# 03 - 312 Acute Respiratory Distress Syndrome

### 312 Acute Respiratory Distress Syndrome

hypoxemia, neuromuscular paralysis, and severe hypotension must be 
ruled out. If there is uncertainty about the cause of coma, studies of 
cerebral blood flow and electroencephalography should be performed.
■
■WITHHOLDING OR WITHDRAWING CARE
(See also Chap. 13) Withholding or withdrawal of care occurs com­
monly in the ICU setting. The Task Force on Ethics of the Society of 
Critical Care Medicine reported that it is ethically sound to withhold or 
withdraw care if a patient or the patient’s surrogate makes such a request 
or if the physician judges that the goals of therapy are not achievable. 
Because all medical treatments are justified by their expected benefits, 
the loss of such an expectation justifies the act of withdrawing or with­
holding such treatment; these two actions are judged to be fundamen­
tally similar. An underlying stipulation derived from this report is that 
an informed patient should have their wishes respected with regard to 
life-sustaining therapy. Implicit in this stipulation is the need to ensure 
that patients are thoroughly and accurately informed regarding the 
plausibility and expected results of various therapies.
The act of informing patients and/or surrogate decision-makers 
is the responsibility of the physician and other health care providers. 
If a patient or surrogate desires therapy deemed futile by the treat­
ing physician, the physician is not obligated ethically to provide such 
treatment. Rather, arrangements may be made to transfer the patient’s 
care to another care provider. Whether the decision to withdraw 
life support should be initiated by the physician or left to surrogate 
decision-makers alone is not clear. One study reported that slightly 
more than half of surrogate decision-makers preferred to receive such 
a recommendation, whereas the rest did not. Critical care providers 
should meet regularly with patients and/or surrogates to discuss prog­
nosis when the withholding or withdrawal of care is being considered. 
After a consensus among caregivers has been reached, this information 
should be relayed to the patient and/or surrogate decision-maker. If a 
decision to withhold or withdraw life-sustaining care for a patient has 
been made, aggressive attention to analgesia and anxiolysis is needed. 
Often, an independent hospital ethics service can be of benefit in navi­
gating complex decision-making.
Acknowledgment
John P. Kress and Jesse B. Hall contributed to this chapter in the 
20th edition and some material from that chapter has been retained here.
■
■FURTHER READING
Andersen-Ranberg NC et al: Haloperidol for the treatment of delir­
ium in ICU patients. N Engl J Med 387:2425, 2022.
Evans L et al: Surviving Sepsis Campaign: International guidelines 
for management of sepsis and septic shock. Crit Care Med 49:e1063, 
2021.
Girard TD et al: An official American Thoracic Society/American 
College of Chest Physicians Clinical Practice Guideline: Liberation 
from mechanical ventilation in critically ill adults. Rehabilitation 
protocols, ventilator liberation protocols, and cuff leak tests. Am J 
Respir Crit Care Med 195:120, 2017.
Guerin C et al: Prone positioning in severe acute respiratory distress 
syndrome. N Engl J Med 368:2159, 2013.
Kapur J et al: Randomized trial of three anticonvulsant medications 
for status epilepticus. N Engl J Med 381:2103, 2019.
Man S et al: Association between thrombolytic door-to-needle time 
and 1-year mortality and readmission in patients with acute ischemic 
stroke. JAMA 323:2170, 2020.
Matthay MA et al: A new global definition of acute respiratory dis­
tress syndrome. Am J Respir Crit Care Med 209:37, 2024.
National Heart, Lung, and Blood Institute Petal Clinical 
Trials Network et al: Early neuromuscular blockade in the acute 
respiratory distress syndrome. N Engl J Med 380:1997, 2019.
Singer M et al: The third international consensus definitions for sepsis 
and septic shock (Sepsis-3). JAMA 315:801, 2016.
Toews I et al: Interventions for preventing upper gastrointestinal 
bleeding in people admitted to intensive care units. Cochrane Data­
base Syst Rev 6:CD008687, 2018.

