Ven t i l a t o r S t r a t e g i e s f o r

C h ro n i c O b s t r u c t i v e
P u l m o n a r y D i s e a s e an d A c u t e
R e s p i r a t o r y D i s t re s s S y n d ro m e
Nathan T. Mowery, MD

KEYWORDS
 Respiratory failure  Hypoxia  ARDS  COPD  APRV
 Airway pressure release ventilation  ALI  PEEP

KEY POINTS
 Identification of high-risk patients for pulmonary complications is an important part of
determining outcomes.
 Low tidal volume ventilation is the only ventilator strategy that has been shown in prospec-
tive randomized trials to improve mortality in ARDS and COPD.
 Once COPD patients are intubated the minute ventilation should be titrated to Ph and not
to the PaCO2.
 A restrictive fluid schedule that maintains perfusion but aims at keeping patients fluid
neutral has been associated with shorter ICU and ventilator days in ARDS.
 In ARDS several studies show APRV to have physiologic benefits and to improve some
measures of clinical outcome, such as oxygenation, use of sedation, hemodynamics,
and respiratory mechanics. None have shown a survival benefit when compared with con-
ventional lung protective ventilation.

INTRODUCTION

Worldwide 52 million people have been diagnosed with COPD. The incidence and the
complications that it has caused are increasing.1 In 1990 it was the 6th most common
cause of death worldwide but is expected to be the third most common by the year
2020.2 Patients with COPD often require respiratory support for a variety of reasons
including exacerbations of the disease, complications related to other medical conditions
and elective and emergent surgical interventions. In these surgical situations if the clinical
situations allows the best time to optimize the patient to prevent complication is pre-oper-
atively. When mechanical ventilation becomes necessary in this challenging population
morbidity can be minimized with the application of evidence-based approaches.

The author has nothing to disclose.

Wake Forest Baptist Medical Center, Department of Surgery, Medical Center Boulevard, Winston-
Salem, NC 27157, USA
E-mail address: nmowery@wakehealth.edu

Surg Clin N Am 97 (2017) 1381–1397

http://dx.doi.org/10.1016/j.suc.2017.07.006 surgical.theclinics.com
0039-6109/17/ª 2017 Elsevier Inc. All rights reserved.
1382 Mowery

Acute respiratory distress syndrome (ARDS) is defined by the acute onset of hypox-
emia and bilateral infiltrates after a trigger. The definition has changed over time to its
current status. Although it only effects about 5% of mechanically ventilated patients,
75% of those present with a moderate or severe form.3 Unlike COPD, the incidence of
ARDS is decreasing secondary to the decrease in the numbers of triggers secondary
to the institution of such interventions, such as limited resuscitations, early source
control, restrictive transfusion strategies, ventilator care bundles, and lung-
protective ventilation.4
This article discusses the basic concepts of mechanical ventilation in patients with
COPD and ARDS, reviews predisposing factors to the development of complications,
and discusses current strategies for the recognition and prevention of these adverse
effects in the application of mechanical ventilation in this population.

PREDICTING PULMONARY COMPLICATIONS

Ventilator strategies can play a pivotal role in the deciding the outcome of patient once
pulmonary complications have developed. The issue is that by far the best means to
improve pulmonary-related morbidity is to prevent it from happening. A large part of
that preventive piece is to recognize high-risk groups so that at the very least prepa-
rations can be made. Virtually all of the interventions described herein have been
shown to be at least partially protective if instituted before pulmonary complications
have developed. For example, low tidal volume ventilation is a proven ventilator strat-
egy for the treatment of both COPD and ARDS, and has also been shown to minimize
the risk of the development of ARDS. In high-risk patient populations, it would only
stand to reason that strict adherence to low tidal volume protocols be observed.
The risk of postoperative pulmonary complications (PPCs) increases nearly up to 3-
fold for patients with a moderate or severe systemic disease (American Society of
Anesthesiology class III) and up to 5-fold in moribund patients (American Society of
Anesthesiology class IV).5 The individual risk does not only relate to a patient’s comor-
bidities, but is also influenced by the type and/or duration of surgery, and it may also
be modified by the corresponding type of anesthesia.6 Therefore, an American Society
of Anesthesiology class IV patient undergoing a short, low-risk procedure under
regional anesthesia might have a lower risk of PPCs than a patient without comorbid-
ities planned to undergo a long-lasting, high-risk surgical procedure under general
anesthesia. Tailoring the type of anesthesia to the patient is an important step in avoid-
ing PCC.
Active smokers have an increase in tracheobronchial secretions and a decrease in
mucociliary clearance. They depend on coughing for the removal of secretions, and
they may need longer weaning from mechanical ventilation on the intensive care
unit (ICU).7 Smoking is also associated with pulmonary and cardiac diseases.
Smokers have been included in all studies on intraoperative lung-protective ventilation
strategies. Whether smokers benefit more than nonsmokers from any specific venti-
lator settings remains unclear.8,9
Advanced age, specifically an age of greater than 65 years, approximately doubles
the risk of PPC not only owing to “accumulating comorbid conditions,”10 but as an in-
dependent predictor of outcome based on age-related changes in the lungs, which
are summarized in Table 1.2,11,12
In an animal model of mechanical ventilation with high tidal volumes, older lungs
developed more severe pulmonary injury than younger ones.13 It seems that elderly
patients are more vulnerable to high tidal volumes, and that, in turn, they may benefit
more from lung-protective mechanical ventilation than younger ones.14
 Ventilator Strategies for COPD and ARDS 1383

The development of PCC starts early in the patient’s hospital course and the intra-
operative ventilator settings have been shown to impact outcome in the elderly. Two
trials so far specifically addressed this patient population and found at low tidal vol-
ume strategies intraoperatively lead to higher intraoperative pulmonary compliance,
lower airway resistance, higher PaO2/FiO2 ratio, and higher PaCO2 levels in the interven-
tion group.8,15

MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Patients with COPD suffer from chronic inflammation of small airways and lung pa-
renchyma, resulting in obstructive bronchiolitis, parenchymal destruction, and
emphysema. Increased airway resistance and decreased elastic recoil lead to
limited airflow and an impaired ability of the airways to remain open at the end of
expiration. In turn, the collapse of airways at the end of expiration results in incom-
plete expiration, higher residual end-expiratory volume, hyperinflation, and auto–
positive end-expiratory pressure (auto-PEEP). Progression of chronic inflammation
and parenchymal destruction result in impaired gas exchange with hypoxemia
and hypercapnia. In case of the need for ventilatory support for acute exacerba-
tions, the use of noninvasive mechanical ventilation reduces mortality in patients
with COPD.9,10
Patients with COPD planning to undergo elective surgery should be in a stable dis-
ease condition, and they should receive optimal individual medical treatment. In case
of acute exacerbations, surgery should be postponed. However, even stable patients
with COPD have an up to a 4-fold increased risk of PPC,16,17 which is higher the worse
the disease is. Absolute cutoff levels as contraindications for surgery18 or predictors of
the perioperative risk of patients with COPD are missing. Nevertheless, patients with
an FEV1 of greater than 60% are typically considered to be at low risk of PPC, even if
they had planned to undergo lung resection.19

Physiologic Changes in Chronic Obstructive Pulmonary Disease Relevant to

Mechanical Ventilation
Expiratory flow limitation is the principal physiologic alteration in COPD and is over-
come by increasing the inspiratory flow and lung volume. Although the issue is expi-
ratory, the compensation is inspiratory, and this, combined with high respiratory drive,
leads to the development of inspiratory muscle fatigue, which is of central pathophys-
iologic importance in the development of acute respiratory failure in these patients.
The airflow obstruction, low elastic recoil, high ventilatory demand, and short expira-
tory time result in air trapping and consequent DH. In patients with COPD with acute res-
piratory failure, DH is the main factor explaining the increased intrathoracic pressure,
increased work of breathing (WOB), ventilator dependency and weaning failure.11,12

Role of Noninvasive Positive-Pressure Ventilation in Treating Obstructive Pulmonary

Disease Patients
Noninvasive positive-pressure ventilation (NPPV) has been accepted widely as the
first choice in treating obstructive airway disease patients with respiratory failure. It
provides a significant reduction in endotracheal intubation and thereby its complica-
tions (eg, ventilator-associated pneumonia, tracheal and laryngeal complications) if
considered early in the course of the disease.10,13,14
Expiratory positive airway pressure applied offsets intrinsic PEEP resulting from
expiratory airflow obstruction. Inspiratory positive airway pressure augments tidal vol-
ume for any given respiratory effort leading to less mechanical disadvantage,
1384 Mowery

decreased respiratory rate, decreased WOB, and improvements in ventilation (gener-

ally reduced PaCO2).20
Indications for Invasive Mechanical Ventilation
Although NPPV is now considered the first choice for the treatment of selected pa-
tients experiencing COPD exacerbations, there are some patients for whom NPPV
may not be suitable owing to the severity of their conditions.9 Another requirement
for continuing with NPPV is the patient maintains a level of alertness to protect their
airway. Having a patient vomit with a tight-fitting NPPV mask in place can be a recipe
for a poor outcome. The main goals of mechanical ventilation are to improve pulmo-
nary gas exchange and to rest compromised respiratory muscles sufficiently to
recover from the fatigued state.
Major criteria (any one of the following)9,21
 Respiratory arrest
 Loss of consciousness
 Psychomotor agitation requiring sedation
 Hemodynamic instability with a systolic blood pressure less than 70 or greater
than 180 mm Hg
 Heart rate less than 50 beats/min with loss of alertness
 Gasping for air
Minor criteria (any two of the following)
 Respiratory rate >35 breath/min
 Worsening acidemia or pH <7.25
 PaO2 less than 40 mm Hg or PaO2/FiO2 less than 200 mm Hg despite oxygen
 Decreasing level of consciousness
Choice of Ventilator Mode in Chronic Obstructive Pulmonary Disease
Accomplishing gas exchange and alleviating respiratory muscle fatigue may be
accomplished using any mode available on the ventilator, but the choice may vary
with the status of the patient with COPD. For the obtunded or postoperative patient,
pressure-support ventilation may not be the first choice until the patient respiratory
drive returns. Therefore, either assist-control or synchronized intermittent mandatory
ventilation, with either volume or pressure targets, should be used. High inspiratory
flow rates are preferred to reduce the inspiratory–expiratory ratio, thus allowing
more time for expiration. If the patient’s respiratory drive is still present after intuba-
tion, the use of pressure-support ventilation or of synchronized intermittent mandatory
ventilation with a low rate is preferable, because this is less likely to induce or worsen
any preexisting DH and auto-PEEP.22
Clinicians have to be aware of the patient’s baseline condition after assuming con-
trol of the pulmonary dynamics of patients with COPD. The main hazard is overventi-
lating the patient. There may be an impulse to increase the respiratory rate and tidal
volumes in an attempt to “normalize” the blood gas of the patient with COPD. The
higher expiratory flows to accomplish this increased minute volume may lead to addi-
tional air trapping. This in turn would lead to worsen hypercapnia and respiratory dys-
synchrony. The increased intrathoracic pressure would also lead to decreased venous
return and right-sided heart failure, exacerbating the situation.
Owing to the patients baseline metabolic compensation, if the PaCO2 is normalized
to 40 mm Hg, acute alkalemia ensues. This alkalemia is a problem, because it prolongs
mechanical ventilation by depressing the respiratory center and increasing respiratory
muscle weakness. Continuing mechanical ventilation in this manner for 2 to 3 days
 Ventilator Strategies for COPD and ARDS 1385

would facilitate renal excretion of bicarbonate, thereby returning the acid–base status
of the patient with COPD to normal. Unfortunately, when weaning is attempted, the
patient is likely to develop acute respiratory acidosis or respiratory failure. To prevent
this cycle, minute ventilation should be titrated to the pH and not to the PaCO2.
As we will see in the treatment of ARDS, the choice of low tidal volume ventilation is
beneficial in the prevention overventilation. Low tidal volumes limit peak alveolar
(plateau) pressure to less than 30 cm H2O for patients with COPD.23 With a lower tidal
volume, the inspiratory–expiratory ratio is decreased, allowing longer expiration so that
the hyperinflated COPD lung can empty. Consequently, this method is unlikely to induce
alkalemia, cause or aggravate DH and auto-PEEP, or overdistend the alveolar lung units
in the ventilated patient with COPD. Reducing respiratory rate and increasing inspiratory
flow also increases expiratory time and facilitates emptying of the lung.

