2222 PART 8 Critical Care Medicine

daily spontaneous breathing trials can identify patients who are ready

for extubation. Accordingly, all intubated, mechanically ventilated

patients should undergo daily screening of respiratory function. If oxygenation is stable (i.e., Pao2

/FIo2

 [partial pressure of oxygen/fraction

of inspired oxygen] >200 and PEEP ≤5 cmH2

O), cough and airway

reflexes are intact, and no vasopressor agents or sedatives are being

administered, the patient has passed the screening test and should

undergo a spontaneous breathing trial (SBT). If sedatives are being

administered, the patient can undergo a spontaneous awakening trial

(SAT), as well, to determine if he or she is able to maintain adequate

alertness and respiratory status without sedatives. The SAT/SBT trial

consists of a period of breathing through the endotracheal tube without ventilator support (continuous positive airway pressure [CPAP] of

5 cmH2

O with or without low-level pressure support [e.g., 5 cmH2

O]

and an open T-piece breathing system have all been validated) for

30–120 min. The spontaneous breathing trial is declared a failure and

stopped if any of the following occur: (1) respiratory rate >35/min for

>5 min, (2) O2

 saturation <90%, (3) heart rate >140/min or a 20% increase

or decrease from baseline, (4) systolic blood pressure <90 mmHg or >180

mmHg, or (5) increased anxiety or diaphoresis. If, at the end of the

spontaneous breathing trial, none of the above events has occurred,

the patient can be considered for an extubation trial. Such protocoldriven approaches to patient care can have an important impact on

the duration of mechanical ventilation and ICU stay. In spite of such

a careful approach to liberation from mechanical ventilation, up to

10% of patients develop respiratory distress after extubation and may

require resumption of mechanical ventilation. Many of these patients

will require reintubation. The use of noninvasive ventilation in patients

in whom extubation fails may be associated in some patients with worse

outcomes than are obtained with immediate reintubation. Some studies

suggest that there are subgroups of patients who might benefit from

administration of high-flow nasal oxygen therapy postextubation, as it is

believed that low levels of PEEP delivered by this device may be helpful.

MULTIORGAN SYSTEM FAILURE

Multiorgan system failure, which is commonly associated with critical

illness, is defined by the simultaneous presence of physiologic dysfunction and/or failure of two or more organs. Typically, this syndrome

occurs in the setting of severe sepsis, shock of any kind, severe inflammatory conditions such as pancreatitis, and trauma. The fact that

multiorgan system failure occurs commonly in the ICU is a testament

to our current ability to stabilize and support single-organ failure. The

ability to support single-organ failure aggressively (e.g., by mechanical

ventilation or by renal replacement therapy) has reduced rates of early

mortality in critical illness. As a result, it is less common for critically

ill patients to die in the initial stages of resuscitation. Instead, many

patients succumb to critical illness later in the ICU stay, after the initial

presenting problem may have been stabilized.

Although there is debate regarding specific definitions of organ failure, several general principles governing the syndrome of multiorgan

system failure apply. First, organ failure, no matter how it is defined,

must persist beyond 24 h. Second, mortality risk increases with the

accrual of failing organs. Third, the prognosis worsens with increased

duration of organ failure. These observations remain true across various critical care settings (e.g., medical vs surgical).

MONITORING IN THE ICU

Because respiratory failure and circulatory failure are common in critically ill patients, monitoring of the respiratory and cardiovascular systems is undertaken frequently. Evaluation of respiratory gas exchange

is routine in critical illness. The “gold standard” remains arterial bloodgas analysis, in which pH, Pao2

, partial pressure of carbon dioxide

(Pco2

), and O2

 saturation are measured directly. With arterial bloodgas analysis, the two main functions of the lung—oxygenation of arterial blood and elimination of CO2

—can be assessed directly. In fact, the

arterial blood pH, which has a profound effect on the drive to breathe,

can be assessed only by such sampling. Although sampling of arterial

blood is generally safe and may be undertaken more frequently through

insertion of a temporary indwelling arterial line, it may be painful and

cannot provide continuous information. In light of these limitations,

noninvasive monitoring of respiratory function is often employed.

■ PULSE OXIMETRY

The most commonly utilized noninvasive technique for monitoring

respiratory function, pulse oximetry takes advantage of differences

in the absorptive properties of oxygenated and deoxygenated hemoglobin. At wavelengths of 660 nm, oxyhemoglobin reflects light more

effectively than does deoxyhemoglobin, whereas the reverse is true in

the infrared spectrum (940 nm). A pulse oximeter passes both wavelengths of light through a perfused digit such as a finger, and the relative intensity of light transmission at these two wavelengths is recorded.

