E a r l y Tre a t m e n t o f Se v e re

A c u t e R e s p i r a t o r y D i s t res s
S y n d ro m e
Thomas M. Przybysz,

MD

, Alan C. Heffner,

MD

a,b,

KEYWORDS
 Acute respiratory distress syndrome  Acute respiratory failure  Hypoxia
 Hypoxemia  Severe ARDS
KEY POINTS
 Severe acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute bilateral pulmonary infiltrates occurring after a recognizable trigger and a
PaO2 to fraction of inspired oxygen (FIO2) ratio of less than 100.
 Patients with all severities of ARDS should be managed with a low tidal volume strategy,
safe plateau pressures, and fluid restriction as tolerated by hemodynamics.
 Patients with severe ARDS should receive early neuromuscular blockade and consideration for prone ventilation. Patients with severe ARDS not responding to therapy should
be transferred to an ECMO center.

INTRODUCTION

ARDS is a rare but life-threatening syndrome characterized by acute bilateral inflammatory pulmonary infiltrates and severe hypoxia. US cases were estimated at
86 per 100,000 individuals, with 74,500 annual deaths in 2005.13 ARDS survival has
improved due to advances in supportive care but mortality remains at 27% to 45%
depending on the severity of ARDS. ARDS is classified into physiologic and prognostic
categories of mild, moderate, and severe based on PaO2 to FIO2 (P/F) ratio (200300,
100200, and <100, respectively).4
ARDS may be triggered by pulmonary and nonpulmonary insults. It most commonly
occurs in patients with acute critical illness due to sepsis, pneumonia, and trauma,

a
Division of Critical Care Medicine, Department of Internal Medicine, Carolinas Medical Center, 1000 Blyth Boulevard, Charlotte, NC 28203, USA; b Medical ICU, Department of Emergency
Medicine, Carolinas Medical Center, University of North Carolina, Charlotte Campus, 1000 Blyth
Boulevard, Charlotte, NC 28203, USA
* Corresponding author. Medical ICU, Department of Emergency Medicine, Carolinas Medical
Center, University of North Carolina, Charlotte Campus, 1000 Blyth Boulevard, Charlotte, NC
28203.
E-mail address: [email protected]

Emerg Med Clin N Am - (2015) -http://dx.doi.org/10.1016/j.emc.2015.08.001

0733-8627/15/$ see front matter 2015 Elsevier Inc. All rights reserved.

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Przybysz & Heffner

where it is often accompanied by multiorgan dysfunction. Primary lung disease may

be the initial or sole manifestation of acute severe ARDS in some cases, with pulmonary aspiration and near-drowning 2 common examples. This review discusses the
clinical presentation of ARDS and provides an evidence-based approach to the early
management of ARDS pertinent to emergency medicine physicians, with a focus on
severe ARDS.
CLINICAL PRESENTATION AND ACUTE RESPIRATORY DISTRESS SYNDROME DEFINITION

Patients with ARDS exhibit hypoxemia associated with acute bilateral pulmonary infiltrates occurring within 1 week of a provoking insult. Intubation and mechanical ventilation with a high FIO2 are often required to compensate for the large alveolar-arterial
oxygen gradient. The former definition of ARDS and acute lung injury required exclusion of left atrial hypertension causing hydrostatic pulmonary edema. The revised
criteria, however, removed this strict criteria, recognizing that inflammatory lung disease and elevated left atrial pressures are not mutually exclusive.4
The pathophysiology of ARDS includes increased pulmonary vascular permeability,
loss of aerated lung, decreased lung compliance, and increase in physiologic dead
space. The damaged capillaries allow protein-rich fluid to overwhelm the normal
lymphatic drainage of the lung.5 Chest radiograph (CXR) frequently demonstrates
diffuse and homogeneous infiltrates; however, CT scans often reveal a heterogeneous
pattern of dependent consolidation.6
PATIENT EVALUATION

