Book Chapter

Acute Respiratory Failure, Acute Lung

Injury/Acute Respiratory Distress
Syndrome, and Acute Chest Syndrome
 Prema R. Menon
 and Gilman B. Allen

Critical Care Secrets, Chapter 24, 166-170

1. What is acute respiratory failure (ARF)?

ARF is a syndrome in which the respiratory system fails in gas exchange, in either
oxygenation, carbon dioxide elimination, or both. ARF can occur within minutes or over
hours.

2. What are the types of ARF?

ARF can be either hypoxemic, hypercapnic, or a combination of both. Arterial blood gas
analysis is the gold standard for diagnosis of respiratory failure. An arterial PO 2 of less than
50 mm Hg while breathing ambient air is considered hypoxemic, and hypercapnia is defined
as a PCO 2 of greater than 50 mm Hg.

3. What are the mechanisms and causes of hypoxemic respiratory failure?

Mechanisms of hypoxemia are as follows: Common causes of hypoxemia and their respective
primary mechanisms are as follows:

▪ Low mixed venous oxygen (low cardiac output, anemia)

▪ Ventilation-perfusion (V/Q) mismatch

▪ Alveolar hypoventilation

▪ Shunt: physiologic (alveolar level) and anatomic (proximal to lung)

▪ Diffusion limitation

▪ Low inspired oxygen fraction

▪ Chronic obstructive pulmonary disease: V/Q mismatch, diffusion limitation

▪ Pneumonia, pulmonary edema, and acute respiratory distress syndrome: physiologic shunt

▪ Pulmonary embolism: V/Q mismatch (physiologic dead space)

▪ Pulmonary fibrosis: diffusion limitation

▪ Obesity: alveolar hypoventilation

4. What are the mechanisms and causes of hypercapnic respiratory failure?

Mechanisms (all related to alveolar hypoventilation) are as follows: Causes are as follows:

▪ Decreased central respiratory drive

▪ Abnormalities of the chest wall leading to excessive restriction

▪ Airways abnormalities leading to excessive dead space or increased work of breathing and
fatigue

▪ Neuromuscular diseases (peripheral nervous system)

▪ Severe asthma

▪ Drug overdose

▪ Myasthenia gravis

▪ Cervical cord injuries

▪ Brain stem injuries

▪ Obesity-hypoventilation
▪ Kyphoscoliosis

5. What are the most important immediate goals of therapy for ARF?

Hypoxia is the major immediate threat to organ function, and therefore initial goals should be
directed toward oxygen supplementation and reversal or prevention of tissue hypoxia.
Hypercapnia is generally better tolerated if not sudden or associated with severe acidosis.
Supplemental oxygen should be delivered to achieve a PaO 2 > 55 mm Hg. This can be
achieved with nasal prongs or face mask, but in many cases mechanical ventilation is
required to reverse hypoxemia. Mechanical ventilation can maximize both inspired O 2 and
alveolar ventilation (decrease PaCO 2 ).

6. What are the main indications for endotracheal intubation and mechanical
ventilation?

Bradypnea, apnea, or respiratory arrest; acute respiratory distress syndrome; respiratory

muscle fatigue; obtundation or coma; PaO 2 less than 55 mm Hg despite supplemental
oxygen; PCO 2 greater than 50 mm Hg with arterial pH < 7.2.

7. What are acute lung injury (ALI) and acute respiratory distress syndrome
(ARDS)?

The American-European Consensus Conference recommended the following criteria for

definition of ARDS:

▪ Acute onset

▪ Bilateral infiltrates on chest radiograph

▪ Pulmonary artery wedge pressure ≤ 18 mm Hg or the absence of clinical evidence of left

atrial hypertension

▪ PaO 2 /FiO 2 ratio ≤ 200 * for ARDS

* Relevance of oxygenation index is questionable because it has not been shown to be

prognostic and does not account for positive end-expiratory pressure, body position,
inspiratory time, or other factors that might influence overall oxygenation.

▪ Acute lung injury is defined by all of the above except a PaO 2 /FiO 2 ratio ≤ 300 *

8. What is the pathogenesis of ARDS?

The early phase of ALI or ARDS is characterized by injury and increased permeability of the
endothelial and epithelial barriers of the lung leading to the accumulation of protein-rich
edema fluid in the interstitium and alveolar airspace. This fluid contains plasma proteins,
inflammatory cells (mostly neutrophils), and necrotic debris that can pack down into dense
eosin-staining hyaline membranes, the latter of which are pathognomonic for the pathology
of ARDS, termed diffuse alveolar damage . Leukocytes, fibroblasts, and epithelial cells
release cytokines that enhance the inflammatory response. Because of up-regulation of
procoagulant pathways diffuse intravascular thrombi formation and fibrin deposition occur.
Patients usually begin to recover in the first 5 to 14 days of disease. During the later phase of
injury, type II pneumocyte hyperplasia and collagen deposition occur and can serve to
repopulate the epithelium during the healing process but can also progress to fibrosis. This
latter fibroproliferative phase can lead to prolonged time using the ventilator and increased
mortality but can also be self-limited and resolve entirely.

9. What are risk factors for the development of ARDS?

Several conditions can predispose one to the development of ARDS, such as aspiration of
gastric contents, pneumonia, sepsis (most common cause), trauma, transfusion of blood
products (particularly plasma-rich products), pancreatitis, fat emboli, and near-drowning.
Comorbid conditions can be predictive of outcomes as well. Patients with a history of active
malignancy, chronic alcoholism, liver disease, and right ventricular dysfunction have a higher
likelihood of death from ALI and ARDS.

10. What is multiple-organ dysfunction syndrome (MODS)?

MODS is a process characterized by incremental degrees of physiologic derangement in

individual organs, such as the liver, gut, kidney, brain, or cardiovascular and hematologic
systems. Alterations in organ function can vary widely from a mild degree of organ
dysfunction to irreversible organ failure. MODS is the single most important predictor of
death in ALI and ARDS and a much more common cause of death in ALI or ARDS than is
refractory hypoxemia.

11. What is the mortality associated with ARDS?

When ARDS was first described in 1967, the mortality rate was approximately 58%. The
overall mortality rate of patients with ARDS over the past several decades is approximately
43%. The mortality rate of ARDS has progressively declined over the last decade to
approximately 30% but is still 41% to 45% in those between 65 and 84 years of age and
approximately 60% in patients over the age of 85 years.

12. How do patients with ARDS die?

Sepsis syndrome with multiorgan failure remains the leading cause of death in patients with
ARDS. Unsupportable respiratory failure is a much less common cause of death.

13. What medical therapy is available for the treatment of ARDS?

Despite many promising results from experimental animal studies, currently no specific
therapies are proven to be effective in reducing ARDS mortality. Surfactant replacement
therapy, N -acetylcysteine, ketoconazole, nitric oxide, steroids, lisofylline, activated protein
C, β-agonists, and inhaled prostacyclins have all been studied in phase III randomized trials.
Although some interventions such as recombinant surfactant protein C and prone positioning
have been effective in improving oxygenation, but none of these therapies has demonstrated a
reduction in mortality. The only interventions thus far shown to reduce ARDS mortality are
the use of low tidal volumes and neuromuscular blockade (NMB). Although low tidal
volumes have since been adopted as best practice, the data on NMB are limited, and
controversy remains over whether paralysis should be uniformly applied to all patients with
ARDS.

14. How should the lungs of patients with ARDS be ventilated?

In the 1980s, animal studies revealed that ventilation with large tidal volumes and high
inspiratory pressures led to the development of inflammatory infiltrates, alveolar flooding,
and hyaline membranes. Since then several clinical studies have shown a benefit from using
low tidal volumes in patients with ARDS. The most influential of these studies, conducted by
the ARDS Network, showed a nearly 9% absolute reduction in the risk of death in patients
with ARDS receiving ventilation with low tidal volumes (6 mL/kg predicted body weight)
and targeted plateau pressures of ≤ 30 cm H 2 O.

Other modes of ventilation in ARDS have been and remain to be studied, such as higher
positive end-expiratory pressure (PEEP), alveolar recruitment maneuvers, prone positioning,
and high-frequency oscillatory ventilation (HFOV). None has demonstrated a reduction in
mortality, but studies evaluating pressure-targeted PEEP and HFOV are ongoing.