The Use of Positive End-Expiratory Pressure in Patients with Chronic Obstructive

Pulmonary Disease
The balance in using PEEP in this patient population that already traps air (and causes
intrinsic or auto-PEEP) is by applying to much PEEP and limiting expiratory flow
(Figs. 1 and 2). To prevent this from occurring, external PEEP should be kept below
75% to 85% of auto-PEEP to avoid any worsening of hyperinflation or circulatory
compromise.16,24 Determination of dynamic pulmonary hyperinflation is, however,
not easy to perform in an ICU. It requires insertion of an esophageal balloon and
assessment of the abdominal muscles that can be recruited during expiration.17 It
has been shown, however, that changes in inspiratory capacity replicate that of hyper-
inflation, the greater the inspiratory capacity, the lower the end-expiratory lung volume
assuming a constant total lung capacity.18

Diagnosis of Auto–positive End-Expiratory Pressure

Quantifying auto-PEEP is not a precise process. Auto-PEEP can vary among individ-
ual lung units owing to different degrees of obstruction; auto-PEEP is not uniformly
distributed throughout the lung, but varies in direct proportion to the airway resistance
present in a particular lung unit. A number of methods can be used to detect auto-
PEEP in the mechanically ventilated patient. On some ventilators, a 2-second pause
can be invoked after the end of expiration. This technique, however, is valid only if

Fig. 1. Generation of auto–positive end-expiratory pressure (PEEP). (From Ahmed SM, Athar
M. Mechanical ventilation in patients with chronic obstructive pulmonary disease and bron-
chial asthma. Indian J Anaesth 2015;59(9):589–98; with permission.)
1386 Mowery

Fig. 2. Air trapping in a flow–volume loop. (From Ahmed SM, Athar M. Mechanical ventila-
tion in patients with chronic obstructive pulmonary disease and bronchial asthma. Indian J
Anaesth 2015;59(9):589–98; with permission.)

the patient is not breathing spontaneously. The auto-PEEP is then calculated by sub-
tracting the external PEEP from the total PEEP.19 This method limits the procedure’s
application to the heavily sedated, paralyzed, or physically exhausted patient with
COPD. An esophageal balloon avoids this problem, but may not be readily available
in all hospital ICUs. If the patient has a central venous pressure (CVP) line, auto-
PEEP effects can be detected owing to the increased WOB reflected by greater
changes in pleural pressure (which are transmitted to intrathoracic blood vessels
and can be measured via CVP or pulmonary artery catheter). A large decrease in
CVP during a spontaneous or assisted breath suggests that a high inspiratory
threshold is needed to trigger the ventilator.
Diagnosis of Dynamic Hyperinflation
1. Slow filling of manual ventilator bag
2. Capnography trace not reaching plateau
3. Expiratory flow not reaching zero in flow-time–volume graph
4. Measure the intrinsic PEEP
Auto-PEEP can also be detected on ventilators equipped with graphic waveform
monitoring. Although not readily quantifiable, auto-PEEP is easily recognized on the
expiratory portion of the flow waveform. If expiratory flow does not return to zero
before the next inspiration, auto-PEEP is present. For patients who are making spon-
taneous efforts to breathe, observing their respiratory efforts and the ventilators
response is another useful technique, provided the ventilators sensitivity is set
correctly (at 1 cm H2O or on flow triggering). Because auto-PEEP increases the
pressure gradient required to inhale, the patient’s effort may not be able to trigger
the ventilator; the result is a missed breath or cycle. Clinical signs associated with
auto-PEEP (in patients making spontaneous efforts to breathe) include accessory
muscle use, retractions, and increased ventilatory drive.
Management of Auto–positive End-Expiratory Pressure
The basic goal in the situation of auto-PEEP is to allowing more time for exhalation.
This can be accomplished by reducing the respiratory rate or inspiratory–expiratory
ratio (typically to 1:3–1:5) to allow more time for exhalation and reduce breath stack-
ing. However, this pattern can result in low minute ventilation causing hypercapnia,
hypoxia, or acidosis. This leads to increased pulmonary vascular resistance and wors-
ened hemodynamic instability. If this is a concern, a higher inspiratory flow rate with
 Ventilator Strategies for COPD and ARDS 1387

high peak pressures can be used, but this places the patient at increased risk of
barotrauma.

Application of Positive End-Expiratory Pressure

The use of external PEEP in ventilated patients with COPD has theoretic benefits by
keeping small airways open during late exhalation, so potentially reducing intrinsic
PEEP or auto-PEEP. Additionally, it has been seen that if external PEEP is kept below
the intrinsic PEEP, no significant increase in alveolar pressure and cardiovascular
compromise occurs.25
There are only 3 factors that determine auto-PEEP: (1) minute ventilation, (2) inspi-
ratory–expiratory ratio, (3) expiratory time constants. Of the 3 factors, minute ventila-
tion is the most important factor that causes DH. Hence, when ventilating patients with
COPD, a smaller tidal volume, slow respiratory rate, and high peak flow should be
used with an aim to target normal pH and not PaCO2 (permissive hypercapnia).

Strategies to Improve Pulmonary Gas Exchange

The hypoxemia of obstructive air diseases is basically due to 1 of the 3 general causes:
shunt, ventilation–perfusion abnormalities, and diffusion defects. In general, individ-
uals with acute exacerbations of COPD have a greater degree of ventilation defect
(causing hypercapnia) than chronic patients, who mainly develop perfusion defect
(causing hypoxia). Nonetheless, hypoxic vasoconstriction and collateral ventilation
in chronic patients decrease the expected ventilation–perfusion abnormalities. Thus,
managing the cause is of prime importance in the treatment of hypoxemia of
COPD. Moreover, evidence shows beneficial effects of controlled breathing tech-
niques such as active expiration, slow and deep breathing, pursed-lips breathing,
relaxation therapy, specific body positions, and inspiratory muscle training.

Strategies to Rest Compromised Respiratory Muscles and Reduce the Work of

Breathing
In patients with COPD they live in a state of compromised pulmonary mechanics
coupled with a high respiratory drive. This combination leaves them teetering at the
edge of their physiologic reserve. Recognition of the factors that contribute to their
already increased work of breathing can help the clinician minimize these factors to
optimize the patient (Table 1). Many of the interventions done to combat COPD
have the goal of decreasing respiratory work load, increasing muscular strength and
if needed providing mechanical ventilatory support.

