Supportive Therapies of Acute Respiratory Distress Syndrome: Comparison
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The management of acute respiratory distress syndrome (ARDS) has made considerable progress both regarding supportive and pharmacologic therapies. Lung protective mechanical ventilation is the cornerstone of ARDS management. ARDS therapies have remained supportive, concentrating on the concept of protective mechanical ventilation strategies with the aim of mitigating ventilator-induced lung injury (VILI). Lung protective ventilation is standard practice, but the use of neuromuscular blocking agents and prone positioning are rescue strategies.

  • ARDS
  • acute respiratory distress syndrome
  • mechanical ventilation

1. Tidal Volume

The cornerstone of lung protective ventilation is the ARMA trial, which demonstrates that a low tidal volume (VT) equal to 6 mL/kg predicted body weight (PBW) compared with a higher VT of 10–12 mL/kg PBW improved survival [1]. Recent trials and meta-analyses [2][3][4] recommend the use of low VT; however, low VT ventilation is often underutilized for acute respiratory distress syndrome (ARDS) [5]. A multicenter international prospective observational study across 50 countries including 3022 patients with ARDS (LUNG SAFE trial) reported that ARDS was recognized only 60% of the time by clinicians, and less than two-thirds of patients with ARDS received a VT ≤ 8 mL/kg PBW [6]. A study with 482 patients with ARDS found that every 1 mL/kg increase in VT above 6.5 mL/kg was associated with a 23% increase in mortality in the ICU (intensive care unit) [7]. In addition, patients exposed to lower VT (6 mL/kg PBW) from the beginning had an overall lower risk of ICU mortality compared with those who received higher VT (8–10 mL/kg PBW) followed by lower VT [7]. This is in contrast to the ARDSNet trials, which reported that ventilation with high VT within the initial 48 h was not associated with increased hospital mortality [1].
Lung protective ventilation targeting low VT and plateau pressure (Pplat) should start in the emergency department (ED). The LOV-ED investigators [8] found that the implementation of an ARDS protocol in the ED with low VT and Pplat resulted in higher probability of using low VT in the ICU, leading to less risk of ventilator-induced lung injury (VILI) and lower mortality.
Current guidelines and clinical approaches suggest individualizing mechanical ventilation according to patient and disease characteristics targeting a VT of 4–6 mL/kg without exceeding a VT of 8 mL/kg PBW and target Pplat of ≤ 30 cmH2O [9] because higher values contribute to an overdistention of alveoli, leading to lung damage and mortality [10].

2. Positive End-Expiratory Pressure and Alveolar Recruitment

The application of positive end-expiratory pressure (PEEP) results in benefits such as alveolar recruitment, reduction in intrapulmonary shunt, and increased arterial oxygenation [11]. Experimental studies demonstrated that PEEP could prevent possible lung injury from cyclic opening and closing and therefore protect patients from VILI by maintaining alveoli open that would otherwise become atelectatic or flooded at end-expiration (recruitment) [12]. However, PEEP also accounts for detrimental effects including increased end-inspiratory lung volume and increased risks of volutrauma and VILI by increasing lung stress and strain [13]. PEEP reduces cardiac output because a certain level of PEEP may increase pleural pressure and right atrial pressure, thus reducing venous return [14]. PEEP also increases pulmonary vascular resistance by narrowing or occluding alveolar septal vessels, thus increasing right ventricular afterload and further reducing cardiac output [14][15].
Four large randomized clinical trials (ART [16], ALVEOLI [17], ExPress [18], and LOV trials [19]) enrolling 3264 patients have compared higher PEEP (approximately 15 cmH2O) with lower PEEP (approximately 8 cmH2O or 13 cmH2O in the ART trial), and all failed to improve survival with higher PEEP, even if a trial suggested a survival benefit in sicker patients [20]. Interestingly, the ART trial reported higher mortality in the presence of high PEEP levels. This was not solely related to high PEEP levels; an extensive recruitment maneuvers (RMs) approach was also applied. Therefore, the underlying pathophysiology, lung mechanics, and degree of recruitability need to be monitored to evaluate the effects of PEEP. The explanation for these controversies may be associated with the application of PEEP in an unselected population, thus leading to overdistension and lung damage [21]. Moreover, high PEEP levels may result in detrimental hemodynamic effects, thus increasing shunt, dead space, and right ventricle afterload as well as reducing cardiac output [14][15]. The assumption that higher PEEP may lead to recruited lung units is not often observed, and it may result in overinflation and reduced lung compliance [22]. In the study by Constatin et al. [23] (the LIVE study), the authors adjusted the PEEP level as well as other strategies according to lung morphology. Patients in the control group received VT of 6 mL/kg PBW and PEEP in accordance with a low PEEP and FiO2 table. Early prone positioning was encouraged. Patients with focal ARDS in the customized group underwent treatment with a VT of 8 mL/kg, minimal PEEP and prone positioning according to the morphology of their lungs at imaging. Patients with non-focal ARDS received recruitment maneuvers, high PEEP, and a VT of 6 mL/kg. This is an example of an attempt to personalize mechanical ventilation according to the pattern of disease.

