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Acute respiratory distress syndrome: Ventilator management strategies for adults

Acute respiratory distress syndrome: Ventilator management strategies for adults
Literature review current through: Jan 2024.
This topic last updated: Jan 25, 2024.

INTRODUCTION — Acute respiratory distress syndrome (ARDS) is a form of lung injury that is associated with a high mortality. Mechanical ventilation and supportive therapies are the mainstays of treatment.

The ventilator strategies used to treat ARDS are reviewed here. In general, these recommendations are in keeping with those issued by several society guideline groups [1-5]. Nonmechanical ventilation related aspects of ARDS management and prone ventilation are discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Prone ventilation for adult patients with acute respiratory distress syndrome".)

SELECTING INVASIVE VERSUS NONINVASIVE VENTILATION — Most clinicians use invasive mechanical ventilation (ie, ventilation via an endotracheal tube or tracheostomy with breaths delivered by a mechanical ventilator) for patients with ARDS, particularly those with moderate or severe ARDS (ie, arterial oxygen tension/fraction of inspired oxygen [PaO2/FiO2] ≤200 mmHg on positive end-expiratory pressure ≥5 cm H2O). Noninvasive ventilation (NIV; ie, ventilation via a mask, nasal prongs, or helmet with breaths delivered by an NIV device) may be reserved for the occasional patient with mild ARDS who is hemodynamically stable, is easily oxygenated, does not need immediate intubation, and has no contraindications to its use. This approach is based upon our experience and conflicting data regarding the benefit of NIV (eg, prevention of intubation, improved mortality) in this population. Importantly, when NIV is implemented, frequent evaluation is necessary and clinicians should have a low threshold for intubation. (See "Noninvasive ventilation in adults with chronic respiratory failure from neuromuscular and chest wall diseases: Patient selection and alternative modes of ventilatory support", section on 'Positive pressure noninvasive ventilation' and "Noninvasive ventilation in adults with chronic respiratory failure from neuromuscular and chest wall diseases: Practical aspects of initiation".)

A small randomized trial reported that compared with high concentration supplemental oxygen via venturi mask, patients with ARDS treated with NIV had improved oxygenation and lower rates of intubation (4.8 versus 36.8 percent) [6]. However, interpretation is limited due to factors including small size, selection bias, lack of blinding, and lack of general applicability based upon the multiple exclusion criteria.

In contrast, a study of patients with hypoxemic respiratory failure, many of whom had ARDS, reported increased mortality in association with NIV when compared with patients treated with high flow nasal cannula [7]. Details of this trial are discussed separately. (See "Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications", section on 'Medical patients with severe hypoxemic respiratory failure'.)

A subset analysis of data from the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) reported that use of NIV in patients with severe ARDS (PaO2/FiO2 ratio <150 mmHg) was an independent predictor for mortality, such that clinicians should be wary of its use in patients with this degree of hypoxemia [8].

The type of mask worn may impact outcome. In a single-center unblinded trial of 83 patients with mild or moderate ARDS, helmet-delivered NIV (figure 1) reduced the need for intubation (18 versus 62 percent) compared with NIV delivered through a full face mask [9]. In addition, helmet-delivered NIV was also associated with a higher rate of ventilator-free days, shorter ICU stay, and lower 90-day mortality without an increase in adverse effects. However, this study was also stopped early, which may have exaggerated the effect size. In addition, helmets are not widely available and expertise in helmet use is low.

NIV failure may be associated with the etiology for ARDS. In one prospective study of 306 patients with ARDS who were treated with NIV, patients who had a pulmonary etiology for ARDS had slower improvement, more NIV failure (55 versus 28 percent), and higher 28-day mortality (47 versus 14 percent) than those who had ARDS due to an extrapulmonary etiology [10].

Most patients with ARDS require intubation and mechanical ventilation. During the peri-intubation period, 95 to 100 percent oxygen should be given to ensure an adequate oxygen saturation. Because oxygen uptake may exceed replenishment in areas with low V/Q ratios, some clinicians use slightly less than 100 percent oxygen (eg, 95 percent) in an attempt to prevent absorptive atelectasis [11]. Once well established, absorptive atelectasis is not rapidly reversed by a reduction of FiO2 to maintenance levels, emphasizing the desirability of limiting prolonged periods of high FiO2 during and following intubation [12]. (See "Direct laryngoscopy and endotracheal intubation in adults" and 'Positive end-expiratory pressure (PEEP), fraction of inspired oxygen, oxygenation target' below.)

LOW TIDAL VOLUME VENTILATION: INITIAL SETTINGS — For patients with ARDS, we and others recommend low tidal volume ventilation (LTVV; also known as lung protective ventilation; 4 to 8 mL/kg predicted body weight [PBW]) (table 1 and table 2 and algorithm 1). LTVV is typically performed using a volume-limited assist control mode, targets a plateau pressure (Pplat) ≤30 cm H2O, and applies positive end-expiratory pressure (PEEP) using a strategy outlined in the table (table 3). This approach is based upon several meta-analyses and randomized trials that report a mortality benefit from LTVV in patients with ARDS. It is thought that low tidal volumes (VT) mitigate alveolar overdistension induced by mechanical ventilation, which can cause additional lung injury and mortality in patients with ARDS. (See 'Efficacy and harm' below and "Ventilator-induced lung injury", section on 'Mechanisms'.)

Despite strong evidence to support the benefit, clinicians underutilize LTVV, perhaps due to under-recognition of ARDS. A 2016 multicenter, international prospective cohort study of 3022 patients with ARDS reported that ARDS was recognized by clinicians only 60 percent of the time, and less than two-thirds of ARDS patients received a VT of ≤8 mL/kg PBW [13]. Data published in 2021 [14] was no more encouraging, with only 31.4 percent of nearly 2500 patients receiving lung protective ventilation as defined as a plateau pressure less than 30 cm H20 and a tidal volume <6.5 mL/kg predicted body weight. In this study, use of early lung protective ventilation was associated with lower standardized mortality ratios. The use of a written protocol outlining how to provide LTVV is associated with enhanced compliance in patients with ARDS [15]. We support the development of institutional protocols that promote LTVV to ventilated patients with ARDS (table 3).

In patients with ARDS, we agree that the use of standard variables (VT and Pplat, lung compliance) should be used to manage ventilator settings. Driving pressure (DP) is being also being increasingly used, although parameters for its use are poorly defined. (See 'Assessment (clinical, gas exchange, plateau and driving pressure)' below.)

Application and titration — LTVV typically involves the following initial steps (table 3):

Choosing volume- or pressure-limited assist-control mode (see 'Volume- versus pressure-limited mode' below)

Setting the initial VT and respiratory rate (see 'Tidal volume and respiratory rate' below)

Setting PEEP and fraction of inspired oxygen (FiO2) (see 'Positive end-expiratory pressure (PEEP), fraction of inspired oxygen, oxygenation target' below)

Volume- versus pressure-limited mode — While practice varies among clinicians, most experts adhere to a strategy of LTVV, using a volume-limited assist-control mode. However, a pressure-limited mode is an acceptable alternative, as long as the resulting tidal volumes are stable and consistent with the strategy of LTVV (table 4). In most patients with ARDS, a volume-limited mode will produce a stable tidal volume while a pressure-limited mode will deliver a stable airway pressure, assuming that breath-to-breath lung mechanics and patient effort are stable. Regardless of whether a volume-limited or pressure-limited mode of ventilation is chosen, fully supported modes of mechanical ventilation (eg, assist-control) are generally favored over partially supported modes (eg, synchronized intermittent mandatory ventilation), particularly for initial settings. Differences between these modes are described separately. (See "Modes of mechanical ventilation".)

