According to these guidelines, ALI exists when the PaO₂/FIO₂ ratio is 300 mm Hg or less regardless of the level of PEEP and FIO₂, and ARDS is present when the PaO₂/FIO₂ ratio is 200 mm Hg or less regardless of the PEEP setting and FIO₂ (Box 36-2). Although this definition formalized the criteria for the diagnosis of ARDS and is simple to apply in the clinical setting, it has been challenged over the years in several studies. Such definitions have limitations: The physiologic thresholds do not require standardized ventilatory support, and the use of PEEP can improve oxygenation indices sufficiently to convert the patient’s status from meeting the definition of ARDS to not meeting the ARDS definition and also can change the physiology in the lung such that the patient does not meet the criteria for ARDS. Therefore, the ARDS criteria may be met when the PaO₂ is measured with zero PEEP but not when measured at a PEEP of 5 or 10 cm H₂O, making patient comparisons difficult. Furthermore, most of the randomized controlled studies did not use the same definition for ARDS, nor did they evaluate the same ventilatory approaches. Diversity among ARDS definitions is apparent in a large number of studies (Table 36-2).

Box 36-2

American-European Consensus Definitions for Acute Lung Injury (ALI) and for Acute Respiratory Distress Syndrome (ARDS)

Acute onset

Severe hypoxemia (PaO₂/FIO₂ <300 mm Hg for ALI OR ≤200 mm Hg for ARDS)

Diffuse bilateral pulmonary infiltrates on frontal chest radiograph

Absence of left atrial hypertension OR pulmonary artery wedge pressure <18 mm Hg if measured

Table 36-2 Definitions of Acute Respiratory Distress Syndrome in Several Published Reports

Published Study	Criteria
Montgomery et al: Am Rev Respir Dis 132:485–489, 1985	PaO₂/FIO₂ <150 mm Hg
Montgomery et al: Am Rev Respir Dis 132:485–489, 1985	PCP <18 mm Hg
Villar et al: Am Rev Respir Dis 140:814–816, 1989	PaO₂ ≤75 mm Hg on FIO₂ ≥0.5
Villar et al: Am Rev Respir Dis 140:814–816, 1989	PCP <18 mm Hg
Bone et al: Chest 96:849–851, 1989	PaO₂/FIO₂ ≤150 mm Hg (with ZEEP)
	OR PaO₂/FIO₂ ≤250 mm Hg with PEEP
	PCP ≤18 mm Hg
Amato et al: N Engl J Med 338:347–354, 1998	Lung injury score ≥2.5 and PCP <16 mm Hg
Stewart et al: N Engl J Med 338:355–361, 1998	PaO₂/FIO₂ <250 mm Hg on PEEP of 5 cm H₂O
Brochard et al: Am J Respir Crit Care Med 158:1831–1838, 1998	Lung injury score >2.5
Villar et al: Intensive Care Med 25:930–935, 1999	PaO₂/FIO₂ ≤150 mm Hg on PEEP ≥5 cm H₂O
ARDSNet: N Engl J Med 342:1301–1308, 2000	AECC
Gattinoni et al: N Engl J Med 345:568–573, 2001	PAO₂/FIO₂ ≤200 mm Hg on PEEP ≥5 cm H₂O
Gattinoni et al: N Engl J Med 345:568–573, 2001	PCP ≤18 mm Hg
Villar et al: Crit Care Med 34:1311–1318, 2006	PAO₂/FIO₂ ≤200 mm Hg on PEEP ≥5 cm H₂O and FIO₂ ≥0.5
Meade et al: JAMA 299:637–645, 2008	PAO₂/FIO₂ <250 mm Hg
Mercat et al: JAMA 299:646–655, 2008	PAO₂/FIO₂ ≤200 mm Hg PCP ≤18 mm Hg

AECC, American-European Consensus Conference; PCP, pulmonary capillary pressure; PEEP, positive end-expiratory pressure; ZEEP, zero PEEP.

Genetics

Critical care physicians have long recognized that some patients progress despite therapy, whereas others do better than predicted. It is now well accepted that these responses may be related to variations in the genome. Little is known, however, about the genes that are responsible for susceptibility to and outcome of ARDS. The search for genetic variants determining susceptibility and predicting outcome is still a developing field. The identification of important associations between genotype and clinical outcomes will have an impact on the development of more efficient genotype- or phenotype-guided therapies for patients with ALI or ARDS. The current understanding is that the pathogenesis of ARDS has a fundamental inflammatory component eliciting a response similar to that observed against any pathogen. In addition, common genetic risk factors with modest effects may be associated with disease susceptibility. Many studies have searched for genetic variations underlying ARDS susceptibility. Owing to the impracticality of classical genetic approximation in ARDS, association studies comparing unrelated ARDS cases with controls for genetic variants at specified locations of the human genome represent the prevailing study design for detecting such loci. The genetic variants explored usually are single base changes in the DNA, known as single-nucleotide polymorphisms (SNPs), because they are the most common variants across the genome. The genetic studies of ARDS have focused largely on candidate genes involved in the response to external stimulus and cell signal transduction, because those genes are assumed to be important in the immune response.