From this information, the relative percentage of oxyhemoglobin is

derived. Since arterial pulsations produce phasic changes in the intensity of transmitted light, the pulse oximeter is designed to detect only

light of alternating intensity. This feature allows distinction of arterial

and venous blood O2

 saturations.

■ RESPIRATORY SYSTEM MECHANICS

Respiratory system mechanics can be measured in patients during

mechanical ventilation (Chap. 302). When volume-controlled modes

of mechanical ventilation are used, accompanying airway pressures

can easily be measured as long as the patient is breathing passively.

The peak airway pressure is determined by two variables: airway resistance and respiratory system compliance. At the end of inspiration,

inspiratory flow can be stopped transiently. This end-inspiratory pause

(plateau pressure) is a static measurement, affected only by respiratory

system compliance and not by airway resistance. Therefore, during

volume-controlled ventilation, the difference between the peak (airway

resistance + respiratory system compliance) and plateau (respiratory

system compliance only) airway pressures provides a quantitative

assessment of airway resistance. Accordingly, during volume-controlled

ventilation, patients with increases in airway resistance typically have

increased peak airway pressures as well as abnormally high gradients

between peak and plateau airway pressures (typically >10–15 cmH2

O)

at a constant inspiratory flow rate of 1 L/s. The compliance of the

respiratory system is defined by the change in volume of the respiratory

system per unit change in pressure.

The respiratory system can be divided into two components: the

lungs and the chest wall. Normally, respiratory system compliance is

~100 mL/cmH2

O. Pathophysiologic processes such as pleural effusions, pneumothorax, and increased abdominal girth all reduce chest

wall compliance. Lung compliance may be reduced by pneumonia,

pulmonary edema, alveolar hemorrhage, interstitial lung disease, or

auto-PEEP. Accordingly, patients with abnormalities in compliance of

the respiratory system (lungs and/or chest wall) typically have elevated

peak and plateau airway pressures but a normal gradient between these

two pressures. Auto-PEEP occurs when there is insufficient time for

emptying of alveoli before the next inspiratory cycle. Because the alveoli

have not decompressed completely, alveolar pressure remains positive at

the end of exhalation (functional residual capacity). This phenomenon

results most commonly from obstruction of distal airways in disease

processes such as asthma and COPD. Auto-PEEP with resulting alveolar overdistention may result in diminished lung compliance, reflected

by abnormally increased plateau airway pressures. Modern mechanical

ventilators allow breath-to-breath display of pressure and flow, permitting detection of potential problems such as patient–ventilator dyssynchrony, airflow obstruction, and auto-PEEP (Fig. 300-6).

■ CIRCULATORY STATUS

Oxygen delivery (Qo2

) is a function of cardiac output and the content

of O2

 in the arterial blood (Cao2

). The Cao2

 is determined by the

hemoglobin concentration, the arterial hemoglobin saturation, and

dissolved O2

 not bound to hemoglobin. For normal adults:

 Qo2

 = 50 dL/min × (1.39 × 15 g/dL [hemoglobin concentration]

 × 1.0 [hemoglobin % saturation] + 0.0031 × 100 [Pao2

])

 = 50 dL/min (cardiac output) × 21.6 mL O2

 per dL blood (Cao2

)

 = 1058 mL O2

 per min

2223Approach to the Patient with Critical Illness CHAPTER 300

It is apparent that nearly all of the O2

 delivered to tissues is bound

to hemoglobin and that the dissolved O2

 (Pao2

) contributes very little

to O2

 content in arterial blood or to O2

 delivery. Normally, the content

of O2

 in mixed venous blood (C–

vo2

) is 15.76 mL/dL since the mixed

venous blood is 75% saturated. Therefore, the normal tissue extraction

ratio for O2

 is Cao2

 – C–

vo2

/Cao2

 ([21.16 – 15.76]/21.16) or ~25%. A

pulmonary artery catheter (see discussion below) allows measurements

of O2

 delivery and the O2

 extraction ratio.

Information on the venous O2

 saturation allows assessment of global

tissue perfusion. A reduced venous O2

 saturation may be caused by inadequate cardiac output, reduced hemoglobin concentration, and/or reduced

arterial O2

 saturation. An abnormally high Vo2

 may also lead to a reduced

venous O2

 saturation if O2

 delivery is not concomitantly increased.