Tidal volume and respiratory rate — We recommend adhering to LTVV using a protocol similar to that used in the ARDS Network low tidal volume study trial (table 3) (calculator 1 and calculator 2), a trial that reported a mortality benefit from LTVV [16]. The initial VT is set at 6 mL/kg PBW and the initial respiratory rate is set to meet the patient's minute ventilation requirements, provided it is ≤35 breaths per minute (most often between 14 and 22 breaths/minute). The PBW is calculated using the following equations (table 1 and table 2):

For females: PBW (kg) = 45.5 + 0.91 * (height [cm] - 152.4)

For males: PBW (kg) = 50 + 0.91 * (height [cm] - 152.4)

Follow-up adjustments and targets used to follow patients with ARDS are discussed below. (See 'Initial follow-up' below.)

Positive end-expiratory pressure (PEEP), fraction of inspired oxygen, oxygenation target — The goal of applied PEEP in patients with ARDS is to maximize and maintain alveolar recruitment, thereby improving oxygenation and limiting oxygen toxicity. While an optimal approach to setting applied PEEP and FiO2 has not been established, we typically set PEEP at 5 cm H2O and FiO2 at 1 at the onset of initiation of mechanical ventilation; if the patient's oxygenation allows it, the FiO2 is rapidly weaned over the next hour to target a peripheral saturation (SpO2) of 88 to 95 percent (typically low to mid-90s). Further adjustments of PEEP and FiO2 are then made using the strategy outlined in the ARDS Network LTVV study (table 3) [16]. A reasonable oxygenation goal during LTVV is an arterial oxygen tension (PaO2) between 55 and 80 mmHg (7.3 to 10.6 kPa) or an oxyhemoglobin saturation between 88 and 95 percent. (See 'Efficacy and harm' below.)

Studies that compare conservative with liberal oxygenation targets in mechanically ventilated patients (as well as other populations) have not yielded clear guidelines on optimal levels of oxygenation in patients with ARDS. One major trial performed exclusively in patients with ARDS found no survival benefit when a conservative oxygen strategy (target PaO2 55 to 70 mmHg; SpO2 88 to 90 percent) was compared with a liberal oxygen strategy (PaO2 90 to 105 mmHg SpO2 ≥96 percent) [17]. This trial and others comparing liberal with conservative targets are described separately. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit", section on 'Fraction of inspired oxygen'.)

Efficacy and harm — Collectively, evidence suggests that the early application of and adherence to LTVV improves mortality, as well as other clinically important outcomes in patients with ARDS [14,16,18-21]:

The multicenter ARDS LTVV trial randomly assigned 861 mechanically ventilated patients with ARDS to receive LTVV (initial VT of 6 mL/kg PBW) or what was considered conventional mechanical ventilation at the time (initial VT of 12 mL/kg PBW) [16]. The LTVV group had a lower mortality rate (31 versus 40 percent) and more ventilator-free days (12 versus 10 days).

A meta-analysis of six randomized trials (1297 patients) found that LTVV significantly improved 28-day mortality (27.4 versus 37 percent; relative risk [RR] 0.74, 95% CI 0.61-0.88) and hospital mortality (34.5 versus 43.2 percent; RR 0.80, 95% CI 0.69-0.92) when compared with conventional mechanical ventilation [19]. This was supported by a subsequent meta-analysis of four randomized trials (1149 patients) that also found that LTVV reduced hospital mortality (34.2 versus 41 percent; odds ratio [OR] 0.75, 95% CI 0.58-0.96) when compared with conventional mechanical ventilation [18]. Another meta-analysis of seven trials reported lower mortality in those treated with LTVV when compared with non-volume-limited strategies (34 versus 40 percent), although the difference was not statistically significant [1]. No difference in rates of barotrauma or ventilator-free days was reported. Although another meta-analysis of three trials also showed no mortality benefit from LTVV, there were several confounding factors that may have influenced the outcome [21].

In two prospective cohort studies of 485 patients undergoing mechanical ventilation for ARDS, poor adherence to LTVV was associated with increased mortality [22,23]. In one analysis, when adherence to LTVV fell from 100 to 50 or 0 percent, two-year mortality increased by 4 and 8 percent, respectively [22]. In the second analysis, an initial VT of 7 mL/kg PBW was associated with a 23 percent increase in ICU mortality when compared with those receiving the standard VT of 6 mL/kg PBW (hazard ratio [HR] 1.23, 95% CI 1.06-1.44) [23]. Later increases in VT by 1 mL/kg PBW also resulted in a 15 percent increase in mortality (adjusted HR 1.15, 95% CI 1.02–1.29). Similarly, one meta-analysis of seven studies reported a similar inverse relationship between VT and death [1].

The mortality benefit associated with LTVV in patients with ARDS may depend on lung elastance. In one secondary analysis of 1096 patients from five randomized trials that compared LTVV with high tidal volume ventilation, the probability of a mortality benefit was greatest in patients with high lung elastance (ie, low lung compliance; posterior median interaction OR 0.80 per cm H2O/[mL/kg], 90% CI 0.63-1.02) [24]. However, it is important to recognize that the original ARDS Network trial [16] targeted a tidal volume of 6 mL/kg PBW but allowed for a tidal volume as high as 8 mL/kg PBW in patients with dyspnea, provided that plateau pressure remained <30 cm H2O (ie, elastance was low enough to allow for this). These results suggest that DP may be a better target than tidal volume as it appears to be more reflective of the potential to induce ventilator-induced lung injury. Measurement of DP is discussed below. (See 'Assessment (clinical, gas exchange, plateau and driving pressure)' below.)

LTVV is generally well-tolerated but potential adverse effects include:

Permissive hypercapnia – Hypercapnic respiratory acidosis (eg, pH <7.35 and partial arterial pressure of carbon dioxide [PaCO2] >45 mmHg) is an expected and generally well tolerated consequence of LTVV [25]. LTVV may require permissive hypercapnic ventilation, a ventilatory strategy that accepts alveolar hypoventilation in order to maintain a low alveolar pressure and minimize the complications of alveolar overdistension (eg, ventilator-associated lung injury). Studies showing benefit to permissive hypercapnia reflect the utilization of LTVV, suggesting the benefit is from the low tidal volume rather than hypercapnia [26]. The degree of hypercapnia can be minimized by using the highest respiratory rate that does not induce auto-PEEP. (See "Permissive hypercapnia during mechanical ventilation in adults".)

Auto-PEEP and over-sedation – Two major concerns were expressed after publication of the ARDS Network LTVV trial [16]. First, the beneficial effects of LTVV may be the result of auto-PEEP rather than the low VT. Second, LTVV may require increased sedation, increasing the risk of sedation-related adverse effects. These concerns have since been addressed:

Auto-PEEP – In theory, the higher respiratory rates that are used to maintain minute ventilation during LTVV may create auto-PEEP by decreasing the time available for complete expiration [27]. However, a subgroup analysis from the ARDS Network LTVV study [16] detected negligible quantities of auto-PEEP in both the LTVV and conventional mechanical ventilation groups, indicating that auto-PEEP is rare during LTVV [28]. However, if auto-PEEP is suspected, clinicians should estimate the contribution of auto-PEEP to the overall level of PEEP being delivered and manage it accordingly. (See "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Prevention and treatment' and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Dynamic hyperinflation'.)

