The Lung in Multiorgan Failure

  • Rob BootsEmail author


The lung is almost invariably involved in the syndrome of multiorgan failure. However the mortality of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is largely determined by concurrent non-lung organ failures. Increasingly, the role of mechanical ventilation has been recognized not only as a cause of ALI/ARDS, but also potentially contributing to the development of mutilorgan failure by the release of inflammatory and programmed cell death biological signals acting on organs distant from the lungs. This review summarizes the current epidemiology of ALI/ARDS, particularly with regards to its contribution to multiorgan failure. The potential mechanisms by which lung injury including that caused by mechanical ventilation are analyzed and current treatment strategies detailed.


Mechanical Ventilation Lung Injury Acute Lung Injury Acute Respiratory Distress Syndrome Multiorgan Failure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

9.1 Introduction

The acute respiratory distress syndrome (ARDS) initially described by Ashbaugh and colleagues encompasses the clinical signs of respiratory distress, hypoxemia, decreased pulmonary compliance and diffuse bilateral infiltrates on the chest X-ray, in the absence of fluid overload (Ashbaugh et al. 1967). Since then it has been described in pediatrics (Holbrook et al. 1980; Lyrene and Truog 1981), while a less severe clinical syndrome, acute lung injury (ALI), has also been reported (Bernard et al. 1994). Clinically it may represent an array of conditions, although pathologically, it is most commonly associated with diffuse alveolar damage. Increasingly it is recognized that there may be a genetic predisposition to the development of ARDS and that ventilatory strategies may also contribute to causing or worsening lung injury (Leikauf et al. 2001). ARDS and ventilatory strategies are also increasingly seen as potential drivers of multiorgan failure (Slutsky and Slutsky 2005).

9.2 Definitions of ARDS

ALI and ARDS have been estimated to affect 78.9 and 58.37 cases per 105 persons per year (Rubenfeld and Herridge 2007). This probably increases significantly where there are respiratory pandemics such as influenza or SARS. However, there is great variability in the reported incidence of ARDS of between 18 and 79 cases per 105 persons per year (Rubenfeld and Herridge 2007). This is most likely due to interpretation of the definition. The syndrome of respiratory failure ­characterized clinically by an acute onset illness with impaired gas transfer of oxygen to the arterial blood, bilateral pulmonary infiltrates on the chest X-ray, and the absence of fluid overload or heart failure (a pulmonary capillary wedge pressure <18 mmHg) was described in 1994 in the American-European Consensus Conference (Bernard et al. 1994). At this time the term “Acute Lung Injury” was coined where the PaO2/FiO2 <300 mmHg, while Acute Respiratory Distress Syndrome (ARDS) was used where the PaO2/FiO2  <  200 mmHg (Table 9.1). The recognized underlying pathology of this condition is generally accepted to be diffuse alveolar damage with hyaline membrane formation. However, pathological correlation with the clinical syndromes is rarely performed.
Table 9.1

Definition of ALI/ARDS

Criteria (Bernard et al. 1994)

1. Acute onset illness

2. Bilateral infiltrates on frontal chest X-ray

3. Pulmonary artery wedge pressure  ≤  18 mmHg or no clinical evidence of pulmonary hypertension

4. PaO2/FiO2  <  200 mmHg (ARDS) or PaO2/FiO2 <300 (ALI)

However, there are problems with this definition. Firstly, the meaning of acute is not specified, nor is the underlying pathology affecting the lung. As such, this definition would fit for a variety of interstitial and inflammatory lung diseases. However, Luhr found that patients requiring oxygen therapy on admission to the ICU who ultimately developed ARDS did so within the first 72 h following admission (Luhr et al. 1999). Secondly, the nature of the pulmonary infiltrates on the chest X-ray is not defined, which does not help characterize the differential diagnosis. Thirdly, the oxygenation index is significantly affected by positive end respiratory pressure (PEEP), which is not part of the definition. Fourthly, it can be difficult to fully differentiate cardiac from noncardiac pulmonary edema even using brain natriuretic peptide or the pulmonary artery catheter (Forfia et al. 2005; Rana et al. 2006). Finally, the often concurrent organ dysfunctions occurring at the time of lung injury are not specified (Abraham et al. 2000). All of the major criteria to diagnose ARDS clinically have been shown to have poor reliability (Rubenfeld 2003). As such, a clearer physiological definition was provided by Murray to describe more explicitly the degree of pulmonary dysfunction (Table 9.2) (Murray et al. 1988). The GOCA (gas exchange, organ failure, cause and associated diseases) is a stratification system for patients with ALI/ARDS, which attempts to provide a uniform stratification to describe patients consistently and succinctly for epidemiological comparisons. It is not designed as a clinical mortality scoring system (Artigas et al. 1998) (Table 9.3).
Table 9.2

ALI score (Murray score)



Number of quadrants of consolidation on chest X-ray


Hypoxemia score

PaO2/FiO2  >  300


PaO2/FiO2  =  225–229


PaO2/FiO2  =  175–224


PaO2/FiO2  =  100–174


PaO2/FiO2  <  100


PEEP Score (cmH2O)

≤ 5 cmH2O


6–8 cmH2O


9–11 cmH2O


12–14 cmH2O


≥ 15 cmH2O


Compliance score (if measurable mLs/cmH2O)

≥ 80










Score  =  (sum of parameter values)/(number of parameters used)

Maximal score 4

Adapted from Murray et al. (1988)

Table 9.3

GOCA scoring for ALI/ARDS






Gas exchange (a numeric descriptor in combination with a letter)


PaO2/FiO2 ≥301


PaO2/FiO2 200–300


PaO2/FiO2 101–200


PaO2/FiO2  ≤  100


Spontaneously breathing – no PEEP


PEEP 0–5 cmH2O


PEEP 6–10 cmH2O


PEEP >10 cmH2O


Organ failure


Lung only


Lung  +  1 organ


Lung  +  2 organs


Lung  +  ≥3 organs






Direct lung injury


Indirect lung injury


Associated Diseases


No associated diseases that would cause death in the next 5 years


Associated diseases that would cause death in the next 5 years


Coexisting disease that would cause death in 6 months

Adapted from Artigas et al. (1998)