Abnormally increased Vo2

 in peripheral tissues may be caused by problems such as fever, agitation, shivering, and thyrotoxicosis.

The pulmonary artery catheter originally was designed as a tool to

guide therapy for acute myocardial infarction but has been used in the

ICU for evaluation and treatment of a variety of other conditions, such

as ARDS, septic shock, congestive heart failure, and acute renal failure.

This device has never been validated as a tool associated with reduction

in morbidity and mortality rates. Indeed, despite numerous prospective

studies, mortality or morbidity rate benefits associated with use of the

pulmonary artery catheter have never been reported in any setting.

Accordingly, it appears that routine pulmonary artery catheterization

is not indicated as a means of monitoring and characterizing circulatory status in most critically ill patients, especially as monitoring of

the venous O2

 saturation has proven helpful in many critical illness

settings. However, there are still select circumstances where pulmonary artery catheterization may prove helpful when used by those with

appropriate experience in its insertion and data interpretation.

PREVENTION OF COMPLICATIONS OF

CRITICAL ILLNESS

■ SEPSIS IN THE CRITICAL CARE UNIT

(See also Chap. 304) Sepsis is defined as life-threatening organ dysfunction (i.e., an increase in SOFA of 2 points or more) caused by a dysregulated response to infection. Poor outcomes can be anticipated in patients

with two or more of the following: respiratory rate ≥22 breaths/min,

altered mentation, and systolic blood pressure ≤100 mmHg. Sepsis is a

leading cause of death in noncoronary ICUs in the United States, with case

rates expected to increase as the population ages and a higher percentage

of people are vulnerable to infection.

■ NOSOCOMIAL INFECTIONS IN THE ICU

Many therapeutic interventions in the ICU are invasive and predispose patients to infectious complications. These interventions include

endotracheal intubation, indwelling vascular catheters, transurethral

bladder catheters, and other catheters placed into sterile body cavities (e.g., tube thoracostomy, percutaneous intraabdominal drainage

catheterization). The longer such devices remain in place, the more

prone to infections patients become from these devices. For example,

ventilator-associated events such as ventilator-associated pneumonia

correlate strongly with the duration of intubation and mechanical ventilation. Therefore, an important aspect of preventive care is the timely

removal of invasive devices as soon as they are no longer needed.

Moreover, multidrug-resistant organisms are commonplace in the ICU.

Infection control is critical in the ICU. Care bundles, which

include measures such as frequent hand washing, are effective but

underutilized strategies. Other components of care bundles, such as

protective isolation of patients colonized or infected by drug-resistant

organisms, are also commonly used. Studies evaluating multifaceted,

evidence-based strategies to decrease catheter-related bloodstream

infections have shown improved outcomes with strict adherence to

measures such as hand washing, full-barrier precautions during catheter insertion, chlorhexidine skin preparation, avoidance of the femoral

site, and timely catheter removal.

■ DEEP-VENOUS THROMBOSIS (DVT) (SEE ALSO CHAP. 279)

All ICU patients are at high risk for this complication because of their

predilection for immobility. Therefore, all should receive some form

of prophylaxis against DVT if feasible. The most commonly employed

forms of prophylaxis are subcutaneous chemoprophylaxis (e.g., lowdose heparin) injections and sequential compression devices for the

lower extremities. Observational studies report an alarming incidence

of DVTs despite the use of these standard prophylactic regimens. Furthermore, heparin prophylaxis may result in heparin-induced thrombocytopenia, another nosocomial complication in critically ill patients.

Low-molecular-weight heparins such as enoxaparin are more effective than unfractionated heparin for DVT prophylaxis in high-risk

patients (e.g., those undergoing orthopedic surgery) and are associated with a lower incidence of heparin-induced thrombocytopenia,

although their use may be limited in patients with renal dysfunction

given their renal clearance.

■ STRESS ULCERS

Prophylaxis against stress ulcers is not necessary for all ICU patients. It

should only be administered to high-risk patients, such as those with

coagulopathy or respiratory failure requiring mechanical ventilation.

While there has been debate about the optimal agent for stress ulcer

prophylaxis, a number of recent studies have supported improved

efficacy of proton pump inhibitors (PPIs) in reducing bleeding risk

compared with other agents (e.g., histamine-2 receptor antagonist [H2

blocker] or sucralfate). There exist concerns for increased risk of pneumonia and Clostridium difficile colitis with PPIs compared with other

agents, although the data are not definitive, and the improved efficacy

of PPIs in patients at high risk for stress ulcers may outweigh these

potential infectious risks.

■ NUTRITION AND GLYCEMIC CONTROL

Nutrition and glycemic control are important issues that may be associated with respiratory failure, impaired wound healing, and dysfunctional immune response in critically ill patients. Early enteral feeding

is reasonable, with some data suggesting that permissive underfeeding

of nonprotein calories is not inferior to full-goal feeding. Certainly,

enteral feeding, if possible, is preferred over parenteral nutrition, which

is associated with numerous complications, including hyperglycemia,

fatty liver, cholestasis, and sepsis. When parenteral feeding is necessary

to supplement enteral nutrition, delaying this intervention until day 8

in the ICU results in better recovery and fewer ICU-related complications. Tight glucose control has been an area of controversy in critical

care. Although one study showed a significant mortality benefit when

Pressure–Time

Flow–Time

cmH2O

L/s

90

0

1.2

–1.2

0 4

4

FIGURE 300-6 Increased airway resistance with auto-PEEP. The top waveform

(airway pressure vs time) shows a large difference between the peak airway

pressure (80 cmH2

O) and the plateau airway pressure (20 cmH2

O). The bottom

waveform (flow vs time) demonstrates airflow throughout expiration (reflected by

the flow tracing on the negative portion of the abscissa) that persists up to the next

inspiratory effort.

2224 PART 8 Critical Care Medicine

glucose levels were aggressively normalized in a large group of surgical

ICU patients, other studies of both medical and surgical ICU patients

suggested that tight glucose control resulted in increased rates of

mortality likely attributable, in part, to hypoglycemic episodes. Thus,

current guidelines suggest targeting glucose levels of ≤180 mg/dL in

critically ill patients, rather than targeting tighter control.

■ ICU-ACQUIRED WEAKNESS

ICU-acquired weakness occurs frequently in patients who survive

critical illness. Both neuropathies and myopathies have been described,

most commonly after ~1 week in the ICU. The mechanisms behind

ICU-acquired weakness syndromes are poorly understood, and they

are known to present with heterogeneous muscle pathophysiology.

Intensive insulin therapy may reduce polyneuropathy in critical illness. Very early physical and occupational therapy in mechanically

ventilated patients reportedly results in significant improvements in

functional independence at hospital discharge as well as in reduced

durations of mechanical ventilation and delirium.

■ ANEMIA

Studies have shown that most ICU patients are anemic as a result of

chronic inflammation. Phlebotomy also contributes to ICU anemia.

A large multicenter study involving patients in many different ICU

settings challenged the conventional notion that a hemoglobin level of

100 g/L (10 g/dL) is needed in critically ill patients, with similar outcomes noted in those whose transfusion trigger was 7 g/dL. Red blood

cell transfusion is associated with impairment of immune function and

increased risk of infections as well as of ARDS and volume overload, all

of which may explain the findings in this study. A conservative transfusion strategy has shown similar outcomes in septic shock, postcardiac

surgery, and post–hip surgery patients.

■ ACUTE KIDNEY FAILURE

(See also Chap. 310) Acute kidney failure occurs in a significant percentage of critically ill patients. The most common underlying etiology

is acute tubular necrosis, usually precipitated by hypoperfusion and/or

nephrotoxic agents. Currently, no pharmacologic agents are available

for prevention of kidney injury in critical illness. Studies have shown

convincingly that low-dose dopamine, fenoldapam, and vasopressin

are not effective in protecting the kidneys from acute injury.

NEUROLOGIC DYSFUNCTION IN

CRITICALLY ILL PATIENTS

■ DELIRIUM

(See also Chaps. 27 and 28) Delirium is defined by (1) an acute

onset of changes or fluctuations in mental status, (2) inattention, (3)

disorganized thinking, and (4) an altered level of consciousness (i.e.,

a state other than alertness). Delirium is reported to occur in a wide

range of mechanically ventilated ICU patients and can be detected by

the Confusion Assessment Method for the ICU (CAM-ICU) or the

Intensive Care Delirium Screening Checklist (ICDSC). These tools are

used to ask patients to answer simple questions and perform simple

tasks and can be used readily at the bedside. The differential diagnosis

of delirium in ICU patients is broad and includes infectious etiologies

(including sepsis), medications (particularly sedatives and analgesics),

drug withdrawal, metabolic/electrolyte derangements, intracranial

pathology (e.g., stroke, intracranial hemorrhage), seizures, hypoxia,

hypertensive crisis, shock, and vitamin deficiencies (particularly thiamine). The etiology of a patient’s ICU delirium impacts the prognosis.