Sedation – Work of breathing and patient-ventilator dyssynchrony may increase when tidal volumes are <7 mL/kg of PBW [29]. While dyssynchrony may require increased sedation soon after the initiation of LTVV, the need for increased sedation does not appear to persist. In a post-hoc analysis of data from a single center involved in the ARDS Network LTVV study, there were no significant differences in the percentage of days patients received sedatives, opioids, or neuromuscular blockade when the LTVV group was compared with the conventional mechanical ventilation group [30]. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal".)

Double-triggering (also known as breath stacking) – Breath stacking is a manifestation of dyssynchrony that can occur despite deep sedation [31]. It causes episodic delivery of higher VTs, which may undermine the benefits of LTVV. Frequent breath stacking (more than three stacked breaths/minute) may be ameliorated by delivering slightly higher VTs (7 to 8 mL/kg PBW), as long as the Pplat remains less than 30 cm H2O, or by administering additional sedation. (See 'Treat dyssynchrony' below.)

INITIAL FOLLOW-UP

Assessment (clinical, gas exchange, plateau and driving pressure) — Following initial low tidal volume ventilation (LTVV), over the next one to four hours, we follow the patient's clinical response, gas exchange, plateau pressure (Pplat), and increasingly, driving pressure (DP) all of which can be used to further adjust ventilator settings. We encourage making bedside adjustments to VT to ensure lung protective ventilation is being appropriately administered and to assess response in real time before obtaining arterial blood gases. Typically, adjustments are made simultaneously to meet clinical and gas exchange, as well as Pplat and DP parameters.

Pplat – The goal Pplat is ≤30 cm H2O. The following is a general guideline for adjustment of the VT based upon Pplat:

When the Pplat is ≤30 cm H2O and VT is 6 mL/kg predicted body weight (PBW), no further adjustments are typically necessary.

When the Pplat is >30 cm H2O and the VT is set at 6 mL/kg PBW or higher, the VT should be decreased in 1 mL/kg PBW increments to a minimum of 4 mL/kg PBW to reach the target plateau. Importantly, any decrease in VT may need to be accompanied by an increase in respiratory rate to maintain an acceptable minute ventilation.

If dyssynchrony is observed (for example, double triggering (figure 2 and figure 3)), the Pplat is <25 cm H2O, and the VT is <6 mL/kg PBW, the VT can be increased in 1 mL/kg PBW increments to Pplat 25 to 30 cm H2O or VT reaches 6 mL/kg PBW (or 8 mL/kg PBW if dyssynchrony is severe).

For patients with severe dyspnea, the VT can be increased from 6 to 7 or 8 mL/kg PBW so long as the Pplat remains ≤30 cm H2O.

While the ideal threshold Pplat below which safety is certain has not been determined, the goal Pplat of ≤30 cm H2O is based upon the ARDS Network LTVV study, which showed benefit from this strategy [16]. It is reasonable to keep the Pplat as low as possible, using LTVV even if the Pplat is already below 30 cm H2O [32]. Further discussion regarding Pplat is provided separately. (See "Diagnosis, management, and prevention of pulmonary barotrauma during invasive mechanical ventilation in adults", section on 'Prevention'.)

Gas exchange – Adjustments to the VT and respiratory rate can also be made based upon gas exchange. There is no consensus regarding an acceptable lower or upper limit for pH or partial arterial pressure of carbon dioxide. However, most experts agree that while the ideal target is a pH 7.35 to 7.45, a pH below 7.25 and above 7.5 should be addressed while maintaining LTVV (ie, a VT between 4 and 8 mL/kg PBW and a Pplat ≤30 cm H2O). Permissive hypercapnia and corrections for respiratory acidosis and respiratory alkalosis are discussed separately. (See "Permissive hypercapnia during mechanical ventilation in adults", section on 'Technique' and "Arterial blood gases", section on 'Respiratory alkalosis'.)

DP – Many experts additionally use DP (initially measured when patients are on LTVV) to help manage ventilator settings, particularly in patients with moderately severe to severe ARDS (ie, arterial oxygen tension/fraction of inspirated oxygen [PaO2/FiO2] ratio <150 mmHg) [33-35]. DP can be calculated using the following:

DP = ventilator-measured Pplat minus applied positive end-expiratory pressure (PEEP) or VT/respiratory system compliance.

Although DP is being increasingly used, guidance regarding ideal target values, patient selection criteria for use, and optimal adjustments based upon a selected target (ie, by changing the tidal volume or PEEP) values are lacking. For example, while some experts target a value <20 cm H2O [33,35,36], data suggest that targeting a value <15 cm H2O may have greater benefit [37]. As another example, some experts target DP from the outset, while others use it in patients with moderately severe to severe ARDS who are refractory to initial LTVV; the latter strategy is based upon the rationale that higher levels of PEEP (which decrease DP) may help identify a subgroup of patients who have recruitable lung and potentially benefit from higher levels of PEEP. Given the potential for harm in some patients left for prolonged periods on high PEEP, we suggest that trials that use high PEEP to lower DP be limited (eg, two to six hours) to ensure benefit or to abandon the strategy if no benefit is seen. In addition, it is unclear whether a ventilator strategy that lowers VT (to decrease the DP) would have the same benefit or harm as raising PEEP (to decrease the DP). Further research is needed to help clinicians confidently use DP for benefit. High PEEP strategies are discussed below. (See 'Further titration/increase in PEEP (high PEEP)' below.)

Prospective data demonstrating benefit from strategies that use DP are lacking. In one retrospective analysis of nine trials that included 3562 patients mechanically ventilated for ARDS [33], among ventilator variables (eg, VT, PEEP, Pplat, DP), DP best predicted survival in patients with ARDS. An increase in DP by 7 cm H2O was associated with increased risk of death (RR 1.41, 95% CI 1.31-1.51), even in patients receiving lung protective ventilation (RR 1.36, 95% CI 1.17-1.58). In another registry-based cohort, an increase in the risk of death was associated with increments in dynamic DP (Pplat – PEEP), a corollary for static DP [37]. However, the risk was marginal and the cohort was mixed with only a minority having ARDS.

Patients who are improving — Most patients improve on LTVV. For these patients, an attempt should be made to wean some of the ventilator settings including reducing the FiO2 and PEEP (table 3), and switching to a partial-assist or spontaneous mode, if tolerated. Medical therapies for the underlying disorder should be optimized and sedation and vasopressor support should be weaned, if feasible. The rate of weaning is individualized such that for some patients, this process may take 24 to 48 hours while for others, it may take days to weeks. (See "Initial weaning strategy in mechanically ventilated adults" and "Weaning from mechanical ventilation: Readiness testing" and "Weaning from mechanical ventilation: Readiness testing", section on 'Rapid shallow breathing index'.)

Patients who are not improving or deteriorating — While many patients initially improve on LTVV, some patients do not tolerate LTVV as evidenced by dyssynchrony or high airway pressures (eg, high Pplat ≥30 cm H2O) or worsening hypoxemia. The principles of management are similar whether intolerance or deterioration is seen soon after ventilation or develop later during the course of ventilation after a brief period of improvement.