15. What is the role of alternate modes of ventilation?

Prone positioning has been shown to improve oxygenation but does not lead to a reduction in
mortality. Although inverse ratio ventilation, airway pressure release ventilation, and HFOV
may be considered as rescue modes in patients with life-threatening refractory hypoxemia
receiving conventional low tidal volume ventilation, randomized controlled trials
demonstrating their efficacy are lacking, and therefore these modes cannot be recommended
for first-line management.

16. What are the sequelae in survivors of ARDS?

The spectrum of impairments in survivors of ARDS is broad. Surprisingly, limitations are

minimal based on mean values of pulmonary function after 5 years. However, the range of
values for forced vital capacity and diffusing capacity among survivors suggest a wide
spectrum from moderate to no impairment at all. The majority of the physical impairment is
related to decreased exercise capacity and musculoskeletal weakness. Quality of life among
survivors is also negatively impacted by a large prevalence of cognitive deficits, depression,
and anxiety as far as 2 years out from discharge, as well as musculoskeletal weakness,
orthopedic injuries (heterotropic ossification, frozen shoulder), vocal cord dysfunction, and
cosmesis (procedural scars from tracheostomy, chest tube insertions, and central and arterial
lines).

17. What is acute chest syndrome (ACS)?

ACS is a frequent complication of sickle cell disease. It is defined as a combination of acute

onset fever, chest pain, new pulmonary infiltrates, and signs and symptoms of pulmonary
disease (i.e., tachypnea, dyspnea, and cough). ACS resembles bacterial pneumonia clinically
but is entirely different in its pathology. It can be brought on by various physiologic insults or
stressors, including infection, vasoocclusive crisis, embolization of marrow fat from infarcted
bone, and lung infarction, but uniformly involves an acute occlusion of the pulmonary
vascular bed by sickle erythrocytes.
18. What are the treatment options for ACS?

Blood transfusion, hydration, pain control, and antibiotics are the current mainstays of
therapy. Red cell transfusion has no proven benefit over standard supportive care, but it can
improve oxygenation and thus is still recommended. The role of corticosteroids is unclear.
Studies examining the use of glucocorticoids have generated variable results. Some experts
recommend the use of dexamethasone, primarily in patients with asthma and ACS. However,
the risk for increased pain and subsequent readmission remains a limitation. A randomized
controlled trial of dexamethasone in the treatment of ACS is currently underway.

19. Is there a role for exchange transfusion in sickle cell disease?

Simple or exchange transfusion successfully and rapidly increases oxygenation in patients

with ACS. In patients requiring mechanical ventilation with multilobar processes who have
already received simple transfusions, the current expert recommendation is to proceed with
red cell exchange transfusions, but no randomized control studies have been done to date that
demonstrate proven benefit from exchange transfusion in ACS.

20. Is pulse oximetry reliable in patients with sickle cell disease?

Pulse oximetry measurements may overestimate the oxygen saturation by including

methemoglobin and carboxyhemoglobin, which are both slightly increased in hemoglobin
(Hb) S disorders. Automated blood gas analyzers may also overestimate the saturation
because they calculate O 2 saturation on the basis of standard HbA. Cooximetry is the most
accurate method to analyze oxygen saturation in HbS disorders.

21. What is the mortality for ACS?

The overall mortality for ACS is 3%. However, adult patients have a higher overall mortality
rate of 9%. The leading causes of death are respiratory failure and bronchopneumonia, but
sepsis, pulmonary hemorrhage, hypovolemic shock, and intracranial hemorrhage are
additional common causes of death in ACS.

Key Points
1. Definition of acute respiratory failure ▪ Hypoxemic respiratory failure: PaO 2 < 50 mm Hg
▪ Hypercapnic respiratory failure: PCO 2 > 50 mm Hg 2. Criteria for ALI or ARDS ▪ Acute
onset ▪ Bilateral infiltrates on chest radiograph ▪ Pulmonary capillary wedge pressure ≤ 18
mm Hg, no evidence of left atrial hypertension ▪ PaO 2 /FiO 2 ≤ 200 (ARDS) ▪ PaO 2 /FiO 2 ≤
300 (ALI) 3. Treatment of ACS ▪ Blood transfusion ▪ Hydration ▪ Pain control ▪ Antibiotics ▪
Exchange transfusion
ARF, ALI/ARDS, and ACS