Acute pulmonary Part 2

Physiologic Testing

Gas exchange in ARDS is characterized initially by hypox-emia that is refractory to increasing concentrations of inspired oxygen, implying the presence of increased intrapulmonary shunting. Intrapulmonary shunting is primarily a consequence of diffuse alveolar filling, collapse, or both, with microatelecta-sis. Diffuse alveolar collapse is believed to be caused by abnormalities in surfactant, a substance that normally helps maintain alveolar distention by lowering the surface tension in the air-liquid interface of the lung.

Initially, arterial carbon dioxide tension (PaCO2) is either low or in the normal range with only a modest increase in minute ventilation. However, the ratio of dead space to tidal volume (VD/VT) tends to increase over time, so that increasing amounts of minute ventilation are required to achieve a normal PaCO2.21 In some cases, the increase in VD/VT is so extreme that hypercapnia cannot be avoided even when minute ventilation is increased to the maximal achievable level. This increase in physiologic dead space results from damage to the pulmonary capillary bed, which creates regions of high ventilation relative to perfusion. A secondary cause of the increased minute-ventilation requirement in ARDS is the presence of increased carbon dioxide production from hypermetabolism. The high VD/VT in ARDS is slow to resolve; this, together with the reduction of lung compliance (which imposes a burden on spontaneous breathing), accounts in part for the frequent need for mechanical ventilatory support for prolonged periods. Such support often must be continued even though hypoxemia has improved sufficiently to make only a modest increase in inspired oxygen concentration necessary.


Figure 2 (a) The first site of injury in ARDS is the endothelium of the pulmonary capillaries. In ARDS caused by sepsis, endotoxin stimulates the production or release of several proinflammatory mediators such as activated complement fragments, coagulation factors, platelet activating factor, eicosanoids, and cytokines/chemokines (e.g., tumor necrosis factor-a [TNF-a], interleukin-1 [IL-1], IL-6, IL-8, and other cytokines), as well as antiinflammatory substances such as IL-10, IL-11, cytokine receptor antagonists, anticytokine autoantibodies, antioxidants, and antiproteases.51 Release of some of these mediators may be induced by the mechanical ventilation that is often required in such cases, and these mediators may play a role in inducing the systemic inflammatory response syndrome and multiorgan failure.52 If there is an imbalance in favor of the inflammatory mediators, the mediators act as primers and secretagogues for neutrophils and other monocytes/macrophages, resulting in aggregation and embolization of these cells in the pulmonary vasculature. (b) The neutrophils adhere to the endothelium by way of specific receptors on the neutrophils (integrins and L-selectin) and receptors on the endothelium (intercellular adhesion molecule-1 [ICAM-1] and E- and P-selectin) and release injurious oxidants, proteolytic enzymes, and arachidonic acid metabolites, resulting in endothelial cell dysfunction and destruction and in denudation of the endothelial side of the basement membrane. Endotoxin may also injure endothelial cells directly. Increased permeability of the alveolocapillary membrane allows plasma to enter the interstitial spaces of the lung and, ultimately, the alveoli. (c) The second site of injury is the alveolar epithelium. Neutrophils penetrate the alveolocapillary membrane and, along with activated macrophages, release oxidants and proteolytic enzymes. As a result, type I pneumocytes die, denuding the alveolar side of the basement membrane. Macrophages produce procoagulant substances, such as tissue factor and factor VII, that produce fibrin, and the alveolus becomes filled with proteinaceous exudate and cellular debris. (d) In response to the death of the type I pneumocytes, type II pneumocytes, under the control of growth factors (keratinocyte growth factor [KGF], hepatocyte growth factor [HGF], and granulocyte-monocyte colony-stimulating factor [GM-CSF] from macrophages), begin to proliferate and attempt to cover the denuded basement membrane. If the injury to the epithelial cells and the basement membrane is severe, progressive interstitial and intra-alveolar fibrosis ensues. Fibroblasts, which are controlled by growth factors (transforming growth factor-p [TGF-p], platelet-derived growth factor [PDGF], and insulinlike growth factor [IGF]) derived from macrophages, invade the exudate, where they proliferate and synthesize collagen (type I), elastin, and other new matrix components. The normal lung architecture is progressively replaced at this point (approximately 2 weeks from onset) by fibrous tissue that severely impairs gas exchange.

(a) The first site of injury in ARDS is the endothelium of the pulmonary capillaries. In ARDS caused by sepsis, endotoxin stimulates the production or release of several proinflammatory mediators such as activated complement fragments, coagulation factors, platelet activating factor, eicