Acute respiratory distress syndrome

Acute respiratory distress syndrome
Classification and external resources

Chest x-ray of patient with ARDS
ICD-10 J80.
ICD-9 518.5, 518.82
DiseasesDB 892
MedlinePlus 000103
eMedicine med/70
MeSH D012128

Acute respiratory distress syndrome (ARDS), also known as respiratory distress syndrome (RDS) or adult respiratory distress syndrome (in contrast with IRDS) is a serious reaction to various forms of injuries to the lung.

ARDS is a severe lung disease caused by a variety of direct and indirect issues. It is characterized by inflammation of the lung parenchyma leading to impaired gas exchange with concomitant systemic release of inflammatory mediators causing inflammation, hypoxemia and frequently resulting in multiple organ failure. This condition is often fatal, usually requiring mechanical ventilation and admission to an intensive care unit. A less severe form is called acute lung injury (ALI).

ARDS formerly most commonly signified adult respiratory distress syndrome to differentiate it from infant respiratory distress syndrome in premature infants. However, as this type of pulmonary edema also occurs in children, ARDS has gradually shifted to mean acute rather than adult. The differences with the typical infant syndrome remain.

Contents

Definition

Historical background

Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et al.[1][2] Initially there was no definition, resulting in controversy over incidence and mortality. In 1988 an expanded definition was proposed which quantified physiologic respiratory impairment.

In 1994 a new definition was recommended by the American-European Consensus Conference Committee.[1][3] It had two advantages: 1 it recognizes that severity of pulmonary injury varies, 2 it is simple to use.[4]

ARDS was defined as the ratio of arterial partial oxygen tension (PaO2) as fraction of inspired oxygen (FiO2) below 200 mmHg in the presence of bilateral alveolar infiltrates on the chest x-ray. These infiltrates may appear similar to those of left ventricular failure, but the cardiac silhouette appears normal in ARDS. Also, the pulmonary capillary wedge pressure is normal (less than 18 mmHg) in ARDS, but raised in left ventricular failure.

A PaO2/FiO2 ratio less than 300 mmHg with bilateral infiltrates indicates acute lung injury (ALI). Although formally considered different from ARDS, ALI is usually just a precursor to ARDS.

Consensus after 1967 and 1994

ARDS is characterized by:[1][3]

To summarize and simplify, ARDS is an acute (rapid onset) syndrome (collection of symptoms) that affects the lungs widely and results in a severe oxygenation defect, but is not heart failure

Patient presentation and diagnosis

ARDS can occur within 24 to 48 hours of an injury or attack of acute illness. In such a case the patient usually presents with shortness of breath, tachypnea, and symptoms related to the underlying cause, i.e. shock.

Long term illnesses can also trigger it, e.g. malaria. ARDS may then occur sometime after the onset of a particularly acute case of the infection. See xray of malarial ARDS.

An arterial blood gas analysis and chest X-ray allow formal diagnosis by the aforementioned criteria. Although severe hypoxemia is generally included, the appropriate threshold defining abnormal PaO2 has never been systematically studied. Note though, that a severe oxygenation defect is not synonymous with ventilatory support. Any PaO2 below 100 (generally saturation less than 100%) on a supplemental oxygen fraction of 50% meets criteria for ARDS. This can easily be achieved by high flow oxygen supplementation without ventilatory support.

Any cardiogenic cause of pulmonary edema should be excluded. This can be done by placing a pulmonary artery catheter for measuring the pulmonary artery wedge pressure. However, this is not necessary and is now rarely done as abundant evidence has emerged demonstrating that the use of pulmonary artery catheters does not lead to improved patient outcomes in critical illness including ARDS.

Plain Chest X-rays are sufficient to document bilateral alveolar infiltrates in the majority of cases. While CT scanning leads to more accurate images of the pulmonary parenchyma in ARDS, it has little utility in the clinical management of patients with ARDS, and remains largely a research tool.

Pathophysiology

A pathohistological image of ARDS.

ARDS is a clinical syndrome associated with a variety of pathological findings. These include pneumonia, eosinophilic pneumonia, cryptogenic organizing pneumonia, acute fibrinous organizing pneumonia, and diffuse alveolar damage (DAD). Of these, the pathology most commonly associated with ARDS is DAD.