Extensive cross-species gene expression pattern comparisons in experimental models of ALI/ARDS have revealed that IL-6, an acute-phase response cytokine with pleiotropic effects, is highly upregulated. This finding is consistent with clinical studies indicating that IL-6 and other cytokines are released from the lungs in patients with ARDS; increased IL-6 concentrations are found in the bronchoalveolar lavage fluid and serum of these patients. IL-6 levels have been correlated with clinical outcome and implicated in the development of multiple system organ failure. A G/C SNP located at position −174 of the promoter region of the IL-6 gene has been shown to functionally affect the activity of the IL-6 gene promoter in vitro. To date, assessing the SNP variation for virtually all common variants of the gene has allowed subsequent studies to reveal a consistent picture for the association of the IL-6 gene with ALI and ARDS.

In case-control studies of patients with severe sepsis and ARDS, several investigators have explored variants of the gene encoding the lipopolysaccharide-binding protein (LBP) and serial measurements of the LBP in serum to relate them with risk gene variants. It has been reported that (1) a four-SNP risk haplotype of the LBP gene is associated with mean serum LBP concentrations within the first week of the disease process; (2) LBP levels at 48 hours are much higher in patients with ARDS than in those with ALI; and (3) a subsequent increase of LBP levels at 48 hours is associated with a four-fold increase in mortality rate. A positive association with ARDS susceptibility and/or outcome has been reported for several other genes, including surfactant pulmonary-associated protein B (SFTPB), angiotensin-converting enzyme (ACE), tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), IL-10, pre-B cell–enhancing factor (PBEF), chemokine CXC motif ligand 2 (CXCL2), mannose-binding lectin-2 (MBL2), myosin light chain kinase (MLCK), nuclear factor κ light polypeptide gene enhancer in B cells (NFKB1), coagulation factor V (F5), and type 2 deiodinase (DIO2) (Table 36-3). These genes are involved mainly in the response to external stimulus and cell signal transduction.

Table 36-3 Positive Genetic Association Studies With Susceptibility to and/or Outcome of Acute Respiratory Distress Syndrome (ARDS)*

Altogether, significant progress has been made in the studies of genetic associations for ARDS. Because all studied candidate genes await repetitive validation in independent studies using larger samples, the search for genetic variants determining susceptibility and outcome in ARDS still needs to grow, to identify associations between genotype and clinical outcomes. The identification of genetic risk factors might allow the development of a new classification of patients and a more accurate determination of patient outcome.

Ventilator-Induced Lung Injury

Unequivocal evidence from both experimental and clinical research shows that mechanical ventilation can damage the lungs and initiate an inflammatory response, possibly contributing to extrapulmonary organ dysfunction. This type of injury, referred to as ventilator-induced lung injury (VILI), resembles the syndromes of ALI and ARDS. VILI can trigger a complex array of inflammatory mediators, resulting in a local and systemic inflammatory response. Substances produced in the lungs can be translocated into the systemic circulation as a result of injury to the pulmonary epithelium and to the capillary endothelium. This type of injury forms the basis for the use of low tidal volumes (in the range of 4 to 8 mL/kg of predicted body weight) during mechanical ventilation of patients with ALI or ARDS. The recognition of VILI has prompted a number of investigators to suggest that ALI and ARDS may in part be a product of efforts to mechanically ventilate patients, rather than representing progression of the underlying disease. On the other hand, current scientific evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, in a manner similar to that in which severe cases of sepsis manifest clinically. In addition, functional genomic approaches using gene array methodology to measure lung gene expression have identified patterns of genes differentially expressed in animal models of VILI, similar to those gene pathways activated during experimental and clinical sepsis.

Ventilators are intended to deliver air or oxygen at tidal volumes and frequencies sufficient to provide adequate alveolar ventilation, to reduce the work of breathing, and to enhance oxygenation (see also Chapter 32). However, mechanical ventilation is a nonphysiologic process, and complications are associated with its application, including increased risk for pneumonia, impaired cardiac performance, and lung injury. During mechanical ventilation, pressures, gas volumes, ventilatory rates, and concentrations of inspired oxygen often are applied at levels that exceed those normally experienced by healthy lungs during spontaneous breathing. VILI is not a new concept—it is the designation historically applied to macroscopic injuries associated with alveolar rupture due to overdistention resulting from application of high inspiratory pressures. Clinical manifestations include interstitial emphysema, pneumothorax, pneumomediastinum, and pneumoperitoneum. The concept of VILI has shifted somewhat from pressure-induced (really volume-induced) injury to increased vascular permeability, accumulation of lung fluid, “atelectrauma,” and inflammation induced by mechanical ventilation.

In 1998 Tremblay and Slutsky coined the term biotrauma to describe the pulmonary and systemic inflammatory response triggered by lung cell distention, alveolar disruption, and/or necrosis after the application of mechanical ventilation. Although a Consensus Conference in 1994 recommended that plateau pressure generally should be limited to 35 cm H₂O, little change in ventilator practice occurred until publication of an ARDS Network study demonstrating that a lung-protective strategy using a tidal volume of 6 mL/kg of predicted body weight and moderate levels of PEEP decreased mortality in patients with ALI. This study confirmed that VILI was not just an interesting experimental entity but also was an important clinical entity. This recognition led to the widespread, albeit not universal, use of lung-protective strategies in patients with ALI. Unequivocal evidence from both experimental and clinical data has proved that mechanical ventilation can cause or aggravate ALI. Many of the pathophysiologic consequences of VILI mimic those of ARDS. A number of specific forms of injury caused by the trauma of mechanical ventilation have been identified: barotrauma, volutrauma, atelectrauma, and biotrauma. Current experimental and clinical evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, by mechanisms similar to those whereby most severe cases of sepsis are clinically manifested (Figure 36-2).