Table 1
Factors affecting respiratory work of breathing

Respiratory Muscle
Obstructions to Inhalation Inhibitors Ventilator Circuit Factors
Resistive load Sedation causing depressed Narrow endotracheal tube
(bronchospasm) drive External PEEP
Parenchymal compliance Muscle weakness Decreased trigger
(pulmonary edema, (electrolyte threshold of the
pneumonia, atelectasis) abnormalities, chronic ventilator
Chest wall compliance atrophy)
(obesity, pleural effusion,
abdominal distention)

Abbreviation: PEEP, positive end-expiratory pressure.

1388 Mowery

OUTCOMES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Predicting PPCs remains a challenge for most of the researchers. Although many
studies have attempted to predict PPCs, they were not specifically for patients with
COPD. Patients with COPD are at an increased risk for PPCs. A recent review esti-
mated the incidence of unadjusted PPCs as 18.2% in patients with COPD undergoing
surgery.5 Increasing severity of COPD confers greater risk, from 10% with mild to
moderate disease to 23% in patients with severe disease.26
Evidence shows that history and physical examination are poor predictors of
airway obstruction and its severity. However, the presence of history of a greater
than 55 pack-year smoking, wheezing on auscultation, and patient self-reported
wheezing can be considered predictive of airflow obstruction, defined as postbron-
chodilator forced expiratory volume 1 (FEV1) or forced vital capacity of less
than 0.70.2 Spirometry is useful to identify airflow obstruction in symptomatic
patients, but its usefulness in patients without respiratory symptoms is questionable.
Smokers with normal spirometry have only a 4% risk of PPC.27 Symptomatic pa-
tients with an FEV1 of less than 60% predicted will benefit from inhaled treatments,
but evidence does not support treating asymptomatic patients, regardless of the risk
factors and airflow obstruction.2 However, unlike in pulmonary resection, there is no
cutoff value of FEV1 or any other spirometric index to consider these patients unsuit-
able for surgery.
Arterial blood gas analyses are not indicated unless the patient’s history suggests
arterial hypoxemia or severe enough COPD that one suspects CO2 retention. Then,
the arterial blood gas should be used in essentially the same manner as one might
use preoperative pulmonary function tests, that is, to look for reversible disease or
to define the severity of the disease at its baseline. Defining baseline PaO2 and
PaCO2 is particularly important if one anticipates postoperatively ventilating a patient
who has severe COPD.

Heliox
Heliox was introduced in 1934 for the treatment of airway obstruction.28 Because
airway turbulence depends on density, heliox (having a lower density) decreases
the airway resistance and, therefore, the WOB, particularly in situations associated
with upper airway obstruction. When used as a carrier, heliox has also been found
to improve the deposition of aerosolized bronchodilators in the lung.29 The percentage
of oxygen in heliox should be at least 20% to prevent hypoxia, and no more than 40%
for heliox to show a clinically significant effect.29 It has been shown to reduce DH by
15%, which will probably place the respiratory muscles at a better mechanical advan-
tage and decrease the WOB.30 Indeed, a significant decline in VCO2 was also noted,
supporting a reduced WOB leading to small but significant decrease in the PaCO2.31
However, owing to presence of conflicting literature, heliox therapy, which is costly
and cumbersome, is not warranted for stable patients with COPD at rest with moder-
ate to severe disease, but could be effective as an adjuvant therapy to enhance the
efficacy of medical treatment. Thus, further research to identify the patients with
COPD potentially able to benefit from this type of therapy is required.31

Corticosteroids
Short courses of systemic corticosteroids may provide important benefits in patients
with exacerbations of COPD a more rapid increase in FEV1, fewer withdrawals, and a
significantly shorter duration of hospital stay.32 This has to be balanced with the infec-
tious complications and wound healing issues in the postoperative patient.
 Ventilator Strategies for COPD and ARDS 1389

WEANING IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Like all ventilator patients, an aggressive weaning policy is justified in patients with
COPD because prolonged intubation is associated with a variety of poor outcomes.
The first step is to address any offending agent that precipitated the COPD exacerba-
tion. Marginal respiratory mechanics and continued presence of auto-PEEP make
weaning difficult in patients with COPD. Hence, factors that increase resistance
such as size, secretions, kinking of the tube, and the presence of elbow-shaped parts
or a heat and moisture exchanger in the circuit have to be optimized to promote early
weaning. Weaning can be done with a pressure support mode, along with sponta-
neous breathing trials. Sequential weaning (early extubation followed by NPPV) is
found to be good alternative in patients showing failed spontaneous breathing trials.33
In contrast, role of tracheostomy is uncertain, but owing to marginal respiratory me-
chanics, it is also expected to help in weaning.
Summary
Ventilatory support is a lifesaving procedure in acute exacerbations of COPD. The
therapeutic goals are to improve gas exchange, rest fatigued respiratory muscles,
and relieve respiratory distress. NPPV is regarded as the first line of treatment,
whereas invasive ventilation is reserved for life-threatening respiratory failure. Howev-
er, it can cause a considerable increase in morbidity and mortality if not used properly.
Therefore, it is necessary to have a good understanding of pathophysiology,
mechanics, and pattern of flow obstruction and DH to provide the most suitable venti-
lation to these patients. The ventilatory graphics (flow, pressure, and volume) of the
most of the modern ventilators becomes a valuable tool in these situations and assist
in early diagnosis and management of the patient’s condition before it becomes clin-
ically overt.

MANAGEMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME

ARDS is a serious clinical problem with more than 200,000 cases annually34 that is
resistant to treatment once the syndrome is fully clinically established. ARDS has a
mortality rate of 30% to 60% with significant costs of care and debilitating lifelong
sequelae for survivors.35 Despite decades of research only one therapeutic modality,
low tidal volume ventilation has been demonstrated to modestly improve ARDS-
related mortality (9%).36 People with ARDS are by definition severely hypoxemic,
and nearly all require invasive mechanical ventilation. Yet mechanical ventilation itself
can further injure damaged lungs (so-called ventilator-induced lung injury); minimizing
any additional damage while maintaining adequate gas exchange (“compatible with
life”) is the central goal of mechanical ventilation in ARDS and acute lung injury, its
less severe form.
Benefits of Low Tidal Volume Ventilation in Acute Respiratory Distress Syndrome
Low tidal volume ventilation reduces the damaging, excessive stretch of lung tissue
and alveoli (so-called volutrauma), and is the standard of care for people with ARDS
requiring mechanical ventilation. The ARDSnet36 is the largest clinical trial supporting
this paradigm. Although it has been noted to have some design flaws (the control arm
had a high 12 mL/kg volume given) and ethical concerns (informed consent issues), it
has been the foundation that using low tidal volumes improves survival for people with
ARDS. Taken together, the trials suggest that a strategy of low tidal volume ventilation
(6–8 mL/kg ideal body weight) reduces absolute mortality by about 7% to 9%, as
compared with using 12 mL/kg tidal volumes (approximately 42% mortality in control
1390 Mowery

groups vs approximately 34% in the low tidal volume ventilation groups). This trans-
lates to a “number needed to treat” of between 11 and 15 people with ARDS to prevent
1 death by using low tidal volume ventilation.