3. Driving Pressure and Plateau Pressure

Driving pressure (∆P) or distending pressure represents the ratio between VT and respiratory compliance, which can be easily obtained by Pplat−PEEP at the bedside [24]. ∆P offers an accurate picture of optimal lung mechanics in ARDS by estimating VT and respiratory compliance, which correlates with aeration of the lung. Therefore, driving pressure represents an easy estimator of strain (VT/aeration of the lung at end-expiration) in ARDS.
The concept of “baby lung” in ARDS was defined as the fraction of lung parenchyma that still preserves normal inflation. Its size depends on the severity of ARDS and relates to static lung compliance. ∆P depends on the VT as well as on the relative balance between the amount of aerated and/or overinflated lung at end-expiration and end-inspiration at different levels of PEEP [25].
In a retrospective analysis of 150 sedated and paralyzed patients with ARDS, Chiumello et al. [26] performed a PEEP trial from 5 to 15 cmH2O at a constant VT and respiratory rate (RR), observing that at both PEEP levels, the group with higher driving pressure had significantly higher lung stress and lung elastance. Studies have reported the association between driving pressure and mortality in patients with ARDS and brain injury [27][28][29], suggesting the importance of using driving pressures as a strategy to target VT and PEEP maintaining low stress. The LUNG SAFE study [30] showed that Pplat, PEEP, and ΔP were associated with ARDS prognosis and ΔP < 14 cmH2O was associated with decreased risk of hospital mortality in patients with moderate to severe ARDS. A recent study from Villar et al. [10] reported that Pplat was a more important determinant of mortality and outcome than ΔP. A meta-analysis of nine prospective trials involving more than 3500 patients showed that even when using lung protective ventilator settings (Pplat ≤ 30 cmH2O and VT ≤ 7 mL/kg IBW), ΔP was the physical variable that best correlated with survival in patients with ARDS [27]. In conclusion, the literature suggests that ΔP should be kept below 13–15 cmH2O and used in association with low VT and Pplat < 30 cmH2O as well as the lowest PEEP that can keep oxygenation at an acceptable value [31].