Rebecca M. Baron, Bruce D. Levy

Acute Respiratory 

Distress Syndrome
Acute respiratory distress syndrome (ARDS) is a clinical syndrome 
of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary 
infiltrates leading to respiratory failure. ARDS can be caused by dif­
fuse lung injury from many underlying medical and surgical disor­
ders. The lung injury may be direct (e.g., toxic inhalation) or indirect 
(e.g., sepsis) (Table 312-1). The clinical features of ARDS are listed in 
Table 312-2. By expert consensus, ARDS was defined in 2012 by three 
categories based on the degrees of hypoxemia (Table 312-2). These 
stages of mild, moderate, and severe ARDS are associated with mortal­
ity risk and with the duration of mechanical ventilation in survivors. 
A more recent global definition of ARDS has been proposed that does 
not rely upon arterial blood gases, chest radiography, or use of posi­
tive end-expiratory pressure on invasive or noninvasive mechanical 
ventilation, recognizing the challenge of resource-poor settings and 
increasing use of high-flow nasal oxygen and noninvasive means of 
respiratory support.
CHAPTER 312
Acute Respiratory Distress Syndrome 
The annual incidence of ARDS prior to the COVID-19 pandemic 
was estimated to be as high as 60 cases per 100,000 population. 
Approximately 10% of all intensive care unit (ICU) admissions involve 
patients with ARDS. This chapter will focus on non–COVID-19 
ARDS. Please see Chap. 205 for more information on COVID.
■
■ETIOLOGY
While many medical and surgical illnesses have been associated with 
the development of ARDS, most cases (>80%) are caused by a relatively 
small number of clinical disorders: pneumonia and sepsis (~40–60%), 
followed in incidence by aspiration of gastric contents, trauma, multiple 
transfusions, and drug overdose. Among patients with trauma, the most 
frequently reported surgical conditions in ARDS are pulmonary contu­
sion, multiple bone fractures, and chest wall trauma/flail chest, whereas 
head trauma, near-drowning, toxic inhalation, and burns are more rare 
causes. The risks of developing ARDS are increased in patients with 
more than one predisposing medical or surgical condition.
Several other clinical variables have been associated with the devel­
opment of ARDS. These include older age, chronic alcohol abuse, 
pancreatitis, pneumonia and sepsis (40–60%, including pandemic 
COVID pneumonia and other respiratory viruses), and severity of 
critical illness. Trauma patients with an Acute Physiology and Chronic 
Health Evaluation (APACHE) II score ≥16 (Chap. 311) have a 2.5-fold 
increased risk of developing ARDS.
■
■CLINICAL COURSE AND PATHOPHYSIOLOGY
The natural history of ARDS is marked by three phases—exudative, 
proliferative, and fibrotic—that each have characteristic clinical and 
pathologic features (Fig. 312-1).
TABLE 312-1  Clinical Disorders Commonly Associated with ARDS
DIRECT LUNG INJURY
INDIRECT LUNG INJURY
Pneumonia
Sepsis
Aspiration of gastric contents
Severe trauma
Pulmonary contusion
  Multiple bone fractures
Near-drowning
  Flail chest
Toxic inhalation injury
  Head trauma
 
  Burns
 
Multiple transfusions
 
Drug overdose
 
Pancreatitis
 
Postcardiopulmonary bypass

TABLE 312-2  Diagnostic Criteria for ARDS Based on 2012 Berlin Criteria
SEVERITY: OXYGENATIONa
ONSET
CHEST RADIOGRAPHb
ABSENCE OF LEFT ATRIAL 
HYPERTENSION
Mild: 200 mmHg < Pao2/Fio2 ≤300 mmHg
Moderate: 100 mmHg < Pao2/Fio2 ≤200 
mmHg
Severe: Pao2/Fio2 ≤100 mmHg
Acute: Within 1 week of a clinical 
insult or new or worsening respiratory 
symptoms
aAs assessed on at least 5 cmH2O of positive end-expiratory pressure (PEEP). 2023 proposed updates to the Berlin criteria include: (1) consideration of ARDS in nonintubated 
patients using Pao2/Fio2 ≤300 mmHg or Spo2/Fio2 (S/F) ≤315 mmHg (if Spo2 ≤97% as measured by pulse oximetry) on high-flow nasal oxygen with flow of ≥30 L/min or 
noninvasive ventilation/continuous positive airway pressure with at least 5 cmH2O of PEEP; (2) addition of S/F ratios to consideration of ARDS in intubated patients (mild: 
235 < Spo2/Fio2 ≤ 315 mmHg; moderate: 148 < Spo2/Fio2 ≤ 235 mmHg; severe: Spo2/Fio2 ≤148 mmHg [if Spo2 ≤97%]); and (3) consideration of ARDS in resource-limited settings if 
Spo2/Fio2 ≤ 315 mmHg (if Spo2 ≤97%) without requirement for PEEP, minimum oxygen flow rate, or specific respiratory support devices. It should be noted that pulse oximetry 
may overestimate the oxygen saturation in patients with darker skin tones, such that correlation with Pao2 should be considered when feasible. bThe 2023 proposed update 
to the Berlin criteria permits ultrasound as an alternative imaging modality, especially in resource-limited settings.
Abbreviations: ARDS, acute respiratory distress syndrome; Fio2, inspired O2 percentage; Pao2, arterial partial pressure of O2, Spo2, peripheral saturation of O2.
PART 8
Critical Care Medicine
Exudative Phase 
In this phase, alveolar capillary endothelial 
cells and type I pneumocytes (alveolar epithelial cells) are injured, 
with consequent loss of the normally tight alveolar barrier to fluid 
and macromolecules. Edema fluid that is rich in protein accumulates 
in the interstitial and alveolar spaces (Fig. 312-2). Proinflammatory 
cytokines (e.g., interleukin 1, interleukin 6, interleukin 8, and tumor 
necrosis factor α [TNF-α]) and lipid mediators (e.g., leukotriene B4) are 
increased in this acute phase, leading to the recruitment of leukocytes 
(especially neutrophils) into the pulmonary interstitium and alveoli. 
In addition, condensed plasma proteins aggregate in the air spaces 
with cellular debris and dysfunctional pulmonary surfactant to form 
hyaline membrane whorls. Pulmonary vascular injury also occurs early 
in ARDS, with vascular obliteration by microthrombi and fibrocellular 
proliferation (Fig. 312-3).
Alveolar edema often predominantly involves dependent portions of 
the lung with diminished aeration. Collapse of large sections of depen­
dent lung can contribute to decreased lung compliance. Consequently, 
intrapulmonary shunting and hypoxemia develop and the work of 
breathing increases, leading to dyspnea. The pathophysiologic altera­
tions in alveolar spaces are exacerbated by microvascular occlusion 
that results in reductions in pulmonary arterial blood flow to ventilated 
portions of the lung (and thus in increased dead space and pulmonary 
vascular resistance) and in pulmonary hypertension. Thus, in addition 
to severe hypoxemia, hypercapnia secondary to an increase in pulmo­
nary dead space can be prominent in ARDS.
The exudative phase usually encompasses the first 7 days of illness 
after exposure to a precipitating ARDS risk factor, with the patient 
experiencing the onset of respiratory symptoms. Although usually pre­
senting within 12–36 h after the initial insult, symptoms can be delayed 
by 5–7 days. Dyspnea develops, with a sensation of rapid shallow 
breathing and an inability to get enough air. Tachypnea and increased 
work of breathing result frequently in respiratory fatigue and ultimately 
in respiratory failure. Laboratory values are generally nonspecific and 
are primarily indicative of underlying clinical disorders. The chest 
radiograph usually reveals opacities consistent with pulmonary edema 
Exudative
Proliferative
Fibrotic
Hyaline
Membranes
Edema
Interstitial Inflammation
Fibrosis
Day:

21. . .
FIGURE 312-1  Diagram illustrating the time course for the development and 
resolution of acute respiratory distress syndrome (ARDS). The exudative phase 
is notable for early alveolar edema and neutrophil-rich leukocytic infiltration of 
the lungs, with subsequent formation of hyaline membranes from diffuse alveolar 
damage. Within 7 days, a proliferative phase ensues with prominent interstitial 
inflammation and early fibrotic changes. Approximately 3 weeks after the initial 
pulmonary injury, most patients recover. However, some patients enter the fibrotic 
phase, with substantial fibrosis and bullae formation.