How to Use Low Tidal Volume Ventilation in Acute Respiratory Distress Syndrome
The protocol from the ARMA trial can serve as a guide to performing low tidal volume
ventilation for mechanically ventilated patients with ARDS:
 Start in any ventilator mode with initial tidal volumes of 8 mL/kg predicted body
weight in kg, calculated by: [2.3  (height in inches - 60) 1 45.5 for women
or 1 50 for men].
 Set the respiratory rate up to 35 breaths/min to deliver the expected minute venti-
lation requirement (generally, 7–9 L/min).
 Set PEEP to at least 5 cm H2O, and FiO2 to maintain an arterial oxygen saturation
(SaO2) of 88% to 95% (PaO2 55–80 mm Hg). Titrate FiO2 to less than 70% when
feasible.
 Over a period of less than 4 hours, reduce tidal volumes to 7 mL/kg, and then to
6 mL/kg.
Ventilator adjustments are then made with the primary goal of keeping plateau pres-
sure (measured during an inspiratory hold of 0.5 seconds) less than 30 cm H2O, and
preferably as low as possible, while keeping blood gas parameters “compatible
with life.” High plateau pressures vastly elevate the risk for harmful alveolar distension
(ie, ventilator-associated lung injury, volutrauma). If plateau pressures remain elevated
after following the this protocol, further strategies should be tried:
 Further reduce tidal volume, to as low as 4 mL/kg by 1 mL/kg stepwise
increments.
 Sedate the patient to minimize ventilator–patient dyssynchrony.
 Consider other etiologies for the increased plateau pressure besides the stiff,
noncompliant lungs of ARDS.

Permissive Hypercapnia in Acute Respiratory Distress Syndrome

This single-minded focus on reducing plateau pressures derives from the likely sur-
vival benefit from low tidal volume ventilation and low plateau pressures observed
in clinical trials. Achieving these low plateau pressures usually requires tidal volumes
low enough to result in hypoventilation, with resulting increases in PCO2 and respiratory
acidemia that can be severe and, to the treating physician, anxiety provoking. This
approach, “permissive hypercapnia,” represents a paradigm shift from previous
eras, in which achieving normal blood gas values was the main goal of mechanical
ventilation. Mechanically ventilated patients with ARDS seem to tolerate very low
blood pH and very high PCO2s without any adverse sequelae:
 Current consensus suggests it is safe to allow pH to fall to at least 7.20.
 The actual PCO2 is of little importance.
 When the pH falls below 7.20, many physicians choose to administer sodium bi-
carbonate, Carbicarb, or THAM (tris-hydroxymethyl amino-methane) to maintain
blood pH between 7.15 and 7.20.
 However, it is unknown whether such correction of acidemia is helpful, harmful,
or neither (good evidence is lacking for any of these hypotheses).
Conditions in which permissive hypercapnia for ARDS could theoretically be harmful
include cerebral edema, mass lesions or seizures, active coronary artery disease,
 Ventilator Strategies for COPD and ARDS 1391

arrhythmias, hypovolemia, gastrointestinal bleeding, and possibly others. These are

hypothetical harms based on pathophysiology and not outcomes data, and the
harm of ventilator-induced lung injury and the benefits of a protective ventilator strat-
egy in ARDS are real and known. The potential risks of hypercapnia in such patients
must be weighed against the risks of ARDS, and therapy individualized.

Limitations in the Use of Plateau Pressure for Acute Respiratory Distress Syndrome
Patients with reduced chest wall compliance—most commonly owing to obesity—may
have higher plateau pressures at baseline37 and during ARDS than nonobese patients.
It is possible that, in some obese patients, titrating tidal volumes to plateau pressures
less than 30 cm H2O may be inadequate38 and result in worsened hypoventilation.
There are no recommendations to treat obese patients with acute lung injury or
ARDS differently than nonobese patients with regard to mechanical ventilation. Esoph-
ageal manometry is considered superior to plateau pressures through its measurement
of transpulmonary pressure, considered a more precise measure of potentially injurious
pressures in the lung. Because it is invasive and the probes are prone to migration,
esophageal manometry is not widely used.

Prone Positioning in Acute Respiratory Distress Syndrome

Prone positioning improves gas exchange and has long been used as an adjunctive or
salvage therapy for severe or refractory ARDS. Prone positioning is gaining credibility
as a new standard of care for ARDS after a multicenter trial published in 2013, demon-
strated a dramatic near 50% relative risk reduction, and a 17% absolute risk reduction
for mortality. Patients were kept in prone position for 16 hours a day in that trial con-
ducted at 27 European centers highly experienced with prone positioning for ARDS.39
The benefits of prone positioning have not yet been replicated in a large US trial, but a
metaanalysis of 6 randomized trials40 also concluded prone positioning saves lives in
ARDS when added to a lung-protective ventilatory strategy.

High Versus Low Positive End-Expiratory Pressure in Acute Respiratory Distress

Syndrome
A strategy using higher PEEP along with low tidal volume ventilation should be consid-
ered for patients receiving mechanical ventilation for ARDS. This suggestion is based
on a 2010 metaanalysis of 3 randomized trials (n 5 2229)41 testing higher versus lower
PEEP in patients with acute lung injury or ARDS, in which ARDS patients receiving
higher PEEP had a strong trend toward improved survival. High versus low PEEP
was defined as a rolling definition as the hospital stay went on but a blunt cutoff would
be 10 cm H2O to define the 2 groups.
However, patients with milder acute lung injury (PaO2/FiO2 ratio >200) receiving
higher PEEP had a strong trend toward harm in that same metaanalysis (27.2% in
the higher PEEP group and 19.4% in the lower PEEP group). Higher PEEP can
conceivably cause ventilator-induced lung injury by increasing plateau pressures, or
cause pneumothorax or decreased cardiac output. The ARDSnet group investigated
the adverse effects of high PEEP and did not find a correlation with poor outcomes.
These investigator concluded that patients who received low tidal volumes and main-
tained plateau pressures less than 30 cm H2O had similar outcomes whether high or
low PEEP was used.42