Hypoxia with acute bilateral infiltrates after a known trigger associated with ARDS is
clinically diagnostic (Table 1). Usually a diagnosis of ARDS is determined with a
good patient history, physical examination, and CXR data. Some patients develop
ARDS during an emergency room course (eg, worsening sepsis, aspiration, and influenza), which can be overlooked without a high index of suspicion. Occasionally
patients with ARDS present without a known trigger or an incomplete history, which
makes a diagnosis of ARDS more difficult to confirm. Incomplete patient history
and nonspecific time-consuming diagnostics are early hurdles in quickly identifying
the inciting cause of ARDS for some atypical presentations and other causes for
bilateral infiltrates should be considered (Table 2). Hydrostatic pulmonary edema
commonly mimics ARDS and can be difficult to correctly identify. CXRs have limited

Table 1
Conditions associated with acute respiratory distress syndrome
Sepsis

Pulmonary contusion

Aspiration

After upper airway obstruction

Infectious pneumonia

Stem cell transplant

Trauma

Drug reaction

Burn

Venous air embolism

Blood product transfusion

Amniotic fluid embolism

Cardiopulmonary bypass

Neurogenic pulmonary edema

Pancreatitis

Acute eosinophilic pneumonia

Drug overdose

Bronchiolitis obliterans organizing pneumonia

Near drowning

Smoke inhalation

Treatment of Severe ARDS

Table 2
Mimics of acute respiratory distress syndrome
Disease

Test

Comment

Pulmonary
edema

BNP
CXR

Not specific for heart failure

Unable to distinguish reliably from
ARDS
Useful at distinguishing from ARDS
Not sensitive for diastolic dysfunction
or volume overload. ARDS can
cause stress-induced systolic
dysfunction
Promising but needs to be verified in
larger study

Chest CT
Echocardiogram

Lung ultrasound
Atelectasis

None

Should improve with proper

recruitment

Diffuse alveolar
hemorrhage

Bronchoscopy or biopsy

Treat underlying disease

Eosinophilic
pneumonia

Bronchoscopy or biopsy

May respond to steroids

Malignancy

Biopsy

Treat underlying disease

Hypersensitivity
pneumonitis

Exposure history, bronchoscopy,

and biopsy

Remove inciting antigen

value in distinguishing these 2 types of edema as do laboratory tests.7 Brain natriuretic

peptide (BNP) values can be elevated in both ARDS and heart failure.8,9 BNP less than
100 pg/mL, however, makes heart failure an unlikely cause of bilateral pulmonary infiltrates.10 Echocardiography is useful to evaluate factors associated with elevated left
atrial pressure, such as systolic dysfunction and valvular disease, but is less accurate
in evaluating diastolic dysfunction. Although the morphology of pulmonary infiltrates
on CT is more useful in differentiating hydrostatic edema from inflammatory ARDS,
obtaining CT imaging may not be feasible in an unstable patient.11 It is also important
to remember that patients do not always follow classic clinical categories. As an
example, ARDS triggers may also provoke stress-induced cardiomyopathy, making
pure clinical differentiation of inflammatory and hydrostatic edema difficult.12
Bedside lung ultrasound is a helpful diagnostic tool. A small study of pulmonary
edema patients suggests clinical utility of bedside lung ultrasound in distinguishing inflammatory and hydrostatic edema.13 Different ultrasound images for ARDS and hydrostatic edema are seen in Figs. 1 and 2. Spared areas, pleural abnormalities, and
consolidation favor inflammatory infiltrates, whereas large effusions, smooth thin
pleural line, and diffuse homogenous alveolar-interstitial syndrome (or white lung) suggest hydrostatic edema (Table 3). Although this study needs to be confirmed in a
larger cohort, the results are encouraging and may allow for improved accuracy and
rapid bedside diagnosis of severe ARDS.
Diffuse alveolar hemorrhage, eosinophilic pneumonia, hypersensitivity pneumonitis,
and malignancy can also present similarly to ARDS. Bronchoscopy and open lung biopsy are generally required to confirm these diagnoses.
EARLY MANAGEMENT

The main priorities of early ARDS management are maintenance of systemic oxygen
delivery (DO2) and avoidance of iatrogenic ventilator-induced lung injury. Always

Przybysz & Heffner

Fig. 1. Lung ultrasound of patient with ARDS. Note the pleural abnormalities. (Courtesy of
Jacob Avila.)