Abrupt changes in the airway pressure in a patient receiving volume-limited ventilation, or in tidal volumes (VT) in a patient receiving pressure-limited ventilation, should prompt an immediate search for a cause of an acute change in compliance (eg, pneumothorax or an obstructed endotracheal tube) and is discussed separately. (See "Assessment of respiratory distress in the mechanically ventilated patient".)

Choosing among the options — Treatment is targeted at the suspected reason for failure to respond to LTVV and includes one or more of the following:

Supportive measures including maximizing therapy for the underlying disorder, conservative fluid management, considering alternate diagnoses and complications of ARDS or of mechanical ventilation, and treating dyssynchrony, if present. (See 'Supportive measures' below.)

Continue LTVV with alternate settings including switching the mode of ventilation (eg, volume- to pressure-limited) and increasing the inspiratory to expiratory ratio. (See 'LTVV with alternate ventilator settings or modes' below.)

The approach is dependent upon the severity of ARDS, the underlying etiology, complications, or comorbidities, including dyssynchrony. Most experts repeat routine laboratory studies and imaging, sometimes including computed tomography (CT) of the chest and/or abdomen, as well as simultaneously treating any potential contributing factors such as bronchospasm, atelectasis, fluid overload, abdominal distention, pneumothoraces, pleural effusions, and fever. In addition, we typically perform a short trial at bedside that involves simple ventilator changes to optimize LTVV (table 3), switch the mode of ventilation (eg, from volume- to pressure-limited modes), and/or increase the inspiratory to expiratory ratio, if oxygenation is an issue. Options should be tailored for each individual. For example, for patients with air hunger, switching from volume- to pressure-limited mode, or increasing inspiratory flow rates, is appropriate. For patients with subsegmental atelectasis causing deterioration in oxygenation, prolonging inspiratory time, either by lowering flow rates in volume-limited modes or increasing inspiratory time in pressure-limited modes, may help. For patients with suspected derecruitment (eg, after periods of ventilator detachment during travel), temporarily increasing PEEP above that recommended by the ARDS Network LTVV protocol is appropriate (table 5) until oxygenation recovers, after which the typical protocol can be resumed (table 3). (See 'Further titration/increase in PEEP (high PEEP)' below.)

Supportive measures

General measures — Therapies targeted at decreasing oxygen consumption may improve the saturation of mixed venous blood (and subsequently arterial saturation) by decreasing the amount of oxygen extracted from the blood. Common causes of increased oxygen consumption include fever, anxiety and pain, and use of respiratory muscles; therefore, arterial saturation may improve after treatment with antipyretics, sedatives, analgesics, or paralytics [38,39].

Although oxygen delivery may be improved by increasing the hemoglobin concentration, data suggest no benefit to increasing the hemoglobin to levels above 7 g/dL. (See "Use of blood products in the critically ill", section on 'Restrictive strategy as the preferred approach'.) Similarly, while raising the cardiac output may also increase oxygen delivery, there is no good evidence to justify routine administration of inotropic agents to raise cardiac output [40,41].

Maximize treatment for underlying disorders — In some cases, failure to respond to LTVV may be due to under-treatment of underlying etiologies or comorbidities. For example, patients with ARDS with chronic obstructive pulmonary disease may benefit from more aggressive bronchodilation and glucocorticoid therapy, or patients with uncontrolled hypertension from alcohol withdrawal may benefit from improved blood pressure control and benzodiazepines to manage their withdrawal (see "Management of moderate and severe alcohol withdrawal syndromes"). Similarly, patients with significant pain, delirium, or agitation may also benefit from optimization of their sedatives or analgesics, and patients with massive ascites or a large compressive pleural effusion may benefit from large volume paracentesis or thoracentesis. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal".)

Conservative fluid management — Pulmonary edema can occur in patients with ARDS due to increased vascular permeability, which is intrinsic to the pathogenesis of ARDS as well as to aggressive intravenous fluid resuscitation prior to intubation. This issue should be addressed by the discontinuation or restriction of fluids and/or diuresis, and in some cases where fluid status is uncertain, consideration should be given to the assessment of fluid status using monitoring tools. Further details regarding fluid management and hemodynamic tools used in the intensive care unit are discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Conservative fluid management' and "Novel tools for hemodynamic monitoring in critically ill patients with shock".)

Consider complications of ARDS or alternate diagnoses — The diagnosis of ARDS depends upon the exclusion of cardiogenic pulmonary edema as well as several other competing etiologies (eg, acute eosinophilic pneumonia). Similarly, ARDS may be complicated by conditions including pneumothorax, ventilator-associated pneumonia, or pulmonary embolism. Reasonably excluding such etiologies is appropriate before discontinuing LTVV and resorting to additional strategies. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Additional testing' and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Differential diagnosis' and "Clinical and physiologic complications of mechanical ventilation: Overview" and "Assessment of respiratory distress in the mechanically ventilated patient".)

Treat dyssynchrony — Ventilator dyssynchrony is best described as mismatching between patient effort and ventilator-delivered breaths. Dyssynchrony is not uncommon and may occur in up to one-quarter of mechanically ventilated patients, [42-44]. Dyssynchrony can lead to increased work of breathing, discomfort, and in some cases, auto-PEEP and poor gas exchange, ultimately leading to prolonged mechanical ventilation, increased need for sedation and/or neuromuscular blockade, and possibly barotrauma [42,45]. Factors that influence synchrony include patient-centered factors (eg, respiratory drive, timing, and respiratory system mechanics, such as lung compliance and airflow resistance) and ventilator-centered factors including respiratory rate, inspiratory flow, and trigger sensitivity. Ineffective triggering (figure 4 and figure 5) or double triggering (figure 2 and figure 3) are common examples of dyssynchrony, and the latter is evident in ARDS when minute ventilation requirements are high (eg, metabolic acidosis, high dead space volume). Reverse triggering is another form of dyssynchrony, which is poorly understood but seems to involve reflex contractions induced by mechanical ventilation [46]. Reverse triggering does not respond to increased sedation and has been observed in deeply sedated patients.

The approach to dyssynchrony starts with examining bedside graphics of flow-versus-time, pressure-versus-time and pressure-volume curves. Initial management often begins with minor adjustments in the trigger sensitivity and inspiratory flow as well as increased sedation and occasionally paralysis. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Paralysis (neuromuscular blockade)'.)

Ventilator adjustments to consider include the following:

Double triggering – Double triggering (breath-stacking) is when a second breath is taken before the ventilator has completed delivery of the first breath. It is most frequently due to the delivery of a tidal volume that is too low to meet the patient’s needs and is, therefore, common during LTVV. Double triggering may be addressed by increasing the VT (while still maintaining LTVV parameters 4 to 8 mL/kg PBW and Pplat ≤30 cm H2O).

Ineffective triggering – Ineffective triggering occurs when patient efforts fail to trigger the ventilator. In ARDS, ineffective triggering is most often due an insensitive inspiratory trigger and may be treated by lowering the trigger sensitivity (figure 6). Ineffective triggering may also imply the presence of auto-PEEP, the management of which is discussed separately. (See "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Dynamic hyperinflation'.)

Flow dyssynchrony – Flow dyssynchrony (ventilator flow delivery is insufficient to meet patient demands) may be treated by increasing flow or switching the mode of ventilation, which is discussed below. (See 'Switching ventilatory mode' below.)