4. Slower Is Better

Lung tissue presents a viscoelastic behavior. It implies that stress is not constant during a sustained constant strain; for example, when the lungs are maintained inflated at a constant volume, the transpulmonary pressure decreases progressively with time. Tissue deformation can be expressed as strain, which is defined as the ratio of VT over the end-expiratory lung volume for the lung. Strain has been used to determine safe thresholds of VT to prevent VILI. In addition, the “strain rate” is the change in lung strain (deformation) with respect to time. Longer times are related to lower strain rates and shorter times are related to higher strain rates. This mechanism can be discussed within all the components of mechanical ventilation. Of utmost interest but never considered is the time at which the changes in ventilator setting are made [32]. As said before, ventilatory parameters do not always account for different time constants at both inspiration and expiration as well as inhomogeneity and heterogeneous ventilation of different alveolar units. Alveolar inflation and deflation manifest at different timings, even in a healthy lung; thus, at low inspiratory time constant, alveoli easily inflate, whereas at high inspiratory time constant, alveoli need more time to completely inflate. This reflects that at a high RR, even at a low time constant, alveoli will have less time to inflate. RR is often underconsidered, but recent findings have suggested its association with mortality and VILI [33]. Given the so-called stress relaxation of the lungs, parenchymal damage can be observed depending on how fast VT or strain is modified for a period of time. Changes to VT are often made abruptly, although the extracellular matrix requires a time of stress relaxation to mitigate the strain. It has been found that when the time of adaptation is shorter rather than abrupt, this attenuates lung injury. However, when the adaptation time is longer, this leads to more lung damage, suggesting that injurious strain is initiated in every case but can be decreased when using a shorter adaptation time [34]. RMs associated with improved oxygenation and lung mechanics have been identified as a potential cause of VILI. RMs need to exceed the critical opening pressure of the small airway to be effective [35], and alveoli recruit with a different time constant in heterogeneous lungs, thus requiring different timings to open each alveolar unit. This highlights the importance of rapid versus slow increases, given that sudden changes in airway pressure and flow increase stress and worsen lung damage [36]. Less VILI was observed in gradual versus abrupt increases in airway pressure [37]. In a recent meta-analysis, the use of stepwise increases in PEEP and/or RMs did not result in survival or less barotrauma compared with a strategy using a PEEP targeted at acceptable oxygenation goals [38]. However, the Survival Sepsis Campaign [39] does not indicate the use of stepwise RMs but instead advises abrupt increases given the results of the ART trial [16] and the PHEARLAP trial [40]. Focusing on PEEP, a recent study showed that lung damage can occur after sustained inflation followed by abrupt deflation, and this can be led by hemodynamic impairment followed by an increase in pulmonary microvascular pressure [41]. Similarly, Rocha et al. [42] investigated an abrupt versus gradual PEEP release combined with standard or high fluid volumes, finding that an abrupt reduction in PEEP, regardless of fluid status, causes greater epithelial cell damage and increases pulmonary arterial pressure. There are several other examples in the literature that may deserve further discussion.

5. Mechanical Power

Mechanical power (MP) is the amount of energy transferred by the mechanical ventilator to the respiratory system per unit of time and is determined by the combined effects of applied VT, ∆P, RR, inspiratory flow, and PEEP, as well as determinants of mechanical properties of the lung (e.g., respiratory system elastance and airway resistance). MP might be a more accurate parameter for lung protective ventilation because it considers the balance of all individual ventilator parameters. MP is calculated using the following formulas: in volume-controlled ventilation, MP = 0.098 × VT × RR × (Ppeak,RS − ΔP,RS/2); in pressure-controlled ventilation, MP = 0.098 × VT × RR × (ΔP,RS + PEEP). An observational study found no causal relationship between the mechanical power and mortality, and MP normalized to the compliance or to the amount of well-aerated tissue was independently associated with ICU mortality [43]. In general critically ill patients, MP > 17 J/min was associated with higher mortality [44]. MP > 22 J/min was associated with increased 3-year mortality and 28-day mortality in patients with ARDS [45]. In a recent experimental study, MP > 25 J/min caused more significant and potentially lethal lung damage than lower values [46]. Similarly, in patients treated with extracorporeal membrane oxygenation (ECMO), MP > 14.4 J/min, during the first 3 days, was the only ventilatory variable independently associated with 90-day hospital mortality [47]. However, the benefit of MP is unclear, and its clinical use is limited by the complexity of measuring and interpreting it, and other variables, such as ∆P, are easily measurable at the bedside and are also predictive of mortality. Another interesting new parameter is the formula of Costa et al. [33] (4 × ∆P) + RR, which showed significant association with mortality (hazard ratio = 1.152, 95% confidence interval (CI) = 1.040–1.276, p = 0.006) and poor neurologic outcome (odds ratio = 1.244, 95% CI = 1.015–1.525, p = 0.036) with a better performance compared with MP in patients after cardiac arrest without ARDS. Despite its potential advantages, this formula has been tested only as an observational association with outcome and deserves further investigation. This formula has been studied recently in patients without ARDS post-cardiac arrest. In the secondary analysis from Robba et al. [48], the composite formula calculated as (4 × ΔP) + RR was independently associated with mortality and poor neurologic outcome. This shows that after cardiac arrest, ventilator settings (specifically ∆P and RR) in the first 3 days after hospital admission influence patient outcomes at 6 months.