remember, the physiologic goals in ARDS management are not intuitive. Strict therapeutic normalization of pH, PCO2, and PO2 is associated with adverse outcomes, as
evidenced by the 9% absolute mortality increase in the ARDSNet trial control group,
despite higher arterial oxygen saturation (SaO2) levels during the first 24 hours of
care.14 Similarly, permissive hypercapnea, which prioritizes safe low tidal volume
mechanical ventilation at the expense of systemic hypercapnea, is associated with
improved outcomes.15,16
SaO2 is easily measured, but the ideal target in ARDS is unknown and may be difficult to standardize because systemic DO2 is the more important variable correlating
with ARDS patient survival.17,18 The relationship between DO2 and SaO2 is described
in Equation 1. Despite poor oxygenation and impaired DO2, a majority of ARDS deaths
are attributed to multiorgan failure rather than refractory hypoxemia.19
DO2 5 [1.39  Hgb  SaO2 1 (0.003  PaO2)]  cardiac output

(1)

Cardiac output (CO) has a linear relationship to systemic DO2 and many patients
have physiologic reserve to dramatically augment CO in the context of severe critical
illness. Adequacy of SaO2 in severe lung disease requires interpretation in the context

Fig. 2. Lung ultrasound of a patient with hydrostatic edema. Note the thin smooth pleural
line. (Courtesy of Jacob Avila.)

Treatment of Severe ARDS

Table 3
Differentiation of acute respiratory distress syndrome and pulmonary edema with lung
ultrasound
Characteristics of Acute Respiratory Distress
Syndrome

Characteristics of Pulmonary Edema

Alveolar-interstitial syndrome

Alveolar-interstitial syndrome

Pleural line abnormality

Large pleural effusions

Reduction of lung sliding

Homogeneous pattern

Spared areas

Consolidation

Small pleural effusion

of systemic hemodynamics. Rather than focusing on the hemoglobin saturation, the

early goals of care for severe ARDS patients are maintaining systemic DO2, optimizing
hemodynamics, and minimizing ongoing lung injury. Patients can die early from severe
ARDS and it is important to have a strategy to deal with life-threatening hypoxia
(Table 4).
TREATMENT OF LIFE-THREATENING HYPOXIA
Fraction of Inspired Oxygen

The quickest and simplest method of improving oxygenation is increasing FIO2 delivery. Knowledge of the delivery systems designed to provide supplemental oxygen is
important. For example, the term, 100% nonrebreather, is a misnomer. Respiratory
DO2 depends on patient-specific respiratory mechanics, such as minute ventilation,
inspiratory flow, and work of breathing. For a fixed nasal cannula flow rate, there is significant variability of delivered oxygen among healthy volunteers.20 In the setting of
high minute ventilation, the FIO2 delivered to alveoli is simply diluted by entrainment
of ambient air.21
Newer humidified high-flow nasal cannulas (Fig. 3) can deliver measured FIO2 closer
to machine-set FIO2, provided the flow rates are high (3060 liters per minute [lpm]),
which allows these devices to provide higher FIO2 than traditional face masks.22
Although a majority of patients with ARDS ultimately require mechanical ventilation,
understanding the limits of supplemental oxygen should improve patient safety
(Table 5). ARDS patients are at increased risk for peri-intubation complications and
Table 4
Life-threatening hypoxia therapies
Physiologic Methods to Improve Life-Threatening Hypoxemia
Increase FIO2

Confirm delivery of 100% oxygen

Increase mean airway pressure

Optimize MAP while monitoring plateau pressure and CO

Recruit more alveoli

Perform RMs, clear secretions, increase PEEP, treat

pneumothorax if present, prone positioning, check for
dynamic hyperinflation

Improve lung diffusion

Assess for response to diuretics or need for ultrafiltration

Improve or redistribute
blood flow

Assess CO and add inotropes if indicated, prone

positioning, inhaled NO, inhaled epoprostenol

Add extracorporeal support

VV-ECMO, VA-ECMO

Przybysz & Heffner

Fig. 3. Typical setup for a humidified high-flow nasal cannula in a patient with severe
hypoxia.

death due to limited pulmonary reserve and hypoxia. Noninvasive ventilation and humidified high-flow nasal cannulas are capable of delivering higher FIO2 than simple
face masks, Venturi masks, and nonrebreathers; consequently, they are useful tools
to preoxygenate prior to intubation.
Patients with severe ARDS are tenuous and the most skilled provider available
should be in charge of safely securing their airways. Rapid sequence intubation with
neuromuscular blocking agents is highly recommended given its association with
reduced aspiration and death.23 Safely intubating hypoxic patients is an important skill
but is not discussed at length in this review. Information about preoxygenation and
about reducing peri-intubation morbidity and mortality is found at www.emcrit.org
and in the article on airway management elsewhere in this issue.
Mean Airway Pressure

After optimizing FIO2, the next maneuvers should focus on increasing mean airway
pressure. Positive pressure ventilation associated with mechanical ventilation increases mean airway pressure and, thereby, recruits functional but collapsed lung.
Increasing mean airway pressure also independently raises the partial pressure of

Table 5
Supplemental oxygen devices and delivered fraction of inspired oxygen
Flow

Delivered Fraction of Inspired Oxygen

Nasal cannula

16 lpm

24%40%

Simple mask

510 lpm

35%50%

Partial or nonrebreather

15 lpm

40%80%

Humidified high-flow cannula

3060 lpm

Near the set FIO2 (21%100%)

Noninvasive ventilation

Closed system

Set FIO2

Mechanical ventilation

Closed system

Set FIO2

Treatment of Severe ARDS

alveolar oxygen in the alveoli (PAO2) and, consequently, the PaO2, based on the alveolar
gas equation:
PAO2 5 FIO2 (Patm

pH2O)

(PaCO2/RQ)

During positive pressure ventilation, mean airway pressure is added to atmospheric

pressure (Patm) in the alveolar gas equation. This additional increase in PAO2 becomes
significant in patients requiring high mean airway pressures associated with severe
ARDS.24
Most ventilators calculate mean airway pressure as the average pressure applied
during a respiratory cycle. Mean airway pressure is dependent on the area under
the pressure-time curve. Increasing the area under this curve via positive endexpiratory pressure (PEEP), respiratory rate, tidal volume, and inspiratory time all
generate higher mean airway pressures. Higher mean airway pressures tend to
improve oxygenation and lead to lower FIO2 requirements, although the clinical benefit
of improved SaO2 does not translate to improved survival among most ARDS patients.
Despite improvements in lung function, reduced organ failure days, and reduced need
for pulmonary rescue therapies, high-quality studies on high PEEP levels versus low
PEEP levels failed to show a mortality benefit.25,26 A 2010 meta-analysis showed an
association between high PEEP levels and decreased mortality in moderate to severe
ARDS (P/F ratio <200) but possible harm in patients with P/F ratio 200 to 300, suggesting higher PEEP levels should be avoided in mild ARDS.27
Reanalysis of 4 ARDS studies also reveals that driving pressure (plateau pressure
minus PEEP, often referred to as deltaP) is strongly associated with mortality.28 This
suggests patient-specific factors and lung mechanics may aid in determining which
patients benefit from higher levels of PEEP. This study found an association
with the protective effects of higher PEEP levels only if they led to improved lung
compliance. As such, PEEP levels higher than those routinely used in the ARDSNet
PEEP-FIO2 tables may be beneficial only when associated with improved lung
compliance.
A seemingly more physiologic strategy at optimizing PEEP is guided by esophageal
pressure measurements.29 A recent study recruited 61 patients with ARDS and randomized them to either standard care with PEEP based on a PEEP to FIO2 table or
PEEP based on transpulmonary pressure (estimated to be PEEP minus esophageal
pressure at end expiration). The goal transpulmonary pressure in this study at endexpiration was 0 cm H2O to 10 cm H2O based on severity of hypoxia, with 10 cm
H2O if the FIO2 required was 95% or higher. The esophageal-guided PEEP group
had significantly increased P/F ratios (90 points better), improved compliance, higher
average PaO2, higher average PEEP levels, and higher average mean airway pressure.
The study was not powered to evaluate mortality but there is a study currently recruiting patients (NCT01681225) by the same group. The primary outcome is a composite
of death and time off the ventilator at 28 days.
Recruitment

The best way to recruit alveoli for a specific patient with ARDS depends on the underlying reason for lung volume loss. Collapse from a large pneumothorax is best treated
with a chest tube. Suctioning or bronchoscopy should be used to treat atelectasis
from mucus plugging or excessive secretions. Dependent atelectasis and lung consolidation are treated with PEEP augmentation, pulmonary recruitment, and positional
change such as prone positioning. Typical recruitment maneuvers (RMs) consist
of prolonged respiratory holds at increased airway pressures (eg, 3040 second