Bilateral opacities consistent with 
pulmonary edema not fully explained 
by effusions, lobar/lung collapse, or 
nodules
Hydrostatic edema is not the primary 
cause of respiratory failure. If no 
ARDS risk factor is present, then 
some objective evaluation is required 
(e.g., echocardiography) to rule out 
hydrostatic edema
and often involves at least three-quarters of the lung fields (Fig. 312-2). 
While characteristic for ARDS, these radiographic findings are not spe­
cific and can be indistinguishable from cardiogenic pulmonary edema 
(Chap. 316). Unlike the latter, however, the chest x-ray in ARDS may 
not demonstrate cardiomegaly, pleural effusions, or pulmonary vas­
cular redistribution as is often present in pure cardiogenic pulmonary 
edema. If no ARDS risk factor is present, then some objective evalua­
tion is required (e.g., echocardiography) to exclude a cardiac etiology 
for hydrostatic edema. Chest computed tomography (CT) in ARDS 
also reveals the presence of bilateral pulmonary infiltrates and demon­
strates extensive heterogeneity of lung involvement (Fig. 312-4).
Because the early features of ARDS are nonspecific, alternative 
diagnoses must be considered, although it is possible that there can 
be coexisting conditions with ARDS. In the differential diagnosis 
of ARDS, the most common disorders are cardiogenic pulmonary 
edema, bilateral pneumonia, and alveolar hemorrhage. Less common 
diagnoses to consider include acute interstitial lung diseases (e.g., 
acute interstitial pneumonitis; Chap. 304), acute immunologic injury 
(e.g., hypersensitivity pneumonitis; Chap. 299), toxin injury (e.g., 
radiation pneumonitis; Chap. 80), and neurogenic pulmonary edema 
(Chap. 39).
Proliferative Phase 
This phase of ARDS usually lasts from 
approximately day 7 to day 21. Many patients recover rapidly during 
this phase. Despite this improvement, many patients still experience 
dyspnea, tachypnea, and hypoxemia. Some patients develop progres­
sive lung injury and early changes of pulmonary fibrosis during the 
proliferative phase. Histologically, the first signs of resolution are often 
FIGURE 312-2  A representative anteroposterior chest x-ray in the exudative phase 
of acute respiratory distress syndrome (ARDS) shows bilateral opacities consistent 
with pulmonary edema that can be difficult to distinguish from left ventricular failure.