6. Other Modes of Ventilation

Airway pressure release ventilation (APRV) is a ventilatory modality that uses continuous positive airway pressure and a partial and short release phase of ventilation that allows the patient to breath spontaneously [49][50]. The patient breaths spontaneously for a predetermined time with a high pressure of 20–30 cmH2O, decreasing to a low pressure according to the elastic recoil of the respiratory system, which is maintained with an expiratory flow around 25–50% of the maximum value [49]. The high and low pressures are usually set according to the P/V loop. In a recent meta-analysis, this novel ventilatory modality demonstrated good efficacy in improving oxygenation and shortening the ICU length of stay in patients with ARDS [50]. Zhong et al. [51][52] and Sun et al. [51][52] concluded that APRV increases compliance, oxygenation, and hemodynamics in comparison with a lung protective ventilator strategy. In addition, APRV resulted in reduced mortality, duration of mechanical ventilation, and ICU length of stay. Animal models suggest that the use of APRV over controlled mechanical ventilation reduces VILI when used with a VT of 6–8 mL/kg PBW, optimal PEEP, and higher total amount of spontaneous breathing (30%–60% of total ventilation). Transpulmonary pressure seems to be lower in APRV than in controlled ventilation but using an RR equal to 50% of the controlled rate or pressure support equal to P high, avoiding P0.1 > 3–4 cmH2O [53][54][55]. Saddy et al. [53] found that different assisted ventilation modes led to improved lung function and reduced inflammation compared with pressure-controlled ventilation.
High-frequency oscillatory ventilation (HFOV) is another mode of ventilation that has been tested in patients with ARDS with contrasting findings. HFOV is actually not recommended by guidelines for its potential for high intrathoracic pressure, altered hemodynamic response on ventricular preload, pneumothorax, airway obstruction, acidosis, and cellular injury [56]. The potential rationale for its use is that HFOV can limit VILI, using VT equal to or lower than dead space (up to 3 mL/kg), thus using high RRs (around 150 breaths/min) with a bias flow of 5–60 L/min [56]. Alveolar ventilation is determined by the following formula: (f) × (VT)2, thus maintaining a continuous distending pressure and facilitating the elimination of carbon dioxide. Despite proven reduced inflammation in an animal model of ARDS [57], HFOV in patients with ARDS improved oxygenation, but mortality was increased in those patients without severe hypoxemia [58][59][60][61]. This could be explained by the modest tidal volumes produced by HFOV, which are often equal to or lower than dead space. The lungs’ constant mean airway pressure and high respiratory rate both contribute to the maintenance of alveolar ventilation. Guidelines suggest using this modality only in cases of rescue therapy or as a research target in those patients who cannot tolerate high VT and distending pressures.

7. Prone Positioning

Prone positioning in patients with ARDS improves oxygenation, increases recruitment potential, and reduces areas of alveolar overdistension, thus ensuring more homogeneous aeration of the lungs and potentially reducing VILI. The initial evidence from the PROSEVA trial was the first study to show a benefit of the prone position on mortality for patients with moderate to severe ARDS with partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) < 150 mmHg with 60% FiO2 with PEEP of at least 5 cmH2O for at least 16 h until clinical improvement. In this study, prone position was associated with an improvement in mortality at day 28 (16% versus 33%, p < 0.0001), which persisted at day 90 (24% vs. 41%, p < 0·0001) [62]. As learned from COVID-19, the response to prone positioning depends on the redistribution of densities and regional perfusion [63].
International guidelines now recommend that the prone position should be instituted early and ideally within 36 h of meeting these criteria and should be used alongside lung protective ventilatory strategies [9][64].
The low incidence of prone positioning is partly explained by concerns regarding adverse events such as endotracheal tube obstruction, pressure sores, and loss of venous access [65]. However, prone positioning is also resource intensive and should be performed by a trained and experienced team. During ECMO, Giani et al. [66] recently showed that the prone position improved oxygenation, reduced intrapulmonary shunt, and reduced hospital mortality.