Reverse triggering – The optimal treatment of reverse triggering is unknown, but potential interventions may include decreasing sedation and increasing or decreasing the set ventilator rate.

LTVV with alternate ventilator settings or modes

Switching ventilatory mode — For patients not tolerating volume-limited LTVV (eg, unable to achieve a plateau pressure ≤30 cm H2O, ventilator dyssynchrony), alternative modes of mechanical ventilation are sometimes attempted at bedside. These modes include pressure-limited modes, most notably pressure-regulated volume control ventilation and pressure support modes, and less commonly, airway pressure release ventilation, volume-targeted pressure controlled ventilation (eg, VC plus), or neurally adjusted ventilatory assist (NAVA) ventilation. The advantages, disadvantages, and application of alternate modes of mechanical ventilation are described separately. (See "Modes of mechanical ventilation".)

Short trials (hours) of alternate modes are typically performed. Close observation of ventilator waveforms, airway pressures, and tidal volumes and assessment of gas exchange are indicated to assess the response. If successful, continuing with that mode is appropriate. LTVV and plateau pressures <30 cm H2O remain important targets, even if the ventilatory mode is switched. Management of patients who are refractory to such measures is discussed below. (See 'Refractory patients' below.)

Increasing the inspiratory to expiratory ratio (eg, inverse ratio ventilation) — In some patients, increasing the inspiratory:expiratory (I:E) ratio by prolonging inspiratory time may improve oxygenation by allowing regions of the lung that require more time to open and participate in gas exchange [47-50]. When the inspiratory time surpasses the expiratory time, this is known as inverse ratio ventilation (IRV). Despite improvements in oxygenation, prolonging inspiratory time or IRV has not been shown to improve clinically meaningful outcomes in ARDS. IRV is discussed separately. (See "Modes of mechanical ventilation", section on 'Inverse ratio ventilation'.)

Additional follow-up — Close monitoring of airway pressures and gas exchange is necessary after every new therapy or ventilator change (eg, within one to four hours) to rapidly identify refractory patients that need additional interventions. Although assessment of the response is subjective, we consider the following actions as appropriate:

We typically consider a successful response as one that maintains or improves PaO2/FiO2 ratio ≥150 mmHg. If successful, optimizing and continuing with those therapies is appropriate until the patient is ready for weaning. (See 'Patients who are improving' above.)

We consider patients with deteriorating clinical status and/or a PaO2/FiO2 ratio <150 mmHg as having ARDS that may warrant additional adjunctive therapy. We choose a PaO2/FiO2 ratio <150 mmHg as a mid-moderate ARDS severity indicator that is frequently used in trials to treat patients with aggressive interventions (eg, prone ventilation). (See 'Refractory patients' below.)

REFRACTORY PATIENTS — A small subset of patients with ARDS pose a special challenge because of refractory hypoxemia (arterial oxygen tension/fraction of inspired oxygen [PaO2/FiO2] <150 mmHg) and/or because acceptable gas exchange cannot be achieved without incurring unacceptably high airway pressures (plateau pressure [Pplat] >30 cm H2O) despite low tidal volume ventilation (LTVV) and other supportive measures targeted at treating ARDS. Management of this group is discussed in this section.

Choosing among the options — Patients who remain hypoxemic despite LTVV, supportive measures, and alternative ventilator settings/modes are very sick and have a high mortality warranting additional adjunctive measures, some of which are well supported with data while others are not. Options include the following:

Prone ventilation. (See 'Prone ventilation' below.)

Ventilatory strategies that maximize alveolar recruitment (eg, the application of high positive end-expiratory pressure [PEEP], an open lung strategy, or recruitment maneuvers). (See 'Ventilator strategies to maximize alveolar recruitment' below.)

Pharmacotherapies (eg, neuromuscular blockers [NMBs] and pulmonary vasodilators). (See 'Pharmacotherapy' below.)

Extracorporeal membrane oxygenation (ECMO). (See 'Extracorporeal membrane oxygenation (ECMO)' below.)

None of these therapies has been directly compared with the other. However, one systematic review and network meta-analysis of 25 randomized trials examined several interventions including open lung strategies (ie, recruitment maneuvers and PEEP), neuromuscular blockade, inhaled nitric oxide, high-frequency oscillatory ventilation, prone positioning, and ECMO in patients with moderate to severe ARDS on LTVV [2]. Among the interventions, only prone positioning (in moderate and severe ARDS patients) and ECMO (in severe ARDS patients; ie, two non-ventilatory strategies) were associated with a lower 28-day mortality (prone positioning risk ratio [RR] 0.69, 95% CI 0.48-0.99; ECMO RR 0.6, 95% CI 0.38-0.93). Rates of barotrauma were similar among the listed interventions (7 percent). Similarly, another network meta-analysis of 34 trials reported that low tidal ventilation in the prone position resulted in improved mortality in patients with moderate to severe ARDS compared with LTVV alone (RR 0.74, 95% CI 0.60-0.92; high quality of evidence) [51]. Among all of the comparisons made, LTVV with prone positioning was associated with the greatest reduction in mortality.

In practice, choosing among these options should be individualized and at the discretion of the treating clinician since several factors influence the choice, including local expertise, the ability to transfer to a center with expertise, severity and stage of ARDS, underlying comorbidities and complications, reversibility of ARDS, and other factors determining prognosis. While we prefer prone ventilation in ARDS patients with severe hypoxemia, this option is not suitable for every patient due to contraindications (table 6). When proning is not feasible or has failed, we typically consider early consultation for ECMO evaluation. However, there is considerable variation in practice such that some experts attempt to maximize alveolar recruitment or administer pulmonary vasodilators while considering the possibility of ECMO. Importantly, early application (eg, within seven days) of one or more of these therapies is critical for their success. Most of these treatments should demonstrate effectiveness quickly (eg, minutes to hours) so that if they fail to improve gas exchange promptly, alternate options can be attempted before it is too late.

While good communication with families is important for all patients with ARDS, conveying the gravity of the patient’s illness to loved ones is particularly critical at this point of care. (See "Communication in the ICU: Holding a meeting with families and caregivers".)

Prone ventilation — Prone ventilation involves ventilating patients with LTVV in the prone position (as opposed to the more commonly used supine position). In patients with moderately severe to severe ARDS (ie, PaO2/FiO2 ratio <150 mmHg on at least 5 cm H2O PEEP) whose oxygenation fails to significantly improve with LTVV alone, regardless of whether a low PEEP or high PEEP strategy has been employed, we suggest a trial of prone ventilation, provided that there are no contraindications (table 6). Importantly, early application (eg, within seven days) is critical for the success of this strategy. If patients do not improve after a short trial of prone ventilation (eg, six to eight hours and occasionally up to 20 hours), then they are unlikely to improve and other measures should be considered next. Further details regarding the application and data to support prone ventilation in patients with ARDS are provided separately. (See "Prone ventilation for adult patients with acute respiratory distress syndrome".)