9.3 Clinical Presentation

Acute respiratory distress syndrome pathologically represents diffuse alveolar damage as a general overwhelming inflammatory reaction of the lung parenchyma to either direct injury or involvement of the lung in a systemic inflammatory process (Table 9.4).
Table 9.4

Clinical conditions associated with ALI/ARDS


Direct insult

Indirect insult


Aspiration pneumonia



Severe multitrauma

Shock, any cause

Less common

Inhalation injury

Acute pancreatitis

Pulmonary contusions

Transfusion related (TRALI)

Fat emboli

Cardiopulmonary bypass

Near drowning


Reperfusion injury

Head injury/neurogenic pulmonary edema

Drug overdose

Disseminated intravascular coagulation


Toxins/drugs, e.g., mitomycin C

Adapted from Atabai and Matthay (2002), Ferguson et al. (2004, 2005c), Ware (2005)

Most frequently, ALI/ARDS is associated with sepsis, pneumonia, peritonitis and multi-/polytrauma (Atabai and Matthay 2002; Ferguson et al. 2005c; Frutos-Vivar et al. 2004; Ware 2005). Multiple potential insults (Pepe et al. 1982) and alcoholism (Moss et al. 2003) are associated with an increased risk of ARDS. Chronic alcohol ingestion has been associated with changes to the function of epithelial and endothelial cells as well as the production of surfactant in the lung, predisposing to malfunction of the alveolar-capillary barrier (Guidot and Roman 2002). Independent risk factors for the development of ARDS include peak airway pressure (OR 1.31), high fluid balance (OR 1.3), transfusion of plasma (OR 1.26), sepsis (OR 1.57) and tidal volume (OR 1.29) (Jia et al. 2008). Moss found that diabetes mellitus patients with sepsis rarely developed ARDS (OR 0.33) (Moss et al. 2000).

ALI/ARDS presents as a rapid onset pulmonary consolidation. The symptoms are non-specific, consisting of increasing dyspnea, hypoxemia and work of breathing associated with tachypnea and increased use of accessory muscles. Additional symptoms and signs relate to the primary cause of the ALI/ARDS in addition to associated organ dysfunction. Respiratory examination findings can be variable, but reflect pulmonary consolidation and possible associated pleural effusions.

The chest X-ray may initially be normal depending upon the primary cause of the ARDS (Caironi et al. 2006). Direct lung injury from pneumonia or aspiration may commence with a focal infiltrate. Progression typically occurs over 48 h to bilateral diffuse interstitial changes or alveolar shadows. Pleural effusions (exudates) are common and do not necessarily imply raised filling pressures. Radiological resolution may be rapid where the insult has not led to physical ­disruption of the alveolar membrane and the edema is rapidly cleared. This may be seen in neurogenic pulmonary edema or near drowning. However, if the fibroproliferative stage develops, particularly if the patient requires mechanical ventilation, pneumothoraces, pneumomediastinum and intrapulmonary pneumatocoeles may develop.

Computerized tomography of the lung has significantly increased our understanding of ALI/ARDS (Gattinoni et al. 2006b). The CT may initially be normal and maintain near normal appearances in the non-dependent lung regions. The infiltrate patterns include a ground-glass infiltrate in the mid-zones whereby the bronchial and vascular edges are preserved. Consolidation often with air bronchograms is seen in the dependent lung regions along with pleural effusions. There does not seem to be a difference in the nature of the infiltrates according to cause (Goodman et al. 1999; Puybasset et al. 2000). The changes in lung compliance are correlated with the amount of “normal” lung that is present, creating the notion of a small, rather than a stiff lung.

Resolution may result in a normal radiological appearance or severe fibrosis with honeycomb appearances (Caironi et al. 2006). A reticular pattern on resolution is commonly found in non-dependent lung regions (Desai et al. 1999). Persisting radiological abnormalities are associated with ventilation strategies producing peak inspiratory pressures greater than 30 mmHg and a requirement for more than 70% inspired oxygen (Nobauer-Huhmann et al. 2001). In surviving patients, pulmonary symptoms are generally mild (10% of patients) and do not correlate with radiological abnormalities (Nobauer-Huhmann et al. 2001). However, the reported frequency of respiratory symptoms may be as high as 55% (Ghio et al. 1989). Some 50% of patients have a persisting restrictive defect on lung function testing with 13% being severe (Ghio et al. 1989). Of those with persisting abnormalities on CT scanning, some 87% have parenchymal changes consistent with pulmonary fibrosis – thickened interlobular septa and localized non-septal lines, parenchymal bands and subpleural/intrapulmonary cysts. Ground-glass appearances may still be found if assessment is performed prior to 6 months from the acute illness. Evidence of pulmonary fibrosis occurs in <15% with localized distortion of architecture, consolidation, bronchiectasis and honeycombing. Ventral involvement is more pronounced (Nobauer-Huhmann et al. 2001).

The prevalence of ALI/ARDS in a general ICU population is 7–20% depending upon definitions and case mix at risk (Vincent et al. 2006). Mortality is generally described between 20% and 65% (Vincent et al. 2006) with less than 20% dying directly of their respiratory failure. Some 50% die as a result of sepsis and multiorgan failure (Ferring and Vincent 1997). Intensive care and hospital mortality is higher for ARDS (49% and 58%, respectively) than ALI (23% and 33%, respectively) (Brun-Buisson et al. 2004). The relatively high mortality rates of acute lung injury/acute respiratory distress syndrome are primarily related to the underlying disease, the severity of the acute illness and the degree of organ dysfunction. Table 9.5 outlines described prognostic factors for ALI/ARDS outcome.
Table 9.5

Prognostic factors for ALI/ARDS





Poor outcome factors

Metabolic acidosis occurring after the diagnosis of ARDS


Ferguson et al. (2005b)

pH  <  7.3 at ARDS onset


Brun-Buisson et al. (2004)