Those with persistent ICU delirium not related to sedatives have

increases in length of hospital stay, time on mechanical ventilation,

cognitive impairment at hospital discharge, and 6-month mortality

rate. Interventions to reduce ICU delirium are limited. The sedative

dexmedetomidine has been less strongly associated with ICU delirium

than midazolam. In addition, very early physical and occupational

therapy in mechanically ventilated patients has been demonstrated to

reduce delirium.

■ ANOXIC CEREBRAL INJURY

(See also Chap. 307) This condition is common after cardiac arrest

and often results in severe and permanent brain injury in survivors.

Active cooling of patients to 33°C after cardiac arrest is controversial,

with some studies showing improved neurologic outcomes and others

showing no such improvement. Certainly, patients post cardiac arrest

should have a temperature targeted to no higher than normothermia.

■ STROKE

(See also Chap. 426) Stroke is a common cause of neurologic critical

illness. Hypertension must be managed carefully, because abrupt

reductions in blood pressure may be associated with further brain

ischemia and injury. Acute ischemic stroke treated with tissue plasminogen activator (tPA) has an improved neurologic outcome when

treatment is given within 4.5 h of onset of symptoms, with likely

increased benefit associated with earlier administration. The mortality rate is not reduced when tPA is compared with placebo, despite

the improved neurologic outcome. The risk of cerebral hemorrhage

is significantly higher in patients given tPA. No benefit is seen when

tPA therapy is given beyond 4.5 h after symptom onset. Heparin has

not been convincingly shown to improve outcomes in patients with

acute ischemic stroke. Decompressive craniectomy is a surgical procedure that relieves increased intracranial pressure in the setting of

space-occupying brain lesions or brain swelling from stroke; available

evidence suggests that this procedure may improve survival among

select patients (e.g., ≤55 years of age), albeit at a cost of increased

disability for some.

■ SUBARACHNOID HEMORRHAGE

(See also Chap. 426) Subarachnoid hemorrhage may occur secondary

to aneurysm rupture and is often complicated by cerebral vasospasm,

re-bleeding, and hydrocephalus. Vasospasm can be detected by either

transcranial Doppler assessment or cerebral angiography; it is typically

treated with the calcium channel blocker nimodipine, aggressive IV

fluid administration to avoid hypovolemia, and therapy aimed at maintaining adequate central perfusion pressure, typically with vasoactive

drugs such as phenylephrine. IV fluids and vasoactive drugs (hypertensive hypervolemic therapy) are used to overcome the cerebral vasospasm. Early surgical clipping or endovascular coiling of aneurysms

is advocated to prevent complications related to re-bleeding. Hydrocephalus, typically heralded by a decreased level of consciousness, may

require ventriculostomy drainage.

■ STATUS EPILEPTICUS (SEE ALSO CHAP. 425)

Recurrent or relentless seizure activity is a medical emergency. Cessation of seizure activity is required to prevent irreversible neurologic

injury. Lorazepam is the most effective benzodiazepine for treating

status epilepticus and is the treatment of choice for controlling seizures

acutely. Maintenance of seizure control should be effected with a loading dose of fosphenytoin, valproate, or levetiracetam, as these agents

have been shown to have similar efficacy and side effects.

■ BRAIN DEATH

(See also Chap. 307) Although deaths of critically ill patients usually

are attributable to irreversible cessation of circulatory and respiratory

function, a diagnosis of death also may be established by irreversible

cessation of all functions of the entire brain, including the brainstem,

even if circulatory and respiratory functions remain intact on artificial

life support. Such a diagnosis requires demonstration of the absence of

cerebral function (no response to any external stimulus) and brainstem

functions (e.g., unreactive pupils, lack of ocular movement in response

to head turning or ice-water irrigation of ear canals, positive apnea test

[no drive to breathe]). Many U.S. institutions have a protocol based

upon their state’s requirements for declaration of brain death. Absence

of brain function must have an established cause and be permanent

without possibility of recovery; a sedative effect, hypothermia, hypoxemia, neuromuscular paralysis, and severe hypotension must be ruled

2225Acute Respiratory Distress Syndrome CHAPTER 301

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 diffuse

lung injury from many underlying medical and surgical disorders. The

lung injury may be direct, as occurs in toxic inhalation, or indirect, as

occurs in sepsis (Table 301-1). The clinical features of ARDS are listed

in Table 301-2. By expert consensus, ARDS is defined by three categories based on the degrees of hypoxemia (Table 301-2). These stages

of mild, moderate, and severe ARDS are associated with mortality risk

and with the duration of mechanical ventilation in survivors.