DAD is characterized by a diffuse inflammation of lung parenchyma. The triggering insult to the parenchyma usually results in an initial release of cytokines and other inflammatory mediators, secreted by local epithelial and endothelial cells.

Neutrophils and some T-lymphocytes quickly migrate into the inflamed lung parynchema and contribute in the amplification of the phenomenon.

Typical histological presentation involves diffuse alveolar damage and hyaline membrane formation in alveolar walls.

Although the triggering mechanisms are not completely understood, recent research has examined the role of inflammation and mechanical stress.

Inflammation

Inflammation alone, as in sepsis, causes endothelial dysfunction, fluid extravasation from the capillaries and impaired drainage of fluid from the lungs. Dysfunction of type II pulmonary epithelial cells may also be present, with a concomitant reduction in surfactant production. Elevated inspired oxygen concentration often becomes necessary at this stage, and they may facilitate a 'respiratory burst' in immune cells.

In a secondary phase, endothelial dysfunction causes cells and inflammatory exudate to enter the alveoli. This pulmonary edema increases the thickness of the alveolo-capillary space, increasing the distance the oxygen must diffuse to reach blood. This impairs gas exchange leading to hypoxia, increases the work of breathing, eventually induces fibrosis of the airspace.

Moreover, edema and decreased surfactant production by type II pneumocytes may cause whole alveoli to collapse, or to completely flood. This loss of aeration contributes further to the right-to-left shunt in ARDS. As the alveoli contain progressively less gas, more blood flows through them without being oxygenated resulting in massive intrapulmonary shunting.

Collapsed alveoli (and small bronchi) do not allow gas exchange. It is not uncommon to see patients with a PaO2 of 60 mmHg (8.0 kPa) despite mechanical ventilation with 100% inspired oxygen.

The loss of aeration may follow different patterns according to the nature of the underlying disease, and other factors. In pneumonia-induced ARDS, for example, large, more commonly causes relatively compact areas of alveolar infiltrates. These are usually distributed to the lower lobes, in their posterior segments, and they roughly correspond to the initial infected area.

In sepsis or trauma-induced ARDS, infiltrates are usually more patchy and diffuse. The posterior and basal segments are always more affected, but the distribution is even less homogeneous.

Loss of aeration also causes important changes in lung mechanical properties. These alterations are fundamental in the process of inflammation amplification and progression to ARDS in mechanically ventilated patients.

Mechanical stress

Mechanical ventilation is an essential part of the treatment of ARDS. As loss of aeration (and the underlying disease) progress, the work of breathing (WOB) eventually grows to a level incompatible with life. Thus, mechanical ventilation is initiated to relieve respiratory muscles of their work, and to protect the usually obtunded patient's airways.

However, mechanical ventilation may constitute a risk factor for the development, or the worsening, of ARDS.[1]

Aside from the infectious complications arising from invasive ventilation with tracheal intubation, positive-pressure ventilation directly alters lung mechanics during ARDS. The result is higher mortality, i.e. through baro-trauma, when these techniques are used.[1]

In 1998, Amato et al. published a paper showing substantial improvement in the outcome of patients ventilated with lower tidal volumes (Vt) (6 mL·kg-1).[1][5] This result was confirmed in a 2000 study sponsored by the NIH.[6] Although both these studies were widely criticized for several reasons, and although the authors were not the first to experiment lower-volume ventilation, they shed new light on the relationship between mechanical ventilation and ARDS.

One opinion is that the forces applied to the lung by the ventilator may work as a lever to induce further damage to lung parenchyma. It appears that shear stress at the interface between collapsed and aerated units may result in the breakdown of aerated units, which inflate asymmetrically due to the 'stickiness' of surrounding flooded alveoli. The fewer such interfaces around an alveolus, the lesser the stress.

Indeed, even relatively low stress forces may induce signal transduction systems at the cellular level, thus inducing the release of inflammatory mediators.

This form of stress is thought to be applied by the transpulmonary pressure (gradient) (Pl) generated by the ventilator or, better, its cyclical variations. The better outcome obtained in patients ventilated with lower Vt may be interpreted as a beneficial effect of the lower Pl. Transpulmonary pressure, is an indirect function of the Vt setting on the ventilator, and only trial patients with plateau pressures (a surrogate for the actual Pl) were less than 32 cmH2O (3.1 kPa) had improved survival.