Luhr et al. (1999); Brun-Buisson et al. (2004)

Air leak for 2 days


Brun-Buisson et al. (2004)

Higher FiO2/oxygenation index


Monchi et al. (1998); Ferguson et al. (2005b)

PF  >  100


Luhr et al. (1999)

Renal failure occurring after the ARDS diagnosis


Ferguson et al. (2005b)

Logistic organ dysfunction score


Brun-Buisson et al. (2004)

ARDS developing after the onset of mechanical ventilation


Monchi et al. (1998); Ferguson et al. (2005c)

SAPS II score


Monchi et al. (1998); Brun-Buisson et al. (2004); Ferguson, et al. (2005c)



Zilberberg and Epstein (1998); Luhr et al. (1999); Brun-Buisson et al. (2004); Ferguson et al. (2005c)

CXR quadrants


Luhr et al. (1999)

Respiratory acidosis occurring after the diagnosis of ARDS


Ferguson et al. (2005b)

Right ventricular dysfunction


Monchi et al. (1998)

Cirrhosis (ARDS)


Monchi, Bellenfant et al. (1998); Zilberberg and Epstein (1998)

Doyle et al. (1995); Luhr et al. (1999)

MODS  >  =8


Rocco et al. (2001)

Direct lung injury


Monchi et al. (1998); Luhr et al. (1999)

APS  >  15


Luhr et al. (1999)

LIS  >  3


Rocco et al. (2001)

LIS 2.76–3


Nonpulmonary organ dysfunction


Doyle et al. (1995)



Doyle et al. (1995); Zilberberg and Epstein (1998)



Zilberberg and Epstein (1998)



Ferguson et al. (2005b)



Zilberberg and Epstein (1998)

Active malignancy


Zilberberg and Epstein (1998)

Protective factors



Ferguson et al. (2005a)

Barotrauma (interstitial emphysema, pneumothorax, pneumomediastinum, pneumoperitoneum or subcutaneous emphysema) occurs in some 2.9% of mechanically ventilated patients with ARDS and is most likely to occur within the first 3 days of mechanical ventilation (Anzueto et al. 2004). Surprisingly, levels of PEEP and inflation pressures were not predictors of the development of barotrauma, but rather the presence of asthma (relative risk 2.58), chronic interstitial lung disease (relative risk 4.23), previous ARDS (relative risk 2.70) and ARDS developing during mechanical ventilation (relative risk 2.53) (Anzueto et al. 2004).

9.4 Pathophysiology

9.4.1 Pathology

ARDS as diffuse alveolar damage can be described in three phases (Atabai and Matthay 2002; Frutos-Vivar et al. 2004).
  1. 1.

    A lung injury characterized by cellular and structural damage, alveolar edema and inflammation in an uneven distribution. This acute phase of ALI/ARDS is associated with disruption of the alveolar-capillary interface with leakage of protein-rich fluid into the interstitium and alveolar space. There is discontinuity of the type I epithelial cells with sometimes complete destruction in many areas. Type II cells are often preserved. Pulmonary and non-pulmonary insults result in inflammatory stimuli for neutrophil attraction via chemoattractants and cellular adhesion molecules.

    Neutrophil infiltration and release of inflammatory cytokines are the result of increased expression of adhesion molecules and chemoattractants such as integrin, ICAM-1 and interleukin (IL)-8. Inflammatory cytokines are increased, whereas anti-inflammatory cytokines such as IL-10, IL-1 receptor antagonist, soluble tumor necrosis factor (TNF) and IL-1 receptors are decreased. Nuclear factor kappa-beta (NF-KB) is a protein complex that directly affects the expression of many of the cytokine and adhesion molecule genes involved in the development of ARDS. The inflammatory process also increases the capillary leakiness. In established ARDS, the additional role of high oxygen concentrations is ill defined in worsening the inflammatory injury.

    Edema, reduced surfactant production and altered surfactant function from inflammatory exudates all promote unstable alveoli with alveolar collapse and ventilatory perfusion mismatching causing hypoxemia. The heavy edematous lung is the initial cause of reduced pulmonary compliance.

  2. 2.

    Tissue repair begins with clearing of edema and intra-alveolar debris.

    Functioning type II pneumocytes would appear to be important in this process of clearance (Olivera et al. 1995; Sznajder et al. 1995).

  3. 3.

    Recovery resulting in tissue restoration of extracellular matrix, revascularization and re-epithelization of alveolar surfaces. This later reparative phase is characterized by fibroproliferation and organization of lung tissue. The scaffold of inflammatory proteins such as fibronectin and fibrin maintain an interstitial structure to allow repair. Disordered collagen deposition occurs, leading to extensive lung scarring where resolution does not occur.


9.4.2 Genetic and Contributing Factors

Increasingly it is recognized that some patients do not seem to develop ALI/ARDS despite similar predisposing causes. Animal studies have shown different susceptibilities to environmental agents known to induce ALI/ARDS perhaps related to the expression of inflammatory agents (Leikauf et al. 2001). However, characterizing specific genetic predispositions is difficult because of the range of inciting causes of ALI and the large number of factors involved in the inflammatory cascade. A specific biomarker of the disease is lacking. There is an increasing range of genetic polymorphisms being described in humans, which influence the functioning of innate and acquired immune systems including mannose-binding lectin and surfactant protein B, as well as the extent of inflammatory cytokines, such as IL-1 family, TNF, IL-6, IL-8, pre B cell colony-enhancing factor 1, macrophage inhibitory factor and vascular endothelial growth factor (VEGF), which may influence responses to infection as well as the inflammatory response in the lung (Villar 2002; Christie 2004; Gao and Barnes 2009). Angiotensin-converting enzyme is rich in the lung, and genetic polymorphisms have been found to increase the risk and mortality of ARDS (Marshall et al. 2002) as well as susceptibility to meningococcal disease (Stuber 2002). Anti-inflammatory cytokine polymorphisms have included IL-10. Myosin-light chain kinase involved in the maintenance of epithelial cell cytoskeleton and barrier function has also been implicated, in addition to cell signaling, blood coagulation, oxidant-mediated systems and altered iron handling (Gao and Barnes 2009).

