule-associated protein-like 4) produces molecular variants with diverse biological functions and affects various signaling pathways [55, 56]. The incidence of cerebral metastases in NSCLC with ALK mutations is high and ALK translocations of primary tumors and their brain metastases are often similar. Interestingly, the progress of brain metastases of tumors with ALK mutations slows down significantly when treated with targeted therapy: over 45% of patients with BM had overall survival rates of three years [57]. Because nearly 45% of patients with ALK-positive NSCLC have developed BM at death [58], cerebral seeding is an important clinical challenge for developing strategies for personalized care in NSCLC [59].