The way Pl is applied on alveolar surface determines the shear stress to which lung units are exposed. ARDS is characterized by a usually inhomogeneous reduction of the airspace, and thus by a tendency towards higher Pl at the same Vt, and towards higher stress on less diseased units.

The inhomogeneity of alveoli at different stages of disease is further increased by the gravitational gradient to which they are exposed, and the different perfusion pressures at which blood flows through them. Finally, abdominal pressure exerts an additional pressure on inferoposterior lung segments, favoring compression and collapse of those units.

The different mechanical properties of alveoli in ARDS may be interpreted as having varying time constants (the product of alveolar compliance × resistance). A long time constant indicates an alveolus which opens slowly during tidal inflation, as a consequence of contrasting pressure around it, or altered water-air interface inside it (loss of surfactant, flooding).

Slow alveoli are said to be 'kept open' using positive end-expiratory pressure, a feature of modern ventilators which maintains a positive airway pressure throughout the whole respiratory cycle. A higher mean pressure cycle-wide slows the collapse of diseased units, but it has to be weighed against the corresponding elevation in Pl/plateau pressure. Newer ventilatory approaches attempt to maximize mean airway pressure for its ability to 'recruit' collapsed lung units while minimizing the shear stress caused by frequent openings and closings of aerated units.

The prone position also reduces the inhomogeneity in alveolar time constants induced by gravity and edema. If clinically appropriate, mobilization of the ventilated patient can assist in achieving the same goal.

Progression

If the underlying disease or injurious factor is not removed, the amount of inflammatory mediators released by the lungs in ARDS may result in a systemic inflammatory response syndrome (or sepsis if there is lung infection).[1] The evolution towards shock and/or multiple organ failure follows paths analogous to the pathophysiology of sepsis.

This adds up to the impaired oxygenation which is the central problem of ARDS, as well as to respiratory acidosis, which is often caused by ventilation techniques such as permissive hypercapnia which attempt to limit ventilator-induced lung injury in ARDS.

The result is a critical illness in which the 'endothelial disease' of severe sepsis/SIRS is worsened by the pulmonary dysfunction, which further impairs oxygen delivery.

Treatment

General

Acute respiratory distress syndrome is usually treated with mechanical ventilation in the Intensive Care Unit. Ventilation is usually delivered through oro-tracheal intubation, or tracheostomy whenever prolonged ventilation (≥2 weeks) is deemed inevitable.

The possibilities of non-invasive ventilation are limited to the very early period of the disease or, better, to prevention in individuals at risk for the development of the disease (atypical pneumonias, pulmonary contusion, major surgery patients).

Treatment of the underlying cause is imperative, as it tends to maintain the ARDS picture.

Appropriate antibiotic therapy must be administered as soon as microbiological culture results are available. Empirical therapy may be appropriate if local microbiological surveillance is efficient. More than 60% ARDS patients experience a (nosocomial) pulmonary infection either before or after the onset of lung injury.

The origin of infection, when surgically treatable, must be operated on. When sepsis is diagnosed, appropriate local protocols should be enacted.

Commonly used supportive therapy includes particular techniques of mechanical ventilation and pharmacological agents whose effectiveness with respect to the outcome has not yet been proven. It is now debated whether mechanical ventilation is to be considered mere supportive therapy or actual treatment, since it may substantially affect survival.

Mechanical ventilation

The overall goal is to maintain acceptable gas exchange and to minimize adverse effects in its application. Three parameters are used: PEEP (positive end-expiratory pressure, to maintain maximal recruitment of alveolar units), mean airway pressure (to promote recruitment and predictor of hemodynamic effects) and plateau pressure (best predictor of alveolar overdistention). [7]

Conventional therapy aimed at tidal volumes (Vt) of 12-15 ml/kg. Recent studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma (secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a landmark trial that showed improved mortality when ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes (Vt) may cause hypercapnia and atelectasis[1] due to their inherent tendency to increase dead space.

Low tidal volume ventilation was the primary independent variable associated with reduced mortality in the NIH-sponsored ARDSnet trial of tidal volume in ARDS. Plateau pressure less than 30 cm H2O was a secondary goal, and subsequent analyses of the data from the ARDSnet trial (as well as other experimental data) demonstrate that there appears to be NO safe upper limit to plateau pressure; that is, regardless of plateau pressure, patients fare better with low tidal volumes (see Hager et al., American Journal of Respiratory and Critical Care Medicine, 2005).