Alternative and Rescue Ventilator Modes in Acute Respiratory Distress Syndrome

Some patients with severe ARDS develop severe hypoxemia or hypercarbia with acid-
emia despite optimal treatment with low tidal volume mechanical ventilation. In these
1392 Mowery

situations, alternative, salvage or “rescue” ventilator strategies are often used. Their
common goal is to maintain high airway pressures to maximize alveolar recruitment
and oxygenation, while minimizing alveolar stretch or shear stress. The most
commonly used alternative ventilatory strategies are high-frequency oscillatory venti-
lation (HFOV) or airway pressure release ventilation (APRV or “bilevel”).
HFOV is not appropriate as a first-line treatment for ARDS.43,44 There have been 2
randomized trials on the topic and neither was able to the show an improvement in
outcomes. In contrast, the North American study showed 47% in the HFOV group
died in-hospital, versus 35% receiving conventional low-tidal volume ventilation (rela-
tive risk for death with HFOV of 1.33; 95% CI, 1.09-1.64; P 5 .005). The trial was
stopped for harm at this point, far short of its planned 1200 patient enrollment,
when statistical analyses showed a near impossibility of equivalence or benefit from
HFOV.43 Both studies showed that HFOV patients required more sedation and more
neuromuscular blockade to keep the patient on HFOV.
APRV maintains a sustained airway pressure over a large proportion of the respira-
tory cycle. Animal and clinical studies have demonstrated that, compared with con-
ventional ventilation, APRV has beneficial effects on lung recruitment, oxygenation,
end-organ blood flow, pulmonary vasoconstriction, and sedation requirements.45,46
APRV has shown promise in both preventing the development on ARDS in animal
models.47 Adequate studies to show a mortality benefit when compared with low tidal
volume ventilation have not yet been performed.

Extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) has also become a more commonly
used salvage therapy for ARDS, thanks to improvements in technology making it safer
and more feasible to administer. The use of ECMO for the treatment of ARDS was
introduced in the early 1970s with the aim of guaranteeing a protective ventilation,
as an artificial lung may provide an adequate blood CO2 removal and oxygenation,
allowing to reduce mechanical ventilation. There remains 1 randomized trial (CESAR
study) of patients with ARDS. In this study, patients referred to an ECMO center
showed a higher 6-month survival rate (63% vs 47%) and no difference in quality of
life and spirometric parameters compared with patients treated with conventional me-
chanical ventilation. There have been no additional studies since then validating
ECMO and its use is limited to specialized centers.48

Pharmacologic Adjuncts to Ventilator Strategies

Treatment with inhaled nitric oxide as a rescue therapy for ARDS has shown significant
improvement in oxygenation for a short period of 48 hours. However, no benefit in
terms of survival has been demonstrated.49 Because the clinical effect of inhaled nitric
oxide is counterbalanced by its very high cost, other inhaled pharmacologic alterna-
tives were explored. Specifically, inhaled prostaglandins have been increasingly
used. A recently published study that compared inhaled epoprostenol versus inhaled
nitric oxide in patients with refractory hypoxemia revealed similar efficacy and safety
outcomes.50 Randomized clinical studies assessing the effectiveness of inhaled pros-
taglandins in ARDS have rarely been performed. A Cochrane review was able to iden-
tify only 1 clinical trial, which included 14 critically ill children with ARDS. The
investigators concluded there was no evidence to support or refute the use of inhaled
prostoglandins.51
Beta-agonist infusions have been tried owing to the idea that they could decrease
patients plateau pressures and pulmonary edema. A randomized trial showed they
were found to be harmful to ARDS patients, likely owing to the associated
 Ventilator Strategies for COPD and ARDS 1393

arrhythmias.52 Similarly, aerosolized beta-agonists have not shown improvements in

outcomes.53
Chemical paralysis
To augment patient–ventilator synchrony and to reduce the oxygen consumption
related to respiratory muscle activity, many clinicians decide to abolish any sponta-
neous respiratory effort by using neuromuscular blocking agents. An additional effect
of neuromuscular blocking agents is the reduction of the negative increase in pleural
pressure seen during spontaneous breathing, with the likely consequent reduction of
stress and strain applied to the lung. It has been shown how patients with severe
ARDS treated with an early, short course of neuromuscular blocking agents pre-
sented with lower mortality, reduced duration of mechanical ventilation, and fewer ep-
isodes of barotrauma. Patients with ARDS who were started on 48 hours of
neuromuscular blockade within the first 48 hours of their symptoms had a significant
mortality reduction 1.6% (95% CI, 25.2–38.8) in the cisatracurium group and 40.7%
(95% CI, 33.5–48.4)54
Systemic corticosteroids
The central role of the inflammatory response in the pathogenesis of ARDS is the ratio-
nale behind the idea to use corticosteroids as a therapy in ARDS patient. Based on
these concepts, several trials investigated corticosteroids use,55,56 however, with het-
erogeneous results. Meduri and colleagues55 in a study conducted in the early phase
of ARDS demonstrated a decrease in ICU mortality rate; however, these findings could
not be replicated in other studies.56,57

Volume Status
Noncardiogenic pulmonary edema is an important part of the ARDS picture. Intrave-
nous fluid management is brought into question for the ability to worsen or improve the
patient’s gas exchange. Intravenous fluids are critical to maintain appropriate intra-
vascular volume to assure hemodynamic stability; however, excessive fluid adminis-
tration can worsen lung edema, further impairing gas exchange. Fluid management
practices are quite variable and are often guided by philosophic approaches ranging
from the very liberal or “wet” approach (prioritizes maximizing perfusion) to the very
conservative or “dry” approach (prioritizes reductions in lung edema). The FACTT trial
(Fluids and Catheters Treatment Trial) was performed by the ARDSnet group to try to
identify the optimal approach in the ARDS setting. The investigators randomized 1000
patients to wet or dry groups with an additional factor of fluid management being
guided by a CVP or a Swan Ganz catheter.58 The wet group was approximately 1 L
positive for the day, which coincided with other ARDSnet trials, suggesting that a lib-
eral fluid strategy was the “normal” approach. The restrictive group was kept fluid
neutral using diuretics. There was no difference in mortality among the groups. The
60-day mortality was 25.5% in the conservative group versus 28.4% in the liberal
group (P 5 .3005; 95% CI for the difference, 2.6 to 18.4). The restrictive group
had a significant improvement in ventilator parameters such as plateau pressure,
and required less PEEP leading to fewer ventilator and ICU days.59