9.4.3 The Role of Mechanical Ventilation in the Development of ARDS and Multiorgan Failure

It is common for the ALI/ARDS to be part of a multi-organ failure (MOF). This condition is associated with systemic inflammation in which the lung is commonly the first organ compromised. However, in many patients the initiating cause for the progressive organ deterioration remains unclear. Such lung disease typically requires commencement of mechanical ventilation to support the progressive respiratory failure. A general outline of possible mechanisms contributing to multiorgan failure and the role of ventilator-induced lung injury is illustrated in Fig. 9.1.
Fig. 9.1

Proposed mechanisms for ventilator-induced lung injury and multiorgan failure

Conditions morphologically, physiologically and radiologically indistinguishable from ALI/ARDS are well described associated with the processes of mechanical ventilation (1999). The term ventilator-induced lung injury (VILI) refers to acute lung injury in animal models directly as a result of the ventilation strategy. Ventilator-associated lung injury is an acute lung injury similar to ARDS in patients receiving mechanical ventilation and may be associated with a pre-existing pulmonary condition. However, whether “protective” ventilation of the ­normal lung causes lung damage and a systemic response is unclear (Wrigge et al. 2004; Plotz et al. 2002).

ARDS is an inhomogeneous disease process with near normal as well as ­collapsed and consolidated areas of lung (Gattinoni et al. 2006b). Conventional ­mechanical ventilation tends to overinflate the near normal areas of lung while having little effect on recruiting the severely diseased lung. Injury can be caused by excessive pressures (barotrauma), volume (volutrauma), and the repeated cycling of opening and closing of collapsed alveoli (shear stress). Mechanisms contributing to lung trauma in mechanical ventilation are synergistic and not mutually exclusive. The processes contributing to VILI include (1) stress failure of the epithelial membrane, which may include necrosis; (2) failure under stress of the endothelial-epithelial ­barrier with loss of compartment integrity between the air and the interstitial-vascular compartments; (3) tissue overdistention without causing tissue destruction but promoting inflammatory and other cellular signaling (mechanotransduction); and (4) positive pressure ventilation raising the pressure in the pulmonary circulation promoting vascular shear stress, cellular signaling and mediator production from the endothelial cells (Uhlig 2002).

The non-homogeneous inflation of lung tissue results in shear forces that are much greater that the applied transalveolar pressure (Mead et al. 1970). Despite transalveolar pressures of 30 cmH2O some 140 cmH2O of shear force can be generated, potentially leading to disruption of the alveolar-capillary basement membrane. Opening and closing of alveoli during mechanical ventilation where surfactant is deficient exacerbate lung injury (Steinberg et al. 2004). In this model, histopathological evidence of injury only occurred in those alveoli that were demonstrated to be unstable. PEEP was shown to stabilize collapsing alveoli and reduce the severity of the lung injury. Preventing the repeated cycle of alveoli opening and collapse decreases lung injury (Ranieri et al. 1999).

High pressure, high volume ventilation in animals is associated with a diffuse alveolar injury similar to ALI/ARDS and exacerbates the injury of previously ­damaged lung (Pinhu et al. 2003). However, high pressure ventilation in the absence of high lung volumes does not necessarily result in VILI. High inflation pressures in rats of 40 cmH2O causes ALI/ARDS, which is prevented by 10 cmH2O of PEEP (Webb and Tierney 1974). High transalveolar pressures applied while preventing large tidal volumes by strapping of the chest avoid the ALI/ARDS, which develops as a result of either high pressure or high volume ventilation (Dreyfuss et al. 1988). PEEP was again demonstrated to limit the development of pulmonary edema.

However, despite an ARDSnet type strategy of low tidal volume (6 mLs/kg) and reducing plateau pressures <30 cmH2O to minimize the risks of barotrauma and volutrauma, and the application of PEEP to limit shear stress, 30% of such ventilated patients with ARDS still demonstrate alveolar overdistention on CT scanning (Terragni et al. 2007). Evidence of overdistention was associated with an increase in inflammatory cytokines in the lung. A more individualized approach may be required because of the varied severity and heterogeneous distribution of the lung injury (Hager et al. 2005).

However, despite numerous studies to determine the best or optimal PEEP for the management of ARDS, a defined strategy remains unclear except for the improvement of oxygenation and avoiding hemodynamic compromise. For most patients, the most beneficial PEEP is a relatively narrow range with the ARDSnet strategy the only recommendations with a large body of evidence (Kallet and Branson 2007). Given the heterogeneity of the lung injury in ARDS, the individualized titration of PEEP could be based upon the respiratory-system pressure-volume curve, PEEP/tidal-volume titration grids or a recruitment maneuver with a PEEP decrement trial (Levy 2002).

Increasing the information available during mechanical ventilation may allow a less arbitrary application of PEEP. Transthoracic impedance tomography by allowing a visual image of lung volume at the bedside may in the future assist in the setting of PEEP (Bikker et al. 2009; Fagerberg et al. 2009). Use of esophageal pressure measurements as a surrogate for pleural pressure results in higher PEEP being applied compared to an ARDSnet protocol with a trend to a lower mortality (Talmor et al. 2008).

Where there are perturbations of excretion and function of surfactant resulting in increased surface tension at the air-alveolar interface, alveoli become unstable and collapse. Higher airway pressures are required to open these airspaces. There is also a resultant transmural pressure increase favoring fluid movement into the alveolar space. These abnormalities are common in ALI/ARDS. Mechanical ventilation has been shown to promote alveolar injury in these circumstances (Taskar et al. 1997). Ventilation with low tidal volumes and adequate PEEP has been shown to maintain function of surfactant aggregates in experimental models of ARDS (Ito et al. 1997).