Acute Respiratory Distress Syndrome 

CHAPTER 312
FIGURE 312-3  The injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome. A variety of insults (e.g., bacteria, viruses) can 
injure the epithelium, and this direct injury is propagated by subsequent activation of downstream pathways. Activation of Toll-like receptors (not shown) on alveolar type 
II (ATII) epithelial cells and resident macrophages induces the secretion of chemokines, which recruit circulating immune cells into the airspaces. As neutrophils migrate 
across the epithelium, they release toxic mediators, including proteases, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which have an important 
role in host defense but also can exacerbate endothelial and epithelial injury. Monocytes also migrate into the lung and can cause injury, including epithelial cell apoptosis 
via interferon (IFN)-β-dependent release of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which activates death receptors. Activated platelets 
form aggregates with polymorphonuclear (PMN) leukocytes (which are involved in NET formation) and monocytes. Red blood cells (RBCs) release cell-free hemoglobin, 
which exacerbates injury via oxidant-dependent mechanisms. Epithelial injury also includes injury to the plasma membrane, which can be induced by bacterial pore-forming 
toxins or mechanical stretch (often related to mechanical ventilation), and mitochondrial dysfunction. Together, these and other effects result in endothelial and epithelial 
permeability, which further facilitate the transmigration of leukocytes and lead to the influx of edematous fluid and RBCs. Airspace filling with edematous fluid causes 
hypoxemia, often resulting in the need for mechanical ventilation. Vascular injury and alveolar edema can contribute to decreased ability to excrete CO2 (hypercapnia), 
accounting for increased pulmonary dead space in acute respiratory distress syndrome. In turn, hypoxemia and hypercapnia impair sodium transport, reducing alveolar 
edema clearance. ATI, alveolar type I cell; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel. (Reproduced with permission from MA Matthay et al: Acute 
respiratory distress syndrome. Nat Rev Dis Primers 5:18, 2019.)
FIGURE 312-4  A representative CT scan of the chest during the exudative phase of 
acute respiratory distress syndrome (ARDS), in which dependent alveolar edema 
and atelectasis predominate.
evident in this phase, with the initiation of lung repair, the organiza­
tion of alveolar exudates, and a shift from neutrophil- to lymphocytepredominant pulmonary infiltrates. As part of the reparative process, 
type II pneumocytes proliferate along alveolar basement membranes. 
These specialized epithelial cells synthesize new pulmonary surfactant 
and differentiate into type I pneumocytes.
Fibrotic Phase 
While many patients with ARDS recover lung 
function 3–4 weeks after the initial pulmonary injury, some enter 
a fibrotic phase that may require long-term support on mechanical 
ventilators and/or supplemental oxygen. Histologically, the alveo­
lar edema and inflammatory exudates of earlier phases convert to 
extensive alveolar-duct and interstitial fibrosis. Marked disruption of 
acinar architecture leads to emphysema-like changes, with large bullae. 
Intimal fibroproliferation in the pulmonary microcirculation causes 
progressive vascular occlusion and pulmonary hypertension. The 
physiologic consequences include an increased risk of pneumothorax, 
reductions in lung compliance, and increased pulmonary dead space. 
Patients in this late phase experience a substantial burden of excess