8. Extracorporeal Membrane Oxygenation and Extracorporeal Carbon Dioxide Removal

Venous–venous (VV)–ECMO has been considered as a rescue therapy for patients with severe ARDS due to the complications related to it and the controversial evidence. The multicenter CESAR trial [67] compared ECMO with conventional management of ARDS and showed that only 76% (n = 68/90) received ECMO, but this group had an improvement in the primary outcome of quality of life at 6 months. The subsequent EOLIA trial showed a signal toward improvement in mortality (relative risk, 0.76; 95% CI, 0.55–1.04, p = 0.09), but it did not achieve statistical significance, and a subsequent post hoc analysis showed that early ECMO was more beneficial. An individual patient data meta-analysis showed a statistically significant benefit in mortality at day 90 in the ECMO group (relative risk, 0.75; 95% CI, 0.6–0.94, p = 0.013) [67]. ECMO has also been shown to be effective in COVID-19, and a cohort of 7345 patients across five countries showed that ECMO was a deliverable therapy in 844 patients, and patients with a PaO2/FiO2 ratio <80 mmHg indicated ECMO was associated with reduced mortality compared with conventional therapy (relative risk, 0.78; 95% CI, 0.75–0.82) [68]. ECMO may have the ability to support lung protective ventilation and maintain low ΔP because a recent meta-analysis including more than 500 patients showed that ΔP during the first 3 days in ECMO had an independent association with in-hospital mortality [69].
It has been suggested that extracorporeal carbon dioxide removal (ECCO2R) can manage both hypoxemic and hypercapnic respiratory failure. ECCO2R uses a blood flow of around 0.5–1.5 L/min, allowing removal of low-flow CO2 and pH control while avoiding the invasiveness of ECMO. Some studies have suggested that ECCO2R is able to decrease MP and VILI and to maintain oxygenation [70][71]. High-flow VV-ECMO makes it more difficult to optimize oxygenation and CO2 removal given the higher flows adopted (2–4 L/min) [72]. Bein et al. [73] compared low VT ventilation (3 mL/kg PBW) versus the ARDSNet strategy (6 mL/kg PBW) during ECCO2R and found that the use of very low VT had a greater potential to further reduce VILI during ECCO2R. Morris et al. [74] concluded there was no significant difference in survival between the mechanical ventilation and the ECCO2R groups, suggesting that further investigations are needed to confirm whether ECCO2R is effective for ARDS. A recent systematic review of both RCTs and observational studies concluded that evidence is lacking to confirm beneficial effects of ECCO2R on outcome in ARDS, although positive insights about lung protective ventilation and VILI were found [75].

9. Fluid Management

The optimal fluid management in ARDS is still unknown. There are risks and benefits to liberal and conservative fluid management strategies.
FACTT was the defining trial testing the effect of a conservative fluid strategy in ARDS [76]. The trial adopted active diuresis, fluid bolus, vasopressor, and/or inotrope based on varying ranges of central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP). After a week, they found a significant difference in the cumulative fluid balance between the conservative and liberal de-resuscitation groups (−136 ± 491 mL versus 6992 ± 502 mL; p < 0.001). The daily cumulative fluid balance in the liberal group was similar to that in other contemporary ARDS trials (4 L and 6 L by day 4 in ARMA and ALVEOLI, respectively) and consistent with usual care at the time. They found no difference in 60-day mortality in these groups (25% with a conservative strategy versus 28% with a liberal strategy, p = 0.30). The conservative strategy group, however, had significantly more ventilator-free days (14.6 ± 0.5 versus 12.1 ± 0.5, p < 0.001) and ICU-free days compared with the liberal strategy group. Despite the aggressive conservative/de-resuscitation strategy, which targeted CVP lower than 4 mmHg and a PAOP lower than 8 mmHg, there was no increase in organ failure between the conservative and liberal arms of the study. Moreover, there were no significant differences in the percentage of patients receiving renal replacement therapy (10% in the conservative group versus 14% in the liberal group, p = 0.06) or the average number of days on renal support. Since this landmark study, practice in critical care has had a significant shift. These findings suggest that liberal fluid management may be more harmful in patients with ARDS by increasing pulmonary edema and prolonging mechanical ventilation days and ICU and hospital stay. Preventing fluid overload may lead to improved outcomes, and active de-resuscitation may mitigate the lung injury associated with excess intravenous fluids without compromising organ perfusion.
Different ARDS phenotypes may respond differently to fluid management. A recent secondary analysis of the FACTT trial suggests that hypoinflammatory and hyperinflammatory phenotypes could differ with regard to fluid responsiveness. In this study, sub-phenotype 1 was characterized by hypoinflammation and a higher proportion of white patients, whereas sub-phenotype 2 was characterized by hyperinflammation and hypotension. According to the sub-phenotypes, two different responses to distinct fluid strategies were found regarding outcome (p = 0.0039). In sub-phenotype 1, mortality was 26% with a liberal fluid strategy versus 18% with a conservative strategy. In sub-phenotype 2, mortality was 40% with a liberal fluid strategy versus 50% with a conservative fluid strategy [77]. Hence, it is key to determine the optimum volume status in each individual patient and to personalize the patient’s treatment according to the sub-phenotype.

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