Mechanical forces have been shown in the lung to induce cellular signal transduction (Riley et al. 1990), including the production of inflammatory mediators (dos Santos et al. 2004). Alveolar epithelial cells on gene expression microarray studies of cellular stretch alter their morphology and gene expression in a synergistic way when there is activation of an inflammatory cascade (dos Santos et al. 2004). Such mechanical forces would seem to be involved with alveolar epithelial cell signaling for membrane proteins, apoptosis as well as intracellular signal ­transduction. Large tidal volume mechanical ventilation has been demonstrated to result in physical fractures in both the alveolar epithelial and endothelial plasma membrane integrity. This triggers a proinflammatory cascade with increased cytokine concentration in the lung and systemic circulations (Vlahakis and Hubmayr 2005). This appears to be important in the generation of multiorgan failure. Protective strategies for mechanical ventilation with lung volume limitation result in a reduction in both pulmonary and systemic circulation cytokine levels and decreased organ dysfunction (Ranieri et al. 1999, 2000).

Bronchoalveolar lavage concentrations of neutrophils, IL-1β, IL-6 and IL-1 receptor antagonist, and plasma concentrations of tumor necrosis factor α, IL-6 and TNF-α receptors were significantly elevated over 36 h in ventilated patients with ARDS comparing a conventional with a volume-restricted strategy (Ranieri et al. 1999). Elevated platelet activating factor and thromboxane-B2 are also released by macrophages in saline lavage models of ARDS (Imai et al. 1994). Neutrophil priming appears important as granulocytopenic models of ARDS demonstrate less lung injury Kawano et al. 1987). Granulocyte-depleted animals maintained gas exchange with only a small protein leak and no hyaline membranes. Upon repletion with donor rabbit granulocytes, gas exchange deteriorates with hyaline membrane formation.

Improved oxygenation is described when inhaled nitric oxide (iNO) is administered at an early stage of ALI, but this has not translated into a mortality benefit (Adhikari et al. 2007). Lung injury is attenuated and alveolar-capillary membrane integrity is preserved with the administration of iNO at the beginning of reperfusion injury (Dong et al. 2009; Phillips et al. 2009; Sedoris et al. 2009). iNO attenuates ALI in a rabbit model in the early stages of ARDS through inhibition of NF-kB (Koh et al. 2001; Skerrett et al. 2004; Hu et al. 2007). It is considered that iNO has a protective role in oxidative lung capillary injury.

In patients receiving mechanical ventilation for ARDS, multi-organ failure scores increase significantly after 72 h of conventional mechanical ventilation when a lung protective strategy is not used (Ranieri et al. 2000). Renal failure was the predominant organ dysfunction. Multiorgan failure was significantly less in patients receiving a volume-limited strategy. The frequency of multiorgan failure was significantly correlated with plasma concentrations of IL-6, α-TNF, IL-1β and IL-8.

Heat shock proteins (HSP-70) have also been seen to be induced in lungs ventilated with low end expiratory pressures in ventilated models of ARDS (Ribeiro et al. 2001; Vreugdenhil et al. 2003). The application of PEEP attenuated this expression. In this setting, heat shock protein expression represents a response from the lung under stress to maintain structural and functional integrity of intracellular proteins. Heat shock protein expression in respiratory epithelial cells reduces inflammatory cytokine production by decreasing nuclear transcription factor κB activation (Yoo et al. 2000). It has been shown that HSP-70 expression decreases the severity of ARDS in experimental models (Weiss et al. 2002).

Inflammatory cytokines and chemokines have been shown to increase epithelial cell apoptosis. This contributes to multiorgan failure in patients dying of sepsis, trauma and shock (Hotchkiss et al. 1999; 2000; Cobb et al. 2000). Apoptosis refers to genetically controlled programmed cell death that is not the result of necrosis, whereby cells fragment and are phagocytosed by surrounding parenchymal or inflammatory cells (Papathanassoglou et al. 2000). Scarring usually does not occur. Specific receptor/ligand interactions activate a cascade of intracellular signaling pathways leading to DNA cleavage and apoptotic cell death. Cytokines IL-8, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene (GRO) and the Fas ligand are principle regulators and are produced during VILI and released into the plasma (Imai et al. 2003). Fas is a cell membrane receptor and soluble ligand that is a part of the tumor necrosis factor family of proteins that accumulates at sites of inflammation and promotes apoptosis of leukocytes, epithelial and parenchymal cells. The expression of the Fas ligand is regulated by such factors as surfactant protein A, angiotensin II, transforming growth factor β and a Fas ligand decoy receptor (Del Sorbo and Slutsky 2010). Inhibition of the soluble Fas ligand, which is released into the circulation during lung injury, decreases the apoptosis in organs distant to the lungs (Imai et al. 2003). High lung injury models cause type II cell necrosis in the lung rather than apoptosis.

Selective blocking of aspects of the inflammatory cascade produces less VILI in experimental models. The use of an interleukin-1 receptor antagonist decreased markers of the inflammatory response and histological evidence of lung injury (Narimanbekov and Rozycki 1995). IL-1 blockade had no effect on the decline in dynamic compliance and oxygenation, implying that given the great redundancy in the inflammatory cascade and multiple pathways, no one specific site of targeting therapy is likely to be successful.

The prone position in animals has been associated with a reduced apoptosis index in lung, diaphragm, liver, intestines and kidney (Nakos et al. 2006). Interestingly, the apoptotic index was highest in dorsal areas compared with ventral areas in both the prone and supine positions. Clinically, renal failure is less common in patients undergoing a protective lung strategy of mechanical ventilation (Ranieri et al. 2000). High frequency oscillation by reducing shear forces applied across the lung during mechanical ventilation in rabbit ARDS models reduces the production of neutrophils and inflammatory cytokines (Imai et al. 1994).

There is abnormal release and dysfunction of surfactant in ARDS. Surfactant is often used to improve oxygenation and lung function, especially in children. However, in experimental ventilated mouse ARDS models, the addition of surfactant augmented ventilator-induced release of TNF and IL-6, but not keto-PGF1α, despite improvement in oxygenation and pulmonary compliance (Stamme et al. 2002). The effect would seem to be due to improved “stretching” of the alveolar epithelial cells rather than an effect on alveolar macrophages. This may risk and increase in the risk of multiorgan failure, but this has not been described in studies of surfactant use in ARDS.