The annual incidence of ARDS prior to the COVID-19 pandemic

was estimated to be as high as 60 cases/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. 199 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

contusion, multiple bone fractures, and chest wall trauma/flail chest,

whereas head trauma, near-drowning, toxic inhalation, and burns are

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

development of ARDS. These include older age, chronic alcohol

abuse, pancreatitis, pneumonia and sepsis (40-60%), [including pandemic COVID pneumonia], and severity of critical illness. Trauma

patients with an Acute Physiology and Chronic Health Evaluation

(APACHE) II score ≥16 (Chap. 300) 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. 301-1).

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

301 Acute Respiratory

Distress Syndrome

Rebecca M. Baron, Bruce D. Levy

TABLE 301-1 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

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. 12) Withholding or withdrawal of care occurs commonly 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 withholding such treatment; these two actions are

judged to be fundamentally similar. An underlying stipulation derived

from this report is that an informed patient should have his or her

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 treating 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 decisionmakers 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

prognosis 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.

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

Devlin JW et al: Clinical practice guidelines for the prevention and

management of pain, agitation/sedation, delirium, immobility, and

sleep disruption in adult patients in the ICU. Crit Care Med 46:e825,

2018.

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.

The 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.

Surviving Sepsis Campaign: International guidelines for the management sepsis and septic shock. Crit Care Med 45:486, 2017.

Toews I et al: Interventions for preventing upper gastrointestinal

bleeding in people admitted to intensive care units. Cochrane Database Syst Rev 6:CD008687, 2018.

2226 PART 8 Critical Care Medicine

in the interstitial and alveolar spaces (Fig. 301-2). Proinflammatory

cytokines (e.g., interleukin 1, 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. 301-3).

Alveolar edema predominantly involves dependent portions of the

lung with diminished aeration. Collapse of large sections of dependent

lung can contribute to decreased lung compliance. Consequently,

intrapulmonary shunting and hypoxemia develop and the work of

breathing increases, leading to dyspnea. The pathophysiologic alterations 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 in pulmonary hypertension. Thus, in addition to severe hypoxemia, hypercapnia

secondary to an increase in pulmonary dead space can be prominent

in early ARDS.

The exudative phase 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 presenting 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 and often

involves at least three-quarters of the lung fields (Fig. 301-2). While

characteristic for ARDS, these radiographic findings are not specific

and can be indistinguishable from cardiogenic pulmonary edema

(Chap. 305). Unlike the latter, however, the chest x-ray in ARDS may

not demonstrate cardiomegaly, pleural effusions, or pulmonary vascular redistribution as is often present in pure cardiogenic pulmonary

edema. If no ARDS risk factor is present, then some objective evaluation is required (e.g., echocardiography) to exclude a cardiac etiology

for hydrostatic edema. Chest computed tomography (CT) in ARDS

Exudative

Hyaline

Edema Membranes

Day: 0 2 7 14 21 . . .

Interstitial Inflammation Fibrosis

Proliferative Fibrotic

FIGURE 301-1 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.

FIGURE 301-2 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.

TABLE 301-2 Diagnostic Criteria for ARDS

SEVERITY: OXYGENATIONa ONSET CHEST RADIOGRAPH

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

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

a

As assessed on at least 5 cm H2

O of positive end expiratory pressure (PEEP).

Abbreviations: ARDS, acute respiratory distress syndrome; Fio2

, inspired O2

 percentage; Pao2

, arterial partial pressure of O2

; PCWP, pulmonary capillary wedge pressure.

also reveals the presence of bilateral pulmonary infiltrates and demonstrates extensive heterogeneity of lung involvement (Fig. 301-4).

Because the early features of ARDS are nonspecific, alternative

diagnoses must be considered. 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. 293), acute immunologic injury (e.g., hypersensitivity pneumonitis; Chap. 288), toxin injury (e.g., radiation pneumonitis; Chap. 75), and neurogenic pulmonary edema (Chap. 37).