PREDICTING SURVIVAL AND OUTCOMES AFTER ACUTE RESPIRATORY DISTRESS

SYNDROME

In a 2012 retrospective analysis in JAMA60 including data from more than 4400 pa-
tients with ARDS enrolled in randomized trials, only the severity of hypoxemia (low
PaO2/FiO2 ratio) was predictive of mortality. Commonly used clinical parameters of
1394 Mowery

severity (static compliance, degree of PEEP, and extent of opacities on chest radiog-
raphy) were not predictive of outcome. A “high-risk” patient profile with a 52% mortal-
ity was identified post hoc, composed of severe ARDS (PaO2/FiO2 ratio <100) with
either a high corrected expired volume of 13 L/min or greater, or a low static
compliance of less than 20 mL/cm H2O. Reviews of ARDS outcomes61 suggest that
most people who survive ARDS recover pulmonary function, but may remain impaired
for months or years in other domains, both physically35 and psychologically.62

SUMMARY

Ventilatory support is a lifesaving procedure in acute exacerbation of COPD and

ARDS. The goals of ventilator support between the 2 groups are the same, which is
to maintain gas exchange and rest fatigued respiratory muscles. Titration of the venti-
lator setting may differ among the groups but low tidal volume ventilation has been
shown to be beneficial in both groups. The use of adjunct interventions may help to
improve patient outcomes in both groups.

REFERENCES

1. Available at: http://www.nhlbi.nih.gov/health/public/lung/other/copd_fact.htm.2006.

COPD: fact sheet. Accessed August 19, 2017.
2. Mannino D. COPD: Epidemiology, preva- lence, morbidity and mortality, and dis-
ease heterogeneity. Chest 2002;121:121s–6s.
3. Esteban A, Ferguson ND, Meade MO, et al. Evolution of mechanical ventilation in
response to clinical research. Am J Respir Crit Care Med 2008;177(2):170–7.
4. Umbrello M, Formenti P, Bolgiaghi L, et al. Current concepts of ARDS: a narrative
review. Int J Mol Sci 2016;18(1) [pii:E64].
5. Smetana GW, Lawrence VA, Cornell JE, American College of Physicians. Preop-
erative pulmonary risk stratification for noncardiothoracic surgery: systematic re-
view for the American College of Physicians. Ann Intern Med 2006;144(8):
581–95.
6. Smetana GW. Postoperative pulmonary complications: an update on risk assess-
ment and reduction. Cleve Clin J Med 2009;76(Suppl 4):S60–5.
7. Bluman LG, Mosca L, Newman N, et al. Preoperative smoking habits and post-
operative pulmonary complications. Chest 1998;113(4):883–9.
8. Ge Y, Yuan L, Jiang X, et al. Effect of lung protection mechanical ventilation on
respiratory function in the elderly undergoing spinal fusion. Zhong Nan Da Xue
Xue Bao Yi Xue Ban 2013;38(1):81–5 [in Chinese].
9. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exac-
erbations of chronic obstructive pulmonary disease. N Engl J Med 1995;333(13):
817–22.
10. Girou E, Schortgen F, Delclaux C, et al. Association of noninvasive ventilation with
nosocomial infections and survival in critically ill patients. JAMA 2000;284(18):
2361–7.
11. Coussa ML, Guérin C, Eissa NT, et al. Partitioning of work of breathing in mechan-
ically ventilated COPD patients. J Appl Physiol (1985) 1993;75(4):1711–9.
12. Purro A, Appendini L, De Gaetano A, et al. Physiologic determinants of ventilator
dependence in long-term mechanically ventilated patients. Am J Respir Crit Care
Med 2000;161(4 Pt 1):1115–23.
13. Evans TW. International Consensus Conferences in Intensive Care Medicine: non-
invasive positive pressure ventilation in acute respiratory failure. Organised jointly
by the American Thoracic Society, the European Respiratory Society, the
 Ventilator Strategies for COPD and ARDS 1395

European Society of Intensive Care Medicine, and the Societe de Reanimation de

Langue Francaise, and approved by the ATS Board of Directors, December
2000. Intensive Care Med 2001;27(1):166–78.
14. Girou E, Brun-Buisson C, Taillé S, et al. Secular trends in nosocomial infections
and mortality associated with noninvasive ventilation in patients with exacerbation
of COPD and pulmonary edema. JAMA 2003;290(22):2985–91.
15. Weingarten TN, Whalen FX, Warner DO, et al. Comparison of two ventilatory stra-
tegies in elderly patients undergoing major abdominal surgery. Br J Anaesth
2010;104(1):16–22.
16. Ranieri VM, Giuliani R, Cinnella G, et al. Physiologic effects of positive end-
expiratory pressure in patients with chronic obstructive pulmonary disease during
acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis
1993;147(1):5–13.
17. Lessard MR, Lofaso F, Brochard L. Expiratory muscle activity increases intrinsic
positive end-expiratory pressure independently of dynamic hyperinflation in me-
chanically ventilated patients. Am J Respir Crit Care Med 1995;151(2 Pt 1):562–9.
18. Yan S, Kaminski D, Sliwinski P. Reliability of inspiratory capacity for estimating
end-expiratory lung volume changes during exercise in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 1997;156(1):55–9.
19. Reddy RM, Guntupalli KK. Review of ventilatory techniques to optimize mechan-
ical ventilation in acute exacerbation of chronic obstructive pulmonary disease.
Int J Chron Obstruct Pulmon Dis 2007;2(4):441–52.
20. Ambrosino N, Strambi S. New strategies to improve exercise tolerance in chronic
obstructive pulmonary disease. Eur Respir J 2004;24(2):313–22.
21. Brochard L, Isabey D, Piquet J, et al. Reversal of acute exacerbations of chronic
obstructive lung disease by inspiratory assistance with a face mask. N Engl J
Med 1990;323(22):1523–30.
22. Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pres-
sures, and circulation in mechanical ventilation of patients with severe air-flow
obstruction. Am Rev Respir Dis 1987;136(4):872–9.
23. Tuxen DV. Permissive hypercapnic ventilation. Am J Respir Crit Care Med 1994;
150(3):870–4.
24. Petrof BJ, Legaré M, Goldberg P, et al. Continuous positive airway pressure re-
duces work of breathing and dyspnea during weaning from mechanical ventila-
tion in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1990;
141(2):281–9.
25. Jolliet P, Watremez C, Roeseler J, et al. Comparative effects of helium-oxygen
and external positive end-expiratory pressure on respiratory mechanics, gas ex-
change, and ventilation-perfusion relationships in mechanically ventilated pa-
tients with chronic obstructive pulmonary disease. Intensive Care Med 2003;
29(9):1442–50.
26. Cook MW, Lisco SJ. Prevention of postoperative pulmonary complications. Int
Anesthesiol Clin 2009;47(4):65–88.
27. Kroenke K, Lawrence VA, Theroux JF, et al. Postoperative complications after
thoracic and major abdominal surgery in patients with and without obstructive
lung disease. Chest 1993;104(5):1445–51.
28. Barach AL. Use of helium as a new therapeutic gas. Proc Soc Exp Biol Med 1934;
32:462–4.
29. Anderson M, Svartengren M, Bylin G, et al. Deposition in asthmatics of particles
inhaled in air or in helium-oxygen. Am Rev Respir Dis 1993;147(3):524–8.
1396 Mowery