There is a body of evidence of suppression of inflammatory responses systemically outside of a local area of inflammation that may play a role in multiorgan failure. A local area of inflammation in the lung may result in a state of general ­immunosuppression whereby peripheral white cell response to cytokine stimulants is reduced. Such an effect may result from inflammation in the lung from injurious mechanical ventilation (Plotz et al. 2002). Also the β2 stimulation of the activation of the adrenergic nervous system in times of stress enhances the production of anti-inflammatory cytokines and downregulates the production of inflammatory cytokines, which may contribute to suppression of the systemic immune response (Kavelaars et al. 1997).

Bacterial translocation from the lung is possible in the presence of low PEEP, high transalveolar pressure ventilation or prolonged inspiratory time (Ozcan et al. 2007). PEEP can ameliorate these effects even with persisting lung overdistention despite increased histological and gravimetric indices of lung injury in dependent lung regions (Nahum et al. 1997). Translocation of bacteria from the gut has also been implicated as a driver of multiorgan failure (Balzan et al. 2007). Ventilation with high airway pressures may diminish mesenteric blood flow and potentially impair the mucosal barrier of the gut. The effect of mechanical ventilation strategies may affect gut permeability (Guery et al. 1997) perhaps as a result of cytokine release (Imai et al. 2003).

9.5 Treatment

Treatment for ALI/ARDS is largely supportive in addition to treatment of the primary inciting condition. Although it is outside the scope of the chapter to give a detailed description of the complex mechanical ventilation options available, a general overview of principles is outlined. As a result of such supportive processes the survival rate has improved to around 70% (National Heart (2006a), Blood Institute Acute Respiratory Distress Syndrome Clinical Trials et al. 2006a). A general ­consideration of strategies is outlined in Table 9.6.
Table 9.6

Therapies commonly used in the management of ALI/ARDS

Therapies of value

Restrict tidal volumes  <  6 mL/kg and plateau pressures  <  30 cmH2O (2000)

Restrict positive fluid balances (aim neutral fluid balance, CVP  <  4 cmH2O if able) (National Heart, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials et al. 2006)

Extracorporeal membrane oxygenation (Peek et al. 2009)

Therapies of uncertain value

High frequency oscillatory ventilation (Imai and Slutsky 2005)

Prone positioning of patient (Sud et al. 2008)

High PEEP levels (Levy 2002)

Corticosteroids (Tang et al. 2009)

Recruitment maneuvers (Gattinoni et al. 2006a)

Surfactant (Davidson et al. 2006; Duffett et al. 2007)

Nitric oxide (Adhikari et al. 2007)

Prostacyclin (Walmrath et al. 1996)

Almitrine (Gillart et al. 1998)

Therapies best avoided

High FiO2 (>0.6) to keep PaO2  >  60 mmHg (Sinclair et al. 2004)

Invasive monitoring (National Heart (2006b), Blood Institute Acute Respiratory Distress Syndrome Clinical Trials et al. 2006b)

9.5.1 Protective Lung Ventilation

Conventional Ventilation

Mechanical ventilation remains the mainstay of the management of ALI/ARDS. It provides support for the patient while awaiting the primary insult causing the lung injury to resolve. Progressively the tidal volumes and inspiratory pressures are reduced, and there are many ventilation methods used for the pressure and volume limit. Few have been rigorously assessed in large randomized trials. Increasingly combined modality approaches are being applied.

In an early trial of protective ventilation strategies, Amato reduced tidal volumes to less than 6 mL/kg with driving pressures of 20 cmH2O above PEEP, PEEP set above the low inflection point of a static compliance curve and pressure limitation to 40 cmH2O. This was compared to 12 mL /kg and the maintenance of normocapnia (Amato et al. 1998). A 32% absolute risk reduction for 28-day mortality, a 37% improvement in weaning rates and a 35% absolute risk reduction in clinical barotraumas was found. The difference in the PEEP was 16.4 versus 8.7 cmH2O in the intervention compared to the conventional ventilation group. There was no difference in hospital survival.

The Acute Respiratory Distress Syndrome Network study in 2000 compared 12 mL/kg predicted body weight and an airway plateau pressure ≤50 cmH2O to an initial tidal volume of 6 mL/kg predicted body weight and a plateau pressure ≤30 cm of water (2000). However, both groups used a complex PEEP-FiO2 titration table with the aim to keep the SpO2  >  88%. The average PEEP in both groups was <10 cmH2O. There was an 8.8% absolute risk reduction in hospital death or failure to wean by day 28 (31% compared to 39.8%), a 3-day reduction in non-pulmonary organ failures and a reduction in plasma IL-6 levels.

Whether other strategies to accomplish a limited tidal volume and limited pressure strategy, such as pressure control, airway pressure release, bilevel, inverse inspiratory:expiratory ratio and pressure-regulated volume control ventilation, offer an advantage or a refinement of these approaches remains to be tested.

Open Lung Strategies

Low tidal volume ventilation prevents alveolar but does not prevent shear injury from repeated opening and closing of alveoli. Such shear injury is reduced by PEEP. The open lung strategy involves the application of recruitment maneuvers of the short applications of increases in mean airway pressure to open collapsed alveoli and, when open, maintains this with higher levels of PEEP (Gattinoni et al. 2006a). This may be done as intermittent sighs, short duration increases in PEEP, stepwise increases in PEEP or sustained application of pressure to achieve total lung capacity (Marini 2001). Recruitment maneuvers are more effective when performed in the presence of PEEP (Foti et al. 2000), when the patients are paralyzed (Lim et al. 2001) or when a higher tidal volume is accomplished during the recruitment (Richard et al. 2001). The variability found in studies for the duration of the effectiveness of recruitment maneuvers possibly relates to the method of PEEP titration used and small studies of heterogeneous patients (Toth et al. 2007; Tugrul et al. 2003; Girgis et al. 2006). In general, the recruitment maneuvers are hemodynamically well tolerated (Toth et al. 2007).