Proliferative Phase This phase of ARDS usually lasts from

approximately day 7 to day 21. Many patients recover rapidly and are

liberated from mechanical ventilation during this phase. Despite this

improvement, many patients still experience dyspnea, tachypnea, and

hypoxemia. Some patients develop progressive lung injury and early

changes of pulmonary fibrosis during the proliferative phase. Histologically, the first signs of resolution are often evident in this phase, with

the initiation of lung repair, the organization of alveolar exudates, and

a shift from neutrophil- to lymphocyte-predominant 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 alveolar edema and

inflammatory exudates of earlier phases convert to extensive alveolarduct 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

2227Acute Respiratory Distress Syndrome CHAPTER 301

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. 300).

Thus, caring for these patients requires close attention to (1) the

recognition and treatment of underlying medical and surgical

disorders (e.g., pneumonia, sepsis, aspiration, trauma); (2) the minimization of unnecessary procedures and their complications; (3)

standardized “bundled care” approaches for ICU patients, including prophylaxis against venous thromboembolism, gastrointestinal 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. 302) Patients meeting clinical criteria for ARDS

frequently become fatigued from increased work of breathing

and progressive hypoxemia, requiring mechanical ventilation for

support.

Minimizing Ventilator-Induced Lung Injury Despite its lifesaving potential, mechanical ventilation can aggravate lung injury.

Experimental models have demonstrated that ventilator-induced

Alveolar

air space

Protein-rich

edema fluid

Inactivated

surfactant

Activated

neutrophil

Alveolar

macrophages

Type I cell

Type II cell

Red blood

cell

Endothelial

cell

Endothelial

basement

membrane

Fibroblasts

Neutrophils

Gap formation

Procollagen

Proteases

IL-8

TNF-α MIF

IL-6, IL-8

Leukotrienes

Oxidants

PAF

Proteases

IL-8

Migrating

neutrophil

Fibroblasts

Capillary

Swollen, injured

endothelial cell

Platelets

Interstitium

Widened

edematous

interstitium

Epithelial

basement

membrane

Sloughing of

bronchial epithelium

Necrotic or apoptotic

type I cell

Red blood cell

Intact type II cell

Cellular

debris

Fibrin

Denuded basement

membrane

Hyaline membrane

Surfactant

layer

Normal alveolus Injured alveolus during the acute phase

FIGURE 301-3 The normal alveolus (left) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right). In the acute

phase of the syndrome (right), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded

basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and transmigrating through the interstitium into the air space, which is filled

with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting proinflammatory cytokines—i.e., interleukins 1, 6, 8 (IL-1, 6, 8) and tumor necrosis factor

α (TNF-α)—that act locally to stimulate chemotaxis and activate neutrophils. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can

release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of anti-inflammatory mediators are also

present in the alveolar milieu, including the IL-1 receptor antagonist, soluble TNF-α receptor, autoantibodies to IL-8, and cytokines such as IL-10 and IL-11 (not shown).

The influx of protein-rich edema fluid into the alveolus can lead to the inactivation of surfactant. MIF, macrophage inhibitory factor. (From LB Ware, MA Matthay. The acute

respiratory distress syndrome. N Engl J Med 342:1334, 2000. Copyright © 2000 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

FIGURE 301-4 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.

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 morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase of ARDS is associated with

increased mortality risk.

2228 PART 8 Critical Care Medicine

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 recurrent alveolar

collapse. As is evident from chest CT (Fig. 301-4), ARDS is a heterogeneous disorder, principally involving dependent portions of

the lung with relative sparing of other regions. Because compliance

differs in affected versus more “normal” 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 cm H2

O

in the low-tidal-volume group versus ≤50 cm H2

O in the hightidal-volume 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

 percentage) and provide adequate Pao2

 (arterial partial pressure of

O2

) without causing alveolar overdistention. Currently, there is no

consensus on the optimal method to set PEEP, because numerous

trials have proved inconclusive. Possible approaches include using

the table of PEEP-Fio2

 combinations from the ARDS Network trial

group, generating a static pressure-volume curve for the respiratory system and setting PEEP just above the lower inflection

point on this curve to maximize respiratory system compliance,

and measuring esophageal pressures to estimate transpulmonary

pressure (which may be particularly helpful 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 available 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 overdistention and hemodynamic instability, and provide adequate Pao2

 while minimizing

Fio2 (Chap. 302).