Ventilator strategies to maximize alveolar recruitment — The strategies outlined in this section are options for refractory patients with severe ARDS who are not candidates for prone ventilation and those who remain severely hypoxemic despite a response to the prone position. Many experts attempt these maneuvers before deciding to ventilate in the prone position. The rationale for their use is based upon the use of pressure to recruit non-gas exchanging regions of the lung involved with ARDS. The recruitment of new gas-exchanging alveolar units improves oxygenation. However, data do not demonstrate a clear mortality benefit and some data also suggest harm. If any of these strategies are performed, we suggest that trials be limited (eg, two to six hours or one to two short recruitment maneuvers) and the threshold be low to abandon these therapies if no improvement in oxygenation is identified.

Further titration/increase in PEEP (high PEEP) — We do not recommend the initial use of a high PEEP strategy in patients with ARDS. Several meta-analyses demonstrated improved oxygenation but no decrease in mortality or ventilator-free days with the use of a high PEEP approach in patients with ARDS [21,52]. However, no consideration was given to heterogeneity of treatment effect regarding whether patients were recruitable with PEEP.

In patients with severe hypoxemia despite standard LTVV, some experts use a high PEEP strategy such as that employed in the ALVEOLI (table 5) [53] or LOVS trials [54] (ie, trials that demonstrated possible benefit). Network meta-analysis does support a high PEEP approach as potentially benefiting mortality when applied without a lung recruitment maneuver [55] and when used, clinicians should assess whether patients' oxygenation improves (ie, responders with recruitable lung) or fails to improve (ie, nonresponders with lung that is not recruitable) so that a decision can be made as to whether it is appropriate to continue or abandon the high PEEP strategy.

In the experience of the authors, improvements in oxygenation generally occur relatively quickly (eg, two to four hours), although data describing an optimal duration for a high PEEP trial are lacking, and the decision to use high PEEP is often left to the discretion of the treating physician and availability of additional ventilator options.

While most clinicians use oxygenation as a guide to adjust PEEP, other tools, typically esophageal pressure measurements to guide the adjustment of PEEP, may be considered at this point, although the impact of esophageal pressure-guided PEEP strategies on clinically meaningful outcomes, such as survival, are unclear. Other options include using the driving pressure to determine who has recruitable lung and therefore may benefit from high PEEP. Further details regarding tools that measure PEEP and value of driving are provided separately. (See "Positive end-expiratory pressure (PEEP)", section on 'Tools for titrating applied PEEP' and 'Low tidal volume ventilation: Initial settings' above.)

It is thought that use of higher levels of PEEP benefits patients by opening collapsed alveoli, which in turn decreases alveolar over-distention because the volume of each subsequent tidal breath is shared by more open alveoli [56-58]. If the alveoli remain open throughout the respiratory cycle (ie, they do not collapse during exhalation), cyclic atelectasis is also reduced. Alveolar over-distention and cyclic atelectasis are the principal causes of ventilator-associated lung injury. However, despite this theory the data suggest that the clinical relevance of improved oxygenation from the application of high PEEP in patients with ARDS is unclear, particularly when LTVV is concurrently used. The application of high PEEP does not appear to be associated with improved mortality except perhaps in those with severe gas exchange abnormalities. Further study is needed to determine the optimal level of PEEP and the ARDS population in whom a clear mortality benefit from high PEEP might be expected. (See "Ventilator-induced lung injury", section on 'Mechanisms'.)

In patients with ARDS, meta-analyses of small randomized trials suggest that, compared with low PEEP, high PEEP improves oxygenation, with unclear effects on mortality [52,55,59]. When considering all patients ventilated in the intensive care unit (ICU) for ARDS, evidence suggests that there is no clear mortality benefit associated with the use of high PEEP, particularly in those on LTVV. However, subgroup analyses suggest a possible benefit in those with moderate to severe ARDS:

A 2022 meta-analysis of 18 randomized trials (over 4500 participants), reported that a high PEEP strategy without lung recruitment maneuver (LRM) was associated with a lower risk of death than a lower PEEP strategy (RR 0.77, 95% CrI 0.6-0.96; high certainty) [55]. A higher PEEP strategy with prolonged LRM strategy was associated with increased risk of death when compared with higher PEEP without LRM (RR 1.37, 95% CrI 1.04-1.81; moderate certainty).

A 2021 meta-analysis of 3851 patients with ARDS compared a low PEEP to high PEEP strategy in patients ventilated with the same low VT [52]. In this setting, high PEEP resulted in improved oxygenation (mean difference in PaO2/FiO2 ratio 51.03, 95% CI 35.86-66.2) without any improvement in hospital mortality (RR 0.97, 95% CI 0.9-1.04), barotrauma (RR 1, 95% CI 0.64-1.57), or ventilator-free days.

Potentially influencing study outcomes is the clinical heterogeneity of ARDS. Some patients have a lot of recruitable lung, while others have little recruitable lung as defined by CT scan [60]. For example, it has been suggested that during the early phase, patients with pulmonary causes of ARDS and have greater lung recruitability than patients with extrapulmonary causes or late ARDS [61]. It has been suggested that the benefits of high PEEP have been underestimated because its advantages in patients with a lot of recruitable lung were mitigated by its detrimental effects in patients with little recruitable lung [62]. This theory was supported by a study that found that high PEEP reduced cyclic atelectasis to a greater extent than it increased alveolar strain among patients with a lot of recruitable lung [63]. In contrast, it increased alveolar strain without reducing cyclic atelectasis among patients with little recruitable lung. Future trials comparing higher levels of PEEP with lower levels should be restricted to patients with a significant amount of recruitable lung, since we believe that this population is most likely to benefit from high PEEP. (See "Ventilator-induced lung injury".)

Increased applied PEEP has the potential to cause pulmonary barotrauma or ventilator-associated lung injury by increasing the Pplat and causing alveolar overdistention. It also has the potential to decrease blood pressure by reducing cardiac output [64,65]. However, these adverse effects have not been universally reported and several meta-analyses have suggested no difference in the rates of barotrauma in patients ventilated with low or high PEEP strategies [52,53,66].

Open lung ventilation — Open lung ventilation (OLV) is a strategy that combines LTVV with a recruitment maneuver and subsequent titration of applied PEEP. In theory, LTVV mitigates alveolar overdistention, while the recruitment maneuver recruits additional atelectatic alveolar units and the applied PEEP maintains alveolar recruitment and minimizes cyclic atelectasis; this combination, in theory, should reduce the risk of inducing further lung injury by the mechanical ventilator itself (see "Ventilator-induced lung injury"). However, on balance, most trials do not show convincing mortality benefit from OLV, despite improvement in oxygenation; in addition, some studies show possible harm such that we suggest avoiding the routine application of OLV as an initial strategy in patients with ARDS and reserve it for patients with severe ARDS who are refractory to standard strategies. Importantly, when OLV is used, patients should be closely observed for an oxygenation response, so that the clinician can decide whether it is appropriate to continue or abandon the OLV trial, which should last for a few hours only (eg, two to six hours).

Although a universally accepted protocol for OLV has not been established and protocols for recruitment and applied PEEP vary among studies, if the decision is made to apply OLV we suggest the following:

Patients should receive LTVV as outlined above (table 3). (See 'Low tidal volume ventilation: Initial settings' above.)

A recruitment maneuver is then performed. (See 'Recruitment maneuvers' below.)

PEEP is then titrated down from the level used for the recruitment maneuver to a higher level than that typically used for LTVV. Criteria for setting PEEP in this setting is unclear; while applied PEEP may be set at least 2 cm above the PEEP, which produces the best lung compliance, most experts use a published protocol that utilizes the fraction of inspired oxygen to guide PEEP, such as one outlined in this table (table 5) or that used by other experts [54].