High Frequency Oscillation

High frequency oscillation ventilation (HFOV) represents a technique where high mean inflation pressures are accomplished (around 30 cmH2O) with CO2 removal achieved by using high frequencies of ventilation (4–6 Hz). Small tidal volumes of around 1–5 mL are used, and the lower the ventilation frequency is, the higher the achieved tidal volume. This approach accomplishes alveolar recruitment, reduces shear injury and may provide a better lung volume for the effectiveness of adjunct therapies such as inhaled nitric oxide (Dobyns et al. 2002). It also has been shown to decrease the levels of systemic inflammatory markers (Imai et al. 2001; Imai and Slutsky 2005). Although better pulmonary outcomes have been demonstrated in children (Courtney et al. 2002), there has not been a clear mortality benefit (Derdak et al. 2002; Dobyns et al. 2002; David et al. 2003; Ferguson et al. 2005a).

Extracorporeal Membrane Oxygenation

Where the lungs are so severely damaged that it is not possible to oxygenate the patient with recruitment, high PEEP and high concentrations of oxygen, using an extracorporeal circuit and a membrane oxygenator is increasingly recognized as a salvage technique (Australia, New Zealand Extracorporeal Membrane Oxygenation Influenza Investigators 2009; Peek et al. 2009). It also allows CO2 elimination. It can be used with veno-venous access to support gas exchange or with arterio-venous access to support both gas exchange and the systemic circulation. The lungs are rested on CPAP or low volume-low frequency ventilation, and anticoagulation is required. The major complications are bleeding, thrombosis and infection. The best outcome would appear to be from units that routinely perform the procedure. Many patients referred to such centers often avoid ECMO by further adjustment of conventional ventilation and attention to fluid balance (Peek et al. 2009). It is unclear whether the avoidance of mechanical ventilation by using CPAP and ECMO can reduce the degree of lung injury.

Liquid Ventilation

Full or partial ventilation with perflurocarbon (PFC) is not commercially available. By filling the functional residual capacity of the lung with PFC, oxygenation and lung mechanics are improved (Reickert et al. 2002). There may be an additional benefit to diluting the inflammatory process in the lung and assisting with the clearance of the inflammatory exudate. Partial liquid ventilation allows gas tidal volume breaths on top of a PFC-filled FRC. However, the technique has not been shown to improve mortality, but may be associated with worsening respiratory failure (Hirschl et al. 2002).

9.5.2 Fluid Management

Randomized controlled trials have demonstrated that a conservative approach to fluid management in ALI/ARDS to maintain an equal fluid balance rather than a liberal administration of fluids results in an improved oxygenation index with a reduction in ventilation time and intensive care stay by 2.5 days (National Heart (2006b), Blood Institute Acute Respiratory Distress Syndrome Clinical Trials et al. 2006b). Mortality, shock and renal failure prevalences were similar. There was however a difference in cumulative fluid balance of some 7 L. Importantly, the use of a pulmonary artery catheter (PAC) to guide fluid therapy in ALI/ARDS only causes catheter-related complications, even in the presence of shock, without improving mortality, ventilation or ICU length of stay or organ function (National Heart (2006a), Blood Institute Acute Respiratory Distress Syndrome Clinical Trials et al. 2006a). Interestingly fluid balance was similar despite the use of the PAC.

9.5.3 Prone Positioning

Prone positioning has been shown to regularly improve oxygenation, ventilation-perfusion matching, secretion clearance and chest wall mechanics. The resulting increase in secretion clearance, reduced lung compression from the abdomen and heart, redistribution of trans-alveolar forces and altered chest wall mechanics results in improved ventilation-perfusion matching and regional ventilation in addition to a reduction in ventilator-associated pneumonia (Guerin 2006; Sud et al. 2008). It may not be as effective when applied late in the course of respiratory failure. There are potential risks with accidental extubation, general care and decubitus pressure effects, including the eyes, when using such an approach, and the turns may be associated with hemodynamic instability. There has been no mortality benefit noted (Guerin 2006; Sud et al. 2008).

9.5.4 Avoiding High Oxygen Concentrations

Both animal and human experimental data confirm that high oxygen concentrations (FiO2  >  0.6) are associated with the development of ALI/ARDS (Burrows and Edwards 1970; Glauser and Smith 1975; Nader-Djalal et al. 1997; Sinclair et al. 2004; Fisher and Beers 2008). It may potentially worsen the effects of VILI (Bailey et al. 2003). However, in the setting of already severe lung injury, it becomes unavoidable in some circumstances in order to maintain tissue oxygenation. All efforts should be used to recruit lung to avoid prolonged periods of a FiO2  >  0.6 as a pragmatic recommendation.

9.5.5 Pharmacologic Approaches


The use of exogenous surfactant has predominantly found benefits in children (Duffett et al. 2007). No clear benefit has been demonstrated in adults despite an improvement in oxygenation regardless of whether artificial or bovine surfactant was used (Davidson et al. 2006). Dosing, mode of delivery, the composition of the surfactant as well as the degree of recruitment on the lung may be significant factors to explain the lack of efficacy. The meta-analysis by Duffett in children noted that the use of surfactant for ALI resulted in a relative risk reduction of 0.7, an increase in ventilator-free days of 2.5 days and a reduced duration of mechanical ventilation of 2.3 days (Duffett et al. 2007). In general it seems well tolerated with reported hypotension, transient hypoxemia and perhaps a reduction in the incidence of ventilator-associated pneumonia.