APRV (Airway Pressure Release Ventilation) and ARDS / ALI

No particular ventilator mode is known to improve mortality in ARDS. The landmark ARDSNet trial used a volume controlled mode and showed decrease mortality with smaller volumes. However, other modes of ventilation have not been directly compared to volume controlled ventilation.

Some practitioners favor airway pressure release ventilation (APRV). Advantages to APRV ventilation include: decreased airway pressures, decreased minute ventilation, decreased dead-space ventilation, promotion of spontaneous breathing, almost 24 hour a day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive effect on cardiac output (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion, potential for increased urine output secondary to increased renal perfusion.

Counterarguments would state that taken to the limit of a paralyzed patient, APRV is essentially a huge tidal volume, low PEEP strategy. While high PEEP is not now felt to improve outcomes in ARDS, high tidal volumes are strongly implicated in worse outcomes. Paradoxically, arterial blood gas results are known to worsen with the ARDSNet low tidal volume strategy, but survival improves, throwing such secondary outcomes usefulness into question. Similarly, in a patient with isolated severe ARDS, other issues such as organ perfusion and cardiac output, or use of sedation are of secondary importance. The patient will live if the lungs heal, or die if the lungs deteriorate. Less severe lung injury in a medically complex patient may entail different trade offs in medical decision making.

Positive end-expiratory pressure

Positive end-expiratory pressure (PEEP) is used in mechanically-ventilated patients with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli which are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas enchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimes. The recruitable aveoli represent a continuous population, some of which can be recruited with minimal PEEP, and others which can only be recruited with high levels of PEEP. An additional complication is that some or perhaps most alveoli can only be opened with higher airway pressures than are needed to keep them open. Hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. Finally, PEEP can be harmful. High PEEP necessarily increases mean airway pressure and alveolar pressure. This in turn can damage normal alveoli by overdistension resulting in DAD.

The 'best PEEP' used to be defined as 'some' cmH2O above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli, and more importantly the overdistension of aerated units, occur throughout the whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some to define the minimum PEEP to be applied to their patients. Some of the newest ventilators have the ability to automatically plot a pressure-volume curve. The possibility of having an 'instantaneous' tracing trigger might produce renewed interest in this analysis.

PEEP may also be set empirically. Some authors suggest performing a 'recruiting maneuver' (i.e., a short time at a very high continuous positive airway pressure, such as 50 cmH2O (4.9 kPa), to recruit, or open, collapsed units with a high distending pressure) before restoring previous ventilation. The final PEEP level should be the one just before the drop in PaO2 (or peripheral blood oxygen saturation) during a step-down trial.

Intrinsic PEEP (iPEEP), or auto-PEEP, first described by John Marini of St. Paul Regions Hospital, is a potentially unrecognized contributor to PEEP in patients. When ventilating at high frequencies, its contribution can be substantial, particularly in patients with obstructive lung disease. iPEEP has been measured in very few formal studies on ventilation in ARDS patients, and its contribution is largely unknown. Its measurement is recommended in the treatment of ARDS patients, especially when using high-frequency (oscillatory/jet) ventilation.

A compromise between the beneficial and adverse effects of PEEP is inevitable.

Prone position

Distribution of lung infiltrates in acute respiratory distress syndrome is non-uniform. Repositioning into the prone position (face down) might improve oxygenation by relieving atelectasis and improving perfusion. However, although the hypoxemia is overcome there seems to be no effect on overall survival.[1][8]

Fluid management

Several studies have shown that pulmonary function and outcome are better in patients that lost weight or pulmonary wedge pressure was lowered by diuresis or fluid restriction.[1]

Corticosteroids

A Meduri et al. study has found significant improvement in ARDS using modest doses of corticosteroids. The initial regimen consists of methylprednisolone 2 mg/kg daily. After 3-5 days a response must be apparent. In 1-2 weeks the dose can be tapered to methylprednisolone 0.5-1.0 mg daily. Patients with ARDS do not benefit from high-dose corticosteroids.[1][9] This was a study involving a small number of patients in one center. A recent NIH-sponsored multicenter ARDSnet LAZARUS study of corticosteroids for ARDS demonstrated that they are not efficacious in ARDS.