Przybysz & Heffner

end-expiratory hold at 40 cm H2O performed on a ventilator circuit) done in the

absence of additional tidal breathing.
RMs are associated with improved PaO2 but may adversely lower CO by decreasing
venous return and increasing right-sided afterload. When performed, controlled RMs
on a ventilator are the recommended approach. Both the beneficial and unwanted effects of RMs tend to be short-lived.30 RMs can hyperinflate some lungs segments
while simultaneously recruiting others and are less likely to benefit if hyperinflation
predominates. In a small study of early ARDS patients, lung morphology seen on
CT scan predicted a sustained improvement in oxygenation in patients with nonfocal
ARDS versus focal disease.31 A typical CT scan of focal ARDS shows posteriordependent consolidation and atelectasis versus a more homogeneous pattern in nonfocal ARDS patients. Focal ARDS is more prone to hyperinflation without sustained
improvement in oxygenation, suggesting that RMs are less likely to benefit patients
with this ARDS morphology. Due to the heterogeneity among ARDS patients and
lack of proved benefit, RMs should not be performed on a routine basis in all ARDS
patients.30 RMs may be helpful during life-threatening hypoxia but the potential risk
and benefit should be assessed by the bedside provider on a case-by-case basis.
Neuromuscular blockade provides another means to improve oxygenation. Muscle
relaxation improves gas exchange by eliminating ventilator dyssynchrony and facilitating alveolar recruitment. Early use of cisatracurium improves 28-day mortality in severe ARDS with P/F ratio less than 150.32 The exact mechanism of benefit is unknown
but may relate to improved respiratory mechanics leading to attenuation of systemic
inflammatory mediators liberated during ventilation of severely injured lung.33 The incidence of muscle weakness was not increased in the treatment group, suggesting that
2 days of neuromuscular blockade does not invoke significant adverse effects. Given
these data, neuromuscular blockade is recommended in the emergency department
for patients with P/F ratio less than 150, even in the absence of refractory hypoxemia.
Diffusion

Pulmonary oxygen diffusion capacity across the alveolar membrane is another target
to improve pulmonary efficiency. In ARDS, diffusion improvements typically require
alveolar fluid removal via active fluid management in the form of diuretics or ultrafiltration. A conservative fluid strategy compared with a liberal fluid strategy was associated with improved oxygenation, length of hospitalization, and ICU days without
increase in other organ failures in a randomized trial of 1000 ARDS patients.34 The
general goals are to maintain a central venous pressure between 4 mm Hg and
8 mm Hg and a urine output greater than 0.5 mL/kg/h while simultaneously ensuring
adequate CO.34 Given these data, net fluid balance should be meticulously maintained
in all patients with ARDS and shocked patients should be evaluated for volume
responsiveness prior to empiric fluid loading whenever possible. Neutral to negative
fluid balance should be the goal for all hemodynamically stable ARDS patients.
Redistribution of Blood Flow

Systemic blood flow (ie, CO) is another therapeutic target to rescue patients from lifethreatening hypoxia. All ARDS patients should be screened for cardiac dysfunction
because conditions causing ARDS can simultaneously induce myocardial dysfunction
(affecting the left ventricle) and the high mean airway pressures associated with ARDS
can reduce right ventricular performance.12 If there is evidence of inadequate CO
(elevated lactate, decreased mixed venous oxygen saturation [SvO2], mottled skin,
or low urine output) with abnormal cardiac performance, inotropic therapy may help
optimize SvO2 and consequently improve arterial oxygenation.

Treatment of Severe ARDS

Blood flow can also be redistributed within the lung via inhaled pulmonary artery vasodilators and prone positioning. Inhaled nitric oxide (iNO) and inhaled epoprostenol
selectively vasodilate the ventilated pulmonary artery beds, thereby improving ventilation to perfusion (V/Q) matching. iNO improves gas exchange in ARDS but unfortunately does not confer a mortality benefit.35,36 The association of iNO and renal
failure contributes to the conclusion that iNO should not be routinely used in ARDS.
Patients with ARDS complicated by acute right ventricular failure have not specifically
been studied. Use of iNO for rescue therapy in refractory hypoxemia or as a bridge to
alternative therapies in patients at high risk of death from hypoxemia may be warranted on an individual basis.
Prone positioning, first described in 1976, is another method to improve gas exchange in ARDS. Prone positioning redistributes pulmonary blood flow to less consolidated anterior lung segments and improves gas exchange by improving V/Q
matching. Mortality benefit was recently validated in ARDS patient with P/F ratio
less than 150.37 This trial enrolled patients after a 12- to 24-hour period of stabilization
if the P/F ratio remained less than 150. The average PaO2 in all the patients constantly
increased during the first 4 hours of prone positioning and consistently decreased during periods of supine ventilation. Prone positioning reduces the need for other rescue
therapies, such as ECMO, iNO, and high-frequency oscillatory ventilation (HFOV).38
This procedure should be performed by personnel familiar with the specific complications. Procedures, such as central lines, nasogastric tubes, and chest tubes, should
be performed prior to prone positioning. Prone ventilation is not consistently associated with an improvement in compliance, suggesting recruitment of healthy lung is
not the only physiologic advantage.37
Extracorporeal Membrane Oxygenation

Venovenous-ECMO (VV-ECMO) maintains systemic gas exchange via a modified cardiopulmonary bypass circuit. Use of ECMO for severe refractory hypoxemia during the
2009 to 2010 influenza H1N1 pandemic highlights the viability of this specialized
rescue therapy for patients with acute refractory disease.39 ECMO is primarily used
as a bridge to native lung recovery. In most cases, gas exchange via the ECMO circuit
provides the opportunity for ultraprotective lung ventilation. The disadvantages of
ECMO include hemorrhage due to the need for systemic anticoagulation and large
vessel cannulation. Indications and contraindications for VV-ECMO are listed in
Table 6.
Based on the results of the 2009 CESAR trial, patients with severe ARDS despite
optimal medical therapy should be referred to an ECMO center. This trial randomized
180 adults with severe ARDS to either standard local care or referral to a specialized
ECMO center. The primary outcome of disability free survival at 6 months was
improved in the ECMO group and the therapy was deemed cost effective. This study
has been criticized because not all of the patients in the intervention group received
ECMO and only 70% of patients in the control group were treated with lungprotective ventilation.40 It was pragmatically designed, however, to help determine
the best real-life patient management strategy in severe ARDS. Referral to an
ECMO center directly from an emergency department should be strongly considered
for patients with early severe ARDS based on this trial.
MECHANICAL VENTILATION

Mechanical ventilation primarily aims to support gas exchange in critically ill patients. Mechanical ventilation in ARDS patients is more difficult due to risk of

10

Przybysz & Heffner

Table 6
Extracorporeal membrane oxygenation indications and contraindications
Extracorporeal Membrane Oxygenation Usage for Acute Respiratory Distress Syndrome
Indications

Contraindications

Consider ECMO if predicted mortality >50%

Condition prohibiting anticoagulation

Strongly consider for severe ARDS despite

optimal medical management for 6 h

Recent central nervous system hemorrhage

Nonrecoverable comorbidity
Major pharmacologic immunosuppression
Age >65 is relative contraindication

inducing or prolonging lung injury secondary to the ventilator induced damage. A

useful analogy when dealing with ARDS patients is the baby lung principle,6 which
refers to the physiologic similarities between an ARDS lung and a miniature lung:
ARDS-induced consolidation significantly reduces the effective lung volume
capable of gas exchange. While manipulating the ventilator, it is helpful to adjust
the perception of normal tidal volume for each particular patient. Table 7 lists goals
of mechanical ventilation among ARDS patients. The 2000 ARDSNet trial of low tidal
volume ventilation is a landmark trial that redefined the standard of care for ARDS
patients. It compared 6 mL/kg to 12 mL/kg of ideal body weight. There was a 9%
absolute mortality benefit with the low-volume strategy despite lower oxygen levels
during the first 24 hours. The advantage is likely related to reduced lung injury and
systemic inflammation in the low tidal volume group. There have not been any headto-head trials of 6 mL/kg compared with 8 mL/kg (common setting today for nonARDS patients) but 6 mL/kg should be considered the proper starting point for all
ARDS patients. The P/F threshold at which a low tidal volume strategy provides
benefit is unclear and some experts propose an initial setting of 6 mL/kg for all ventilated patients, regardless of lung disease. This strategy for non-ARDS patients,
however, may lead to more ventilator dysynchrony and increasing sedation requirements without much benefit.
One side effect of the low tidal volume strategy is reduced minute ventilation.
Compensatory increase in respiratory rate is limited by expiratory time. Inadequate
expiratory time must be avoided to prevent dynamic hyperinflation leading to autoPEEP. Furthermore, the pathologic dead space associated with ARDS contributed
to hypercapnia despite supranormal minute ventilation. Permissive hypercapnea during ARDS management is well tolerated and considered safe in most clinical scenarios, although patients with acute brain injury, arrhythmias, or right ventricular
failure are possible exceptions. Hypercapnea also increases pulmonary vascular