Glucocorticoids have been used in the management of ARDS to try to dampen the fibroproliferative phase. The doses, type of corticosteroids and duration of treatment vary significantly in the studies. The meta-analysis by Tang reports an average dose of 140 mg of methylprednisolone or the equivalent used per day (Tang et al. 2009). Although neither cohort nor randomized controlled studies have demonstrated a mortality benefit, the combined relative risk was 0.62. The duration of mechanical ventilation was reduced by 4 days, with reduction in the severity scores for multiple organ dysfunction and lung injury in addition to improving oxygenation. Complications are uncommon, but include infection, neuropathy/myopathy and gastrointestinal bleeding, but do not seem to be increased over control groups.

Nitric Oxide

Inhaled nitric oxide (iNO) is used in doses up to 100 ppm to improve the pulmonary hypertension and oxygenation in ALI/ARDS. In general up to 10 ppm is used for the management of hypoxemia and more than this for the management of pulmonary hypertension. In addition to its effects as a pulmonary vasodilator (with a half-life of some 20 s due to its inactivation by binding with hemoglobin), iNO also has an antithrombotic effect (Gries et al. 1998). Its selectivity as a pulmonary vasodilator is due to having a localized effect of ventilation-perfusion matching achieved by being delivered by the inhaled route. In ARDS/ALI, iNO is associated with less neutrophil migration, reduced neutrophil and macrophage function and reduced lung parenchymal damage in experimental models, and has been shown to attenuate lung injury. Adequate lung recruitment seems important to its effects. There may be tachyphylaxis to its efficacy (Gerlach et al. 2003). It has been seen to be additive to the effects of prone positioning and high frequency oscillation. It potentially causes met-hemoglobinemia, and higher oxides of nitrogen are produced when combined with high concentrations of oxygen such as NO2, which are corrosive to the lung. However, with modern mass flow controller delivery and monitoring, these issues are not a common problem. Commercially available nitric oxide is expensive to use. Despite the effects on oxygenation and pulmonary pressures, there has not been a mortality benefit demonstrated in adult patients (Dellinger et al. 1998; Lundin et al. 1999; Taylor et al. 2004).

Inhaled Prostacycline

Inhaled prostacycline is used as an alternative to iNO in doses up to 50 ng/kg/min. It also has local vasodilation effects improving oxygenation and pulmonary pressures in ALI/ARDS, as well as an antithrombotic effect. As it is aerosolized, its effectiveness may vary with the delivery system used. No mortality benefit has been reported (Walmrath et al. 1996; Dahlem et al. 2004).

9.6 Outcomes

The mortality rate from ALI/ARDS is around 30–40% with a falling case fatality rate accounted for by increasing rates of trauma (Stapleton et al. 2005). Death most commonly occurs from multiorgan failure (30–50%) rather than refractory hypoxemia (<20%). The mortality rate in sepsis patients with ARDS has not changed. Death less than 72 hours from the onset of ARDS represents 26–44% of the total mortality. There is great heterogeneity of outcome, but it is unclear whether this represents different mechanisms or responses to treatment (Dicker et al. 2004). Eisner reviewed the outcome of patients in the ARDSnet trial of low tidal volume ventilation (Eisner et al. 2001). Mortality was highest in patients with sepsis (43%) with pneumonia 36% and aspiration 37%, and lowest in trauma at 11%. Low tidal volume ventilation was equally beneficial in all primary causes of ARDS, and no difference was found in the rates of ventilation wean or the development of non-pulmonary organ failures. It is also possible to predict which patients with mild respiratory failure will deteriorate to having ARDS (Rubenfeld and Christie 2004).

The long-term morbidity of patients surviving ARDS is similar to that of any patient with multi-organ failure and a prolonged ICU stay. Persistent respiratory symptoms are common after recovery from ARDS/ALI. Most patients have a reduced diffusion capacity and a restrictive defect. Airways obstruction and reactive airways disease are also described. Importantly, the major morbidity for ARDS patients is not pulmonary disease. Principally, these are neuromuscular dysfunction including critical illness, polyneuropathy and myopathy, neurocognitive dysfunction and neuropsychological dysfunction, including depression, anxiety and post-traumatic stress disorder (Rubenfeld and Herridge 2007). Physical disorders are generally related to prolonged immobility such as joint contractures and calcification. There is increasing recognition of the costs of caregiver support and financial burdens to both families and the health care system (Rubenfeld and Herridge 2007).

Previous studies note that 12 months following illness some 60% of patients may not have returned to regular activity and that lung function remains stable after this time with between 50% and 60% having spirometry of less than 80% of the predicted value (Heyland et al. 2005). Lung function is strongly correlated to physical function. With the advent of lung rest strategies such as extracorporeal membrane oxygenation, 75% of patients are described as returning to their previous employment, and no patients required the use of supplementary oxygen (Linden et al. 2009). In general, functional outcome scores in this ECMO group were higher compared to previous studies (Davidson et al. 1999; Heyland et al. 2005; Groll et al. 2006).

In the meta-analysis of quality of life following ARDS by Dowdy assessed using the SF-36, it was uncommon for there to be improvement in functioning after 6 months from critical illness (Dowdy et al. 2006). Each of the eight scales of the SF-36 represents the weighted sums of the questions with each scale. Each scale is directly transformed into a 0–100 scale assuming that each question carries equal weight. For patients assessed more than 12 months from hospital discharge, on average there was a mean fall between 15 and 25 points from previous functioning for physical functioning, bodily pain, general health perceptions, vitality, social functioning and emotional role. Patient’s physical role (a 40 point decrement) was the worst outcome with mental health deteriorating by 11 points. A sleep disorder in patients screened for sleeping problems after ARDS included chronic conditioned insomnia (71%), parasomnia (14%) and obstructive sleep apnea (14%), with 57% having periodic leg movements of uncertain clinical significance.

9.7 Summary

ALI/ARDS continues to represent diagnostic and therapeutic challenges in the intensive care unit. Increasingly it is recognized as part of the spectrum of multiorgan failure. In addition there is evidence that mechanical ventilation practices influence the severity of the illness and may also influence the degree of organ dysfunction. Preventative and therapeutic approaches will need to consider multiple modalities and approaches.


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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Intensive Care Medicine, Royal Brisbane and Women’s HospitalThe University of QueenslandHerstonAustralia

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