PART 8
Critical Care Medicine
morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase 
of ARDS is associated with increased mortality risk.
TREATMENT
Acute Respiratory Distress Syndrome 
GENERAL PRINCIPLES
Recent reductions in ARDS mortality rates are largely the result of 
general advances in the care of critically ill patients (Chap. 311). 
Thus, caring for these patients requires close attention to (1) the 
recognition and treatment of underlying medical and surgical dis­
orders (e.g., pneumonia, sepsis, aspiration, trauma); (2) the mini­
mization of unnecessary procedures and their complications; (3) 
standardized “bundled care” approaches for ICU patients, includ­
ing prophylaxis against venous thromboembolism, gastrointesti­
nal bleeding, aspiration, excessive sedation, prolonged mechanical 
ventilation, and central venous catheter infections; (4) prompt 
recognition of nosocomial infections; and (5) provision of adequate 
nutrition via the enteral route when feasible. 
MANAGEMENT OF MECHANICAL VENTILATION
(See also Chap. 313) Patients meeting clinical criteria for ARDS 
frequently become fatigued from increased work of breathing and 
progressive hypoxemia, requiring mechanical ventilation for sup­
port, although increasing use of high-flow nasal oxygen and non­
invasive ventilation has enabled some patients to avoid mechanical 
ventilation. 
Minimizing Ventilator-Induced Lung Injury  Despite its life-saving 
potential, mechanical ventilation can aggravate lung injury from 
high tidal volumes. Experimental models have demonstrated that 
ventilator-induced lung injury can arise from at least two principal 
mechanisms: “volutrauma” from repeated alveolar overdistention 
from excess tidal volume (that might also coincide with increased 
alveolar pressures, or “barotrauma”) and “atelectrauma” from recur­
rent alveolar collapse. As is evident from chest CT (Fig. 312-4), 
ARDS is a heterogeneous disorder, often principally involving 
dependent portions of the lung with relative sparing of other 
regions. Because compliance differs in affected versus more “nor­
mal” areas of the lung, attempts to fully inflate the consolidated lung 
may lead to overdistention of and injury to the more normal areas. 
Ventilator-induced injury can be demonstrated in experimental 
models of acute lung injury, in particular with high-tidal-volume 
(VT) ventilation.
A large-scale, randomized controlled trial sponsored by the 
National Institutes of Health and conducted by the ARDS Network 
compared low VT ventilation (6 mL/kg of predicted body weight) 
to conventional VT ventilation (12 mL/kg predicted body weight). 
Lower airway pressures were also targeted in the low-tidal-volume 
group (i.e., plateau pressure measured on the ventilator after a 0.5-s 
pause after inspiration), with pressures targeted at ≤30 cmH2O in 
the low-tidal-volume group versus ≤50 cmH2O in the high-tidalvolume group. The mortality rate was significantly lower in the low 
VT patients (31%) than in the conventional VT patients (40%). This 
improvement in survival represents a substantial ARDS mortality 
benefit. 
Minimizing Atelectrauma by Prevention of Alveolar Collapse  In 
ARDS, the presence of alveolar and interstitial fluid and the loss 
of surfactant can lead to a marked reduction of lung compliance. 
Without an increase in end-expiratory pressure, significant alveolar 
collapse can occur at end-expiration, with consequent impairment 
of oxygenation. In most clinical settings, positive end-expiratory 
pressure (PEEP) is adjusted to minimize Fio2 (inspired O2 percent­
age) and provide adequate Pao2 (arterial partial pressure of O2) 
without causing alveolar overdistention. It should be noted that 
high-flow nasal cannula may provide low levels of PEEP. Currently, 
there is no consensus on the optimal method to set PEEP on the 
ventilator because numerous trials have proved inconclusive. Pos­
sible approaches include using the table of PEEP-Fio2 combinations 
from the ARDS Network trial group, generating a static pressurevolume curve for the respiratory system and setting PEEP just 
above the lower inflection point on this curve to maximize respira­
tory system compliance, and measuring esophageal pressures to 
estimate transpulmonary pressure (which may be particularly help­
ful in patients with a stiff chest wall). Of note, a recent phase 2 trial 
in patients with moderate-to-severe ARDS demonstrated no benefit 
of routine use of esophageal pressure-guided PEEP titration over 
empirical high PEEP-Fio2 titration. Until more data become avail­
able on how best to optimize PEEP settings in ARDS, clinicians can 
use these options or a practical approach to empirically measure 
“best PEEP” at the bedside to determine the optimal settings that 
best promote alveolar recruitment, minimize alveolar overdisten­
tion and hemodynamic instability, and provide adequate Pao2 while 
minimizing Fio2 (Chap. 313). 
Prone Positioning  While several prior trials demonstrated that 
mechanical ventilation in the prone position improved arterial 
oxygenation without a mortality benefit, a 2013 trial demonstrated 
a significant reduction in 28-day mortality with prone position­
ing (32.8 to 16.0%) for patients with severe ARDS (Pao2/Fio2 
<150 mmHg) early in their course of illness. Thus, many centers 
increased the use of prone positioning in severe ARDS, especially 
during the COVID pandemic, with the understanding that this 
maneuver requires a critical care team that is experienced in “pron­
ing,” as repositioning critically ill patients can be hazardous, leading 
to accidental endotracheal extubation, loss of central venous cath­
eters, and orthopedic injury. 
OTHER STRATEGIES IN MECHANICAL VENTILATION
Recruitment maneuvers that transiently increase PEEP to high 
levels to “recruit” atelectatic lung can increase oxygenation, but 
a mortality benefit has not been established, and in fact, recruit­
ment maneuvers were shown to increase mortality when combined 
with higher baseline PEEP settings. Alternate modes of mechanical 
ventilation, such as airway pressure release ventilation and highfrequency oscillatory ventilation, have not been proven beneficial 
over standard modes of ventilation in ARDS management. In 
one study, lung-replacement therapy with extracorporeal membrane 
oxygenation (ECMO) was shown to improve mortality for patients 
with ARDS in the United Kingdom who were referred to an ECMO 
center (though only 75% of referred patients received ECMO) and 
thus may have utility in select adult patients with severe ARDS as 
a rescue therapy. A subsequent study demonstrated that initial use 
of ECMO in patients with severe ARDS was not superior to use of 
ECMO as a rescue strategy for patients who failed standard ARDS 
management. 
FLUID MANAGEMENT
(See also Chap. 311) Increased pulmonary vascular permeability 
leading to interstitial and alveolar edema fluid rich in protein is a 
central feature of ARDS. In addition, impaired vascular integrity 
augments the normal increase in extravascular lung water that 
occurs with increasing left atrial pressure. Maintaining a low left 
atrial filling pressure minimizes pulmonary edema and prevents 
further decrements in arterial oxygenation and lung compliance; 
improves pulmonary mechanics; and shortens ICU stay and the 
duration of mechanical ventilation. Thus, aggressive attempts to 
reduce left atrial filling pressures with fluid restriction and diuret­
ics should be an important aspect of ARDS management, limited 
only by hypotension and hypoperfusion of critical organs such as 
the kidneys. 
NEUROMUSCULAR BLOCKADE
In severe ARDS, sedation alone can be inadequate for the patientventilator synchrony required for lung-protective ventilation. In a 
multicenter, randomized, placebo-controlled trial of early neuro­
muscular blockade (with cisatracurium besylate) for 48 h, patients 
with severe ARDS had increased survival and ventilator-free days 
without increasing ICU-acquired paresis. A subsequent trial dem­
onstrated no mortality benefit for early neuromuscular blockade for

48 h in patients with moderate-to-severe ARDS. This more recent 
study supports the notion that selective use of neuromuscular 
blockade might be beneficial in those ARDS patients with ventila­
tory dyssynchrony despite sedation. 
GLUCOCORTICOIDS
Many attempts have been made to treat both early and late ARDS 
with glucocorticoids, with the goal of reducing potentially del­
eterious pulmonary inflammation. Few studies have shown any 
significant mortality benefit. Current evidence does not support the 
routine use of glucocorticoids in the care of ARDS patients. More 
recent guidelines have supported the use of low-dose hydrocorti­
sone (200 mg over 24 h) in sepsis patients with refractory hypoten­
sion and in patients with severe community-acquired pneumonia, 
which are conditions that often coexist with ARDS. 
OTHER THERAPIES
Clinical trials of surfactant replacement and multiple other medical 
therapies have proved disappointing. Pulmonary vasodilators such as 
inhaled nitric oxide and inhaled epoprostenol sodium can transiently 
improve oxygenation in some patients but have not been shown to 
improve survival or decrease time on mechanical ventilation. 
RECOMMENDATIONS
Many clinical trials have been undertaken to improve the outcome 
of patients with ARDS; most have been unsuccessful in modifying 
the natural history. While results of large clinical trials must be 
judiciously applied to individual patients, evidence-based recom­
mendations are summarized in Table 312-3, and an algorithm for 
the initial therapeutic goals and limits in ARDS management is 
provided in Fig. 312-5. Please note that these recommendations 
apply to non–COVID-19 ARDS. Please see recommendations for 
COVID-19 ARDS in Chap. 205.
TABLE 312-3  Evidence-Based Recommendations for ARDS Therapies
TREATMENT
RECOMMENDATIONa
Mechanical ventilation
 
  Low tidal volume
A
  Minimized left atrial filling 
pressures
B
  High-PEEP or “open lung”
Bb
  Prone position
Bb
  Recruitment maneuvers
Cb
  High-frequency ventilation
D
ECMO
Bb
Early neuromuscular blockade 
(routine use)
Cb
Glucocorticoid treatment
Dc
Inhaled vasodilators (e.g., inhaled 
NO, inhaled epoprostenol)
C
Surfactant replacement, and other 
anti-inflammatory therapy (e.g., 
ketoconazole, PGE1, NSAIDs)
D
aKey: A, recommended therapy based on strong clinical evidence from randomized 
clinical trials; B, recommended therapy based on supportive but limited clinical 
data; C, recommended only as alternative therapy on the basis of indeterminate 
evidence; D, not recommended on the basis of clinical evidence against efficacy of 
therapy. bAs described in the text, there is no consensus on optimal PEEP setting 
in ARDS, but general consensus supports an open lung strategy that minimizes 
alveolar distention with some studies favoring the high PEEP-Fio2 ARDS table; prone 
positioning was shown to improve mortality in severe ARDS in one randomized 
controlled clinical trial; recruitment maneuvers combined with high PEEP were 
shown to increase mortality in one study; ECMO may be beneficial in select patients 
with severe ARDS; early neuromuscular blockade demonstrated a mortality benefit 
in one randomized controlled trial in patients with severe ARDS but was not 
replicated in a subsequent study, suggesting routine use of early neuromuscular 
blockade in all subjects with moderate-severe ARDS may not be beneficial. cWhile 
there are no direct supportive data for use of glucocorticoids in ARDS, there 
are recent data supporting the consideration of low-dose hydrocortisone in two 
conditions frequently encountered in patients with ARDS: (1) the 2021 Surviving 
Sepsis guidelines recommend consideration of low-dose hydrocortisone in 
patients with refractory hypotension due to septic shock, and (2) a recent study 
demonstrated a mortality benefit of low-dose hydrocortisone in patients with severe 
community-acquired pneumonia.
Abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal 
membrane oxygenation; NO, nitric oxide; NSAIDs, nonsteroidal anti-inflammatory 
drugs; PEEP, positive end-expiratory pressure; PGE1, prostaglandin E1.

Goals and Limits:
Initiate
volume/pressure-limited
ventilation
Tidal volume ≤6 mL/kg PBW
Plateau pressure ≤30 cmH2O
RR ≤35 bpm
FIO2 ≤0.6
SpO2 88–95%
Oxygenate
pH ≥7.30
RR ≤35 bpm
Minimize acidosis
MAP ≥65 mmHg
Avoid hypoperfusion
CHAPTER 312
Diuresis
FIGURE 312-5  Algorithm for the initial management of acute respiratory distress 
syndrome (ARDS). Clinical trials have provided evidence-based therapeutic goals 
for a stepwise approach to the early mechanical ventilation, oxygenation, and 
correction of acidosis and diuresis of critically ill patients with ARDS. Fio2, inspired 
O2 percentage; MAP, mean arterial pressure; PBW, predicted body weight; RR, 
respiratory rate; Spo2, arterial oxyhemoglobin saturation measured by pulse 
oximetry.
Acute Respiratory Distress Syndrome 
■
■PROGNOSIS
Mortality 
In the Large Observational Study to Understand the 
Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) trial, 
hospital mortality estimates for ARDS were 34.9% for mild ARDS, 
40.3% for moderate ARDS, and 46.1% for severe ARDS. There is sub­
stantial variability, but a trend toward improved ARDS outcomes over 
time appears evident. Of interest, mortality in ARDS is largely attribut­
able to nonpulmonary causes, with sepsis and nonpulmonary organ 
failure accounting for >80% of deaths. Thus, improvement in survival 
is likely secondary to advances in the care of septic/infected patients 
and those with multiple organ failure (Chap. 311).
The major risk factors for ARDS mortality are nonpulmonary. 
Advanced age is an important risk factor. Patients aged >75 years have 
a substantially higher mortality risk (~60%) than those <45 (~20%). 
Moreover, patients >60 years of age with ARDS and sepsis have a 
threefold higher mortality risk than those <60 years of age. Other risk 
factors include preexisting organ dysfunction from chronic medical 
illness—in particular, chronic liver disease, chronic alcohol abuse, and 
chronic immunosuppression (Chap. 311). Patients with ARDS arising 
from direct lung injury (including pneumonia, pulmonary contusion, 
and aspiration; Table 312-1) are nearly twice as likely to die as those 
with indirect causes of lung injury, while surgical and trauma patients 
with ARDS—especially those without direct lung injury—generally 
have a higher survival rate than other ARDS patients.
Increasing severity of ARDS, as defined by the consensus Berlin 
definition, predicts increased mortality. Surprisingly, there is little 
additional value in predicting ARDS mortality from other parameters 
of lung injury, including the level of PEEP (≥10 cmH2O), respiratory 
system compliance (≤40 mL/cmH2O), the extent of alveolar infiltrates 
on chest radiography, and the corrected expired volume per minute 
(≥10 L/min) (as a surrogate measure of dead space).
Functional Recovery in ARDS Survivors 
While it is common 
for patients with ARDS to experience prolonged respiratory failure 
and remain dependent on mechanical ventilation for survival, it is 
a testament to the resolving powers of the lung that the majority of