Clinical trials indicate that while OLV improves oxygenation, mortality rates have been conflicting [67-71]. Many of the trials used different types of recruitment maneuvers and PEEP strategies, which may explain the variability in the responses to OLV noted among trials; alternatively, variability may suggest possible subgroups, some that may respond to OLV and others that do not respond (ie, responders versus non responders). Several earlier trials reported a survival benefit with OLV [67,68]. However, many of these trials were fundamentally flawed due to the high VT ventilation strategy used in the control groups, which may have explained the higher than usual rates of mortality in the control groups, thereby casting doubt over the validity of the true benefit of OLV. In contrast, a well-conducted international randomized trial (Alveolar Recruitment for ARDS Trial [ART]) reported possible harm with OLV. In ART, 983 mechanically ventilated patients with moderate to severe ARDS were randomized to a conventional low VT strategy (see 'Low tidal volume ventilation: Initial settings' above) versus an OLV strategy that included a prolonged recruitment maneuver (two to four minutes) and a decremental titration of PEEP [72]. Patients managed with OLV had higher 28-day mortality (55 versus 49 percent, hazard ratio [HR] 1.20, 95% CI 1.01-1.42) and a higher six-month mortality (65 versus 60 percent; HR 1.18, 95% CI 1.01-1.38). Additionally, the OLV group had an increased risk of barotrauma (6 versus 2 percent) and pneumothorax requiring drainage (3 versus 1 percent).

Recruitment maneuvers — A recruitment maneuver is the application of a high level of continuous positive airway pressure (CPAP) or PEEP, with the goal of recruiting non-gas exchanging parts of the lung involved with ARDS to become involved in gas exchange. Recruitment maneuvers may be performed as an independent maneuver or as part of an open lung approach (when recruitment is followed by higher than usual titrated levels of PEEP). (See 'Open lung ventilation' above.)

Most experts agree that prolonged duration recruitment is not warranted [21]. However, network meta-analysis suggests potential benefit to a short duration recruitment maneuver, such as used in the LOVS trial [55]. We suggest the following:

Indications – We believe that there is insufficient evidence to support the routine use of recruitment maneuvers in patients with ARDS. However, recruitment maneuvers may be performed in select patients as an attempt to improve oxygenation in those with moderate to severe hypoxemia (PaO2/FiO2 <150 mmHg). For example, we sometimes also apply a recruitment maneuver when a patient demonstrates desaturation after disconnection from the ventilator (eg, derecruitment after tubing changes, transport) because even a brief period without PEEP can result in alveolar collapse [73,74]. Other potential indications might include desaturations that occur in the context of suctioning, bronchoscopy, or patient repositioning, all of which can induce derecruitment [21].

Level and type of pressure – We typically apply PEEP of 35 to 40 cm H2O, although several studies have applied lower or higher levels. We generally do not apply higher levels of PEEP due to the potential for harm, particularly when applied for prolonged periods.

Duration – While there is no consensus regarding the optimal duration of the maneuvers, we typically apply PEEP for 40 seconds. We avoid recruitment of extended durations (ie, >40 seconds) since one study found that most of the alveolar recruitment occurred during the first 10 seconds of the maneuver [75]; in addition, extended duration recruitment maneuvers as part of an OLV strategy in another study (two to four minutes) may have contributed to increased mortality in the OLV group [72]. (See 'Open lung ventilation' above.)

Frequency – The optimal timing and frequency are also unknown. Significant alveolar overdistention does not appear to occur during a single recruitment maneuver but may occur with frequent recruitment maneuvers [76-79]. Thus, we prefer to perform one recruitment maneuver, although consideration can be given to repeating it one more time if a response was observed but only temporarily maintained. Although there are no data, most experts perform recruitment early in the course (ie, early exudative stage; first 7 to 10 days) since most studies have only tested recruitment in that setting and biologically, recruitment may not be as effective when ARDS moves into the fibroproliferative phase. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Pathologic diagnosis and stages'.)

Efficacy – Most studies of recruitment maneuvers report improvement in oxygenation, although meta-analyses do not report convincing benefits on mortality, length of hospital stay, or the incidence of barotrauma [71,80-84]. Data suggest that the magnitude of the increase in oxygenation is greatest when the recruitment maneuver is followed by high levels of PEEP (eg, 16 cm H2O), compared with when it is followed by lower levels of PEEP (eg, 9 cm H2O) [85], but the benefits of high PEEP are also unclear. (See 'Further titration/increase in PEEP (high PEEP)' above.)

Adverse effects – The most common adverse effects of recruitment maneuvers are hypotension and oxygen desaturation [83]. These effects are generally self-limited and without serious consequences. Nevertheless, there may be some risk of barotrauma and cardiac arrest when a recruitment maneuver is carried out for an extended duration. Careful monitoring for hemodynamic instability should be undertaken whenever a recruitment maneuver is performed.

Pharmacotherapy — Several medications may be of value in patients with severe ARDS including NMBs, pulmonary vasodilators, and glucocorticoids. NMBs and pulmonary vasodilators generally have an effect within hours such that trials may last up to 12 to 24 hours. In some cases, both options may be tried simultaneously. Glucocorticoids may also be considered in patients with severe ARDS not responsive to standard therapies, although the effect is unlikely to be immediate. Data that supports the potential value in patients with ARDS are provided separately.

Neuromuscular blockers — (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects" and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Paralysis (neuromuscular blockade)'.)

Pulmonary vasodilators — (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Inhaled nitric oxide' and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Inhaled prostaglandins' and "Inhaled nitric oxide in adults: Biology and indications for use".)

Glucocorticoids — (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)

Extracorporeal membrane oxygenation (ECMO) — ECMO, which is being increasingly used as a rescue therapy for improving oxygenation, may be suitable for patients with severe ARDS who have failed standard low VT ventilator strategies. We typically use ECMO in patients who have also failed or are not suitable for prone ventilation and high PEEP/recruitment strategies. There are few absolute contraindications other than a pre-existing condition that is incompatible with recovery (severe neurologic injury, end-stage malignancy), and relative contraindications include uncontrollable bleeding and very poor prognosis from the primary condition. Importantly, early application (eg, within seven days) is critical for the success of ECMO; thus, for centers that do not have ECMO, early transfer is critical. Further details regarding the application and data to support ECMO in patients with ARDS are provided separately. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

VENTILATOR STRATEGIES OF QUESTIONABLE BENEFIT OR HARM — Strategies of limited or no benefit or associated with potential harm include the following:

High-frequency oscillatory ventilation (HFOV) – While in the past HFOV was a popular rescue mode of ventilation for patients with ARDS, it has now fallen out of favor since studies suggest no benefit and possible harm associated with its use. (See "High-frequency ventilation in adults".)

Ultra-low tidal volume ventilation – Ultra-low tidal volume ventilation routinely employing a tidal volume of 4 mL/kg ideal body weight has not been shown to provide a mortality benefit in either COVID-19 or non-COVID-19 patients with acute hypoxemic respiratory failure [86,87]. This approach can include the use of extracorporeal carbon dioxide removal (ECCO2R; see next bullet below).