30. Swidwa DM, Montenegro HD, Goldman MD, et al. Helium-oxygen breathing in se-
vere chronic obstructive pulmonary disease. Chest 1985;87(6):790–5.
31. Rodrigo G, Pollack C, Rodrigo C, et al. Heliox for treatment of exacerbations of
chronic obstructive pulmonary disease. Cochrane Database Syst Rev
2002;(2):CD003571.
32. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to
hospital with exacerbations of chronic obstructive pulmonary disease: a prospec-
tive randomised controlled trial. Lancet 1999;354(9177):456–60.
33. Glossop AJ, Shephard N, Bryden DC, et al. Non-invasive ventilation for weaning,
avoiding reintubation after extubation and in the postoperative period: a meta-
analysis. Br J Anaesth 2012;109(3):305–14.
34. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury.
Chest 2007;131(2):554–62.
35. Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute
respiratory distress syndrome. N Engl J Med 2011;364(14):1293–304.
36. The Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA,
Morris A, et al. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 2000;342(18):1301–8.
37. Sohl AE. Critical care management of the obese patient. New York: Wiley-Black-
well; 2012. p. 254.
38. Talmor D, Sarge T, O’Donnell CR, et al. Esophageal and transpulmonary pres-
sures in acute respiratory failure. Crit Care Med 2006;34(5):1389–94.
39. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respi-
ratory distress syndrome. N Engl J Med 2013;368(23):2159–68.
40. Sud S, Friedrich JO, Adhikari NK, et al. Effect of prone positioning during me-
chanical ventilation on mortality among patients with acute respiratory distress
syndrome: a systematic review and meta-analysis. CMAJ 2014;186(10):E381–90.
41. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pres-
sure in patients with acute lung injury and acute respiratory distress syndrome:
systematic review and meta-analysis. JAMA 2010;303(9):865–73.
42. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-
expiratory pressures in patients with the acute respiratory distress syndrome.
N Engl J Med 2004;351(4):327–36.
43. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early
acute respiratory distress syndrome. N Engl J Med 2013;368(9):795–805.
44. Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory
distress syndrome. N Engl J Med 2013;368(9):806–13.
45. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing
during ventilatory support in patients with acute lung injury. Am J Respir Crit Care
Med 2001;164(1):43–9.
46. Falkenhain SK, Reilley TE, Gregory JS. Improvement in cardiac output during
airway pressure release ventilation. Crit Care Med 1992;20(9):1358–60.
47. Roy S, Habashi N, Sadowitz B, et al. Early airway pressure release ventilation pre-
vents ARDS-a novel preventive approach to lung injury. Shock 2013;39(1):28–38.
48. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of
conventional ventilatory support versus extracorporeal membrane oxygenation
for severe adult respiratory failure (CESAR): a multicentre randomised controlled
trial. Lancet 2009;374(9698):1351–63.
 Ventilator Strategies for COPD and ARDS 1397

49. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in pa-
tients with acute lung injury: a randomized controlled trial. JAMA 2004;291(13):
1603–9.
50. Torbic H, Szumita PM, Anger KE, et al. Inhaled epoprostenol vs inhaled nitric ox-
ide for refractory hypoxemia in critically ill patients. J Crit Care 2013;28(5):844–8.
51. Afshari A, Brok J, Møller AM, et al. Aerosolized prostacyclin for acute lung injury
(ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database Syst
Rev 2010;(8):CD007733.
52. Gao Smith F, Perkins GD, Gates S, et al. Effect of intravenous beta-2 agonist treat-
ment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a
multicentre, randomised controlled trial. Lancet 2012;379(9812):229–35.
53. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome
(ARDS) Clinical Trials Network, Matthay MA, Brower RG, Carson S, et al. Ran-
domized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for
treatment of acute lung injury. Am J Respir Crit Care Med 2011;184(5):561–8.
54. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute
respiratory distress syndrome. N Engl J Med 2010;363(12):1107–16.
55. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone
therapy in unresolving acute respiratory distress syndrome: a randomized
controlled trial. JAMA 1998;280(2):159–65.
56. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticoste-
roids for persistent acute respiratory distress syndrome. N Engl J Med 2006;
354(16):1671–84.
57. Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients
with the adult respiratory distress syndrome. N Engl J Med 1987;317(25):
1565–70.
58. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome
(ARDS) Clinical Trials Network, Wheeler AP, Bernard GR, Thompson BT, et al. Pul-
monary-artery versus central venous catheter to guide treatment of acute lung
injury. N Engl J Med 2006;354(21):2213–24.
59. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome
(ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, et al.
Comparison of two fluid-management strategies in acute lung injury. N Engl J
Med 2006;354(24):2564–75.
60. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, et al.
Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307(23):
2526–33.
61. Herridge MS. Recovery and long-term outcome in acute respiratory distress syn-
drome. Crit Care Clin 2011;27(3):685–704.
62. Adhikari NK, Tansey CM, McAndrews MP, et al. Self-reported depressive symp-
toms and memory complaints in survivors five years after ARDS. Chest 2011;
140(6):1484–93.