Nitric oxide

Inhaled nitric oxide (NO) potentially acts as selective pulmonary vasodilator. Rapid binding to hemoglobin prevents systemic effects. It should increase perfusion of better ventilated areas. There are no large studies demonstrating positive results. Therefore its use must be considered individually.

Almitrine bismesylate stimulates chemoreceptors in carotic and aortic bodies. It has been used to potentiate the effect of NO, presumably by potentiating hypoxia-induced pulmonary vasoconstriction. In case of ARDS it is not known whether this combination is useful.[1]

Surfactant therapy

To date no prospective controlled clinical trial has shown a significant mortality benefit of exogenous surfactant in ARDS.[1]

Complications

Since ARDS is an extremely serious condition which requires invasive forms of therapy it is not without risk. Complications to be considered are:[1]

Epidemiology

The annual incidence of ARDS is 1.5–13.5 people per 100,000 in the general population. Its incidence in the intensive care unit (ICU), mechanically ventilated population is much higher. Brun-Buisson et al. (2004) reported a prevalence of acute lung injury (ALI) (see below) of 16.1% percent in ventilated patients admitted for more than 4 hours. More than half these patients may develop ARDS.

Mechanical ventilation, sepsis, pneumonia, shock, aspiration, trauma (especially pulmonary contusion), major surgery, massive transfusions, smoke inhalation, drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy may all trigger ARDS. Pneumonia and sepsis are the most common triggers, and pneumonia is present in up to 60% of patients. Pneumonia and sepsis may be either causes or complications of ARDS.

Elevated abdominal pressure of any cause is also probably a risk factor for the development of ARDS, particularly during mechanical ventilation.

The mortality rate varies from 30% to 85%. Usually, randomized controlled trials in the literature show lower death rates, both in control and treatment patients. This is thought to be due to stricter enrollment criteria. Observational studies generally report 50%–60% mortality.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Irwin RS, Rippe JM (2003). Irwin and Rippe's Intensive Care Medicine (5th ed.). Lippincott Williams & Wilkins. ISBN 0-7817-3548-3. 
  2. ↑ Ashbaugh D, Bigelow D, Petty T, Levine B (1967). "Acute respiratory distress in adults". Lancet 2 (7511): 319–23. doi:10.1016/S0140-6736(67)90168-7. PMID 4143721. 
  3. ↑ 3.0 3.1 Bernard G, Artigas A, Brigham K, Carlet J, Falke K, Hudson L, Lamy M, Legall J, Morris A, Spragg R (1994). "The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination". Am J Respir Crit Care Med 149 (3 Pt 1): 818–24. PMID 7509706. 
  4. ↑ Ware L, Matthay M (2000). "The acute respiratory distress syndrome". N Engl J Med 342 (18): 1334–49. doi:10.1056/NEJM200005043421806. PMID 10793167. 
  5. ↑ Amato M, Barbas C, Medeiros D, Magaldi R, Schettino G, Lorenzi-Filho G, Kairalla R, Deheinzelin D, Munoz C, Oliveira R, Takagaki T, Carvalho C (1998). "Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome". N Engl J Med 338 (6): 347–54. doi:10.1056/NEJM199802053380602. PMID 9449727. 
  6. ↑ MacIntyre N (2000). "Mechanical ventilation strategies for lung protection". Semin Respir Crit Care Med 21 (3): 215–22. doi:10.1055/s-2000-9850. PMID 16088734. 
  7. ↑ Malhotra A (2007). "Low-tidal-volume ventilation in the acute respiratory distress syndrome". N Engl J Med 357 (11): 1113–20. doi:10.1056/NEJMct074213. PMID 17855672. 
  8. ↑ Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Di Giulio P, Fumagalli R, Pelosi P, Brazzi L, Latini R (2001). "Effect of prone positioning on the survival of patients with acute respiratory failure". N Engl J Med 345 (8): 568–73. doi:10.1056/NEJMoa010043. PMID 11529210. 
  9. ↑ Meduri G, Tolley E, Chrousos G, Stentz F (2002). "Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids". Am J Respir Crit Care Med 165 (7): 983–91. PMID 11934726. 

Further reading

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Conditions
Organ system failure

Shock sequence: SIRS · Sepsis · Severe sepsis · Septic shock

Other shock: Cardiogenic shock · Distributive shock

Organ failure: Acute renal failure · Acute respiratory distress syndrome · Acute liver failure · Respiratory failure · Multiple organ dysfunction syndrome

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