ECCO2R combined with low tidal volume ventilation (LTVV) – Using ECCO2R to allow additional reduction in the tidal volume below the standard of 4 to 8 mL/kg predicted body weight (PBW) in patients with acute hypoxemic respiratory failure does not appear to be beneficial. One study randomized 412 patients with acute hypoxemic respiratory failure, two-thirds of whom had ARDS, to receive ECCO2R in conjunction with lowering of tidal volumes to a target of <3 mL/kg PBW for at least 48 hours and was compared with standard LTVV (initial tidal volume 6 mL/kg PBW) [86]. Despite a lower mean tidal volume and mean plateau pressure, receiving ECCO2R combined with lower tidal volumes did not impact 90-day morality (42 versus 40 percent), and it resulted in fewer ventilator-free days (7.1 versus 9.2 days) and an increased rate of adverse events, most of which were due to the study device (31 versus 9 percent; eg, hemorrhage, hemolysis, infection, thrombocytopenia, stroke). However, the trial was stopped early for futility, and the lack of mortality benefit may have been influenced by a mean tidal volume in the interventional group that was within the lower limits of that which is considered standard LTVV. Mortality at one year remained unchanged [88]. Future studies will be needed to identify if subgroups might benefit from ECCO2R.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute respiratory failure and acute respiratory distress syndrome in adults" and "Society guideline links: Assessment of oxygenation and gas exchange".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Acute respiratory distress syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Invasive versus noninvasive – Acute respiratory distress syndrome (ARDS) is a form of lung injury that is associated with a high mortality. Mechanical ventilation is the cornerstone of treatment. For most patients with ARDS, we suggest proceeding directly to invasive mechanical ventilation, rather than performing an initial trial of noninvasive ventilation (NIV) (Grade 2C). NIV may be reserved for the occasional patient with mild ARDS who is hemodynamically stable, is easily oxygenated, does not need immediate intubation, and has no contraindications to its use. (See 'Selecting invasive versus noninvasive ventilation' above.)

Initial settings – For patients with ARDS who are mechanically ventilated, we recommend low tidal volume ventilation (LTVV; 4 to 8 mL/kg predicted body weight [PBW]) (table 1 and table 2 and algorithm 1) (calculator 1 and calculator 2) rather than high tidal volume (VT) strategies (Grade 1B). LTVV is typically performed using a volume-limited assist control mode, beginning with a VT of 6 mL/kg PBW, which targets a plateau pressure (Pplat) ≤30 cm H2O and applies positive end-expiratory pressure (PEEP) according to the strategy outlined in the table (table 3). This approach is based upon several meta-analyses and randomized trials that have reported improved mortality from LTVV in patients with ARDS. Patients should be followed closely using clinical, gas exchange, and ventilator parameters. (See 'Low tidal volume ventilation: Initial settings' above.)

For patients with ARDS who improve, an attempt should be made to wean some of the ventilator settings including reducing the fraction of inspired oxygen (FiO2) and PEEP (table 3), and switching to a partial-assist or spontaneous mode, if tolerated. The rate of weaning is individualized and may take days or weeks. (See 'Patients who are improving' above and "Initial weaning strategy in mechanically ventilated adults" and "Weaning from mechanical ventilation: Readiness testing".)

Optimizing management – For patients with who do not improve on initial LTVV settings, the next step is to optimize general management, which may include the following:

Optimizing therapy for the underlying disorder (see 'Maximize treatment for underlying disorders' above)

Conservative fluid management (see "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Conservative fluid management')

Assessing for alternate diagnoses and complications of ARDS or mechanical ventilation that may be causing deterioration (see 'Consider complications of ARDS or alternate diagnoses' above and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Differential diagnosis')

Treating dyssynchrony (if present) (see 'Treat dyssynchrony' above)

Trialing a different settings or modes of ventilation (eg, pressure- rather than volume-limited) (see "Modes of mechanical ventilation" and 'LTVV with alternate ventilator settings or modes' above)

If the patient stabilizes or improves (arterial oxygen tension [PaO2]/FiO2 ≥150 mmHg), optimizing and continuing with these therapies is appropriate until the patient is ready for weaning. (See 'Patients who are not improving or deteriorating' above.)

Abrupt changes in gas exchange or airway compliance should prompt an immediate search for a cause (eg, pneumothorax, displaced or obstructed endotracheal tube), as discussed separately. (See "Assessment of respiratory distress in the mechanically ventilated patient".)

Refractory patients – For patients who continue to have moderate to severe hypoxemia and/or require unacceptably high ventilator settings to achieve adequate gas exchange (ie, PaO2/FiO2 <150 mmHg or Pplat >30 cm H2O) despite optimizing LTVV settings, management is individualized and depends upon the severity of ARDS, underlying comorbidities or complications, reversibility of the underlying etiology, other factors determining prognosis, local resources and expertise, and safety of transfer to another center (algorithm 1). Practice varies from center to center. Options include prone ventilation, high PEEP, open lung ventilation, recruitment maneuvers, pharmacologic agents including neuromuscular blockers, pulmonary vasodilators, and extracorporeal membrane oxygenation (ECMO). Importantly, early application (eg, within seven days) of one or more of these therapies is critical for their success and trials should be short so that alternate options can be reasonably attempted before it is too late if the therapies do not work. Our general approach is as follows (see 'Refractory patients' above):

For most patients with refractory ARDS (as defined above) despite LTVV, we recommend prone ventilation rather than ongoing LTVV alone (Grade 1B) and we suggest prone ventilation rather than other ventilation strategies (eg, high PEEP) (Grade 2C). Contraindications to prone ventilation are listed in the table (table 6). (See 'Prone ventilation' above and "Prone ventilation for adult patients with acute respiratory distress syndrome".)

If proning is contraindicated or unsuccessful, we obtain early consultation for ECMO evaluation. In our centers, we reserve ECMO for patients with severe ARDS refractory to other management strategies (including LTVV and proning). Early application of ECMO (ie, within seven days of onset) is critical for its success. Thus, trials of other therapies should be brief so that if the patient does not improve, ECMO can be attempted before it is too late. For centers that do not have ECMO, early transfer is critical. (See 'Extracorporeal membrane oxygenation (ECMO)' above and "Extracorporeal life support in adults: Management of venovenous extracorporeal membrane oxygenation (V-V ECMO)".)

While awaiting ECMO evaluation, we suggest a trial of high PEEP with or without short recruitment maneuvers. The patient's oxygenation should be assessed several hours after initiating high PEEP (Grade 2C) to determine the response (ie, whether the lungs are recruitable). If the patient fails to improve, the high PEEP trial should be stopped. (See 'Ventilator strategies to maximize alveolar recruitment' above.)

Medications that are sometimes used in the management of patients with refractory ARDS include neuromuscular blockers, pulmonary vasodilators, and glucocorticoids (the latter is unlikely to have an immediate effect). These medications are discussed in greater detail separately. (See 'Pharmacotherapy' above and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Inhaled pulmonary vasodilators' and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Sedation' and "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects", section on 'Clinical use'.)

We suggest not using high-frequency oscillatory ventilation (HFOV) for management of patients with ARDS (Grade 2B). While in the past, HFOV was a popular rescue mode of ventilation for patients with severe ARDS, it has now fallen out of favor since available data suggest no benefit and possible harm associated with its use. (See 'Ventilator strategies of questionable benefit or harm' above and "High-frequency ventilation in adults".)

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Topic 1653 Version 79.0

References

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