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 positioning (32.8 to

16.0%) for patients with severe ARDS (Pao2

/Fio2

 <150 mm Hg). Thus,

many centers are increasing the use of prone positioning in severe

ARDS, with the understanding that this maneuver requires a criticalcare team that is experienced in “proning,” as repositioning critically

ill patients can be hazardous, leading to accidental endotracheal

extubation, loss of central venous catheters, 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, recruitment maneuvers may increase mortality when they are 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. 300) 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 diuretics 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

patient-ventilator synchrony required for lung-protective ventilation. In a multicenter, randomized, placebo-controlled trial of early

neuromuscular blockade (with cisatracurium besylate) for 48 h,

patients with severe ARDS had increased survival and ventilatorfree days without increasing ICU-acquired paresis. A subsequent

trial demonstrated 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

ventilatory dyssynchrony despite sedation.

GLUCOCORTICOIDS

Many attempts have been made to treat both early and late ARDS

with glucocorticoids, with the goal of reducing potentially deleterious 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.

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 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 recommendations are summarized in Table 301-3, and an algorithm for

the initial therapeutic goals and limits in ARDS management is

provided in Fig. 301-5. Please note that these recommendations

apply to non-COVID-19-ARDS. Please see recommendations for

COVID-19-ARDS in Chap. 199.

■ PROGNOSIS

Mortality In the recent report from 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%

2229Acute Respiratory Distress Syndrome CHAPTER 301

with severe ARDS. There is substantial variability, but a trend toward

improved ARDS outcomes over time appears evident. Of interest,

mortality in ARDS is largely attributable 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. 300).

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. 300). Patients with ARDS arising

from direct lung injury (including pneumonia, pulmonary contusion,

and aspiration; Table 301-1) 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 cm H2

O), respiratory

system compliance (≤40 mL/cm H2

O), 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

patients who survive regain nearly normal lung function. Patients

usually recover maximal lung function within 6 months. One year

after endotracheal extubation, more than one-third of ARDS survivors have normal spirometry values and diffusion capacity. Most of

the remaining patients have only mild abnormalities in pulmonary

function. Unlike mortality risk, recovery of lung function is strongly

associated with the extent of lung injury in early ARDS. Low static

respiratory compliance, high levels of required PEEP, longer durations of mechanical ventilation, and high lung injury scores are all

associated with less recovery of pulmonary function. Of note, when

physical function is assessed 5 years after ARDS, exercise limitation

and decreased physical quality of life are often documented despite

normal or nearly normal pulmonary function. When caring for ARDS

survivors, it is important to be aware of the potential for a substantial

burden of psychological problems in patients and family caregivers,

including significant rates of depression and posttraumatic stress

disorder. Please see Chap. 199 for information regarding COVID

prognosis and recovery.

Acknowledgment

The authors acknowledge the contributions to this chapter by the previous

authors, Drs. Augustine Choi and Steven D. Shapiro.

■ FURTHER READING

ARDS Definition Task Force: Acute respiratory distress syndrome:

The Berlin definition. JAMA 307:2526, 2012.

ARDS Network: 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 342:1301, 2000.

Beitler JR et al: Effect of titrating positive end-expiratory pressure

(PEEP) with an esophageal pressure-guided strategy vs an empirical

high PEEP-FiO2 strategy on death and days free from mechanical

ventilation among patients with acute respiratory distress syndrome.

JAMA 321:846, 2019.

Bellani G et al: Epidemiology, patterns of care, and mortality for

patients with acute respiratory distress syndrome in intensive care

units in 50 countries. JAMA 315:788, 2016.

Combes A et al: Extracorporeal membrane oxygenation for severe

acute respiratory distress syndrome. N Engl J Med 378:1965, 2018.

The National Heart, Lung, and Blood Institute Petal Clinical

Trials Network: Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 380:1996, 2019.

Ware LB, Matthay MA: The acute respiratory distress syndrome.

N Engl J Med 342:1334, 2000.

TABLE 301-3 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 D

Inhaled vasodilators (e.g., inhaled NO, inhaled

epoprosteol)

C

Surfactant replacement, and other antiinflammatory therapy (e.g., ketoconazole, PGE1

,

NSAIDs)

D

a

Key: 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. b

As 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; 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.

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

.

Initiate

volume/pressure-limited

ventilation

Oxygenate

Minimize acidosis

Diuresis

Goals and Limits:

Tidal volume ≤6 mL/kg PBW

Plateau pressure ≤30 cmH2O

RR ≤35 bpm

FIO2 ≤0.6

SpO2 88–95%

MAP ≥65 mmHg

Avoid hypoperfusion

pH ≥7.30

RR ≤35 bpm

FIGURE 301-5 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.