Table 7
Mechanical ventilation goals in acute respiratory distress syndrome
Tidal volume

46 mL/kg of ideal body weight

Plateau pressure

Ideally <30 cm H2O but lower may be better

pH, respiratory rate, minute ventilation

Depends on patient comorbidities but pH of 7.2 is

widely accepted as acceptable permissive
hypercapnia; lower may also be acceptable

PEEP

Unknown; higher may be better for severe ARDS

FIO2

Unknown; titration based on PEEP to FIO2 table is

appropriate

Treatment of Severe ARDS

resistance. Although this is generally well tolerated, it may be a contributing factor in

acute right ventricular failure during ARDS.
MODES OF VENTILATION

When changing modes of ventilation or ventilator settings in ARDS, the primary physiologic goal is supporting oxygenation via augmented mean airway pressure while
maintaining a safe plateau pressure. In addition to the former consideration,
lengthening inspiratory time helps achieve this goal. At extremes of prolonged inspiratory period, this is often referred to as inverse ratio ventilation. Inverse ratio ventilation
may increase oxygenation but has not been shown to improve outcomes in ARDS
patients. A majority of ARDS trials were conducted with volume control ventilation
although pressure control ventilation is generally comparable, as long as the dependent variables are appropriately monitored in each mode.41
HFOV and airway pressure release ventilation represent the extreme of a prolonged
inspiratory time strategy. HFOV has the theoretic advantage of safely maximizing the
mean airway pressure because the mean airway pressure and plateau pressure are
effectively the same. Unfortunately, early HFOV failed to show benefit in 2 randomized
trials of ARDS patients and cannot be recommended as routine therapy in severe
ARDS.42,43 HFOV cannot be routinely recommended for severe ARDS patients but
may have some value as rescue therapy in selected patients with severe ARDS failing
other modalities.
MEDICATIONS

As discussed previously, early use of muscle relaxants provides a survival benefit for
patients with ARDS and P/F ratio less than 150. Several other medications have been

Fig. 4. Guide to therapies for acute respiratory distress syndrome based on PaO2 to fraction
of inspired oxygen ratio.

11

12

Przybysz & Heffner

studied with no difference in outcomes. b-Agonists were studied in a multicenter, randomized, placebo-controlled trial and no clinically important differences were found.44
Rosuvastatin was compared with placebo in 745 patients with ARDS from sepsis and
did not show any improvement in mortality or ventilator-free days and there was actually an increase in kidney and liver dysfunction in the rosuvastatin group.45
SUMMARY

The summary of effective therapies for ARDS patients is listed in Fig. 4. All ARDS patients should be ventilated with a low-volume strategy aiming to maintain the plateau
pressure less than 30 cm H20. Volume control ventilation is recommended, although
pressure control ventilation and pressure-regulated volume control are also safe.
Permissive hypercapnea to a pH of 7.20 is safe and may be protective. A conservative
fluid strategy should be used for all ARDS patients not in shock. PEEP should probably
be increased for patients with P/F ratio less than 200 although specific patient
populations benefiting from this practice are not fully elucidated. For ARDS patients
with P/F ratio less than 150, early neuromuscular blocking agents, prone positioning,
and referral to an ECMO center have been shown to reduce mortality. b-Agonists, iNO,
and HFOV have failed to show improvements in mortality or other clinically important
endpoints and cannot be recommended.
ACKNOWLEDGMENTS

Special acknowledgment to Dr Holt Murray at the University of Pittsburgh Medical

Center for his guidance on this article.
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Treatment of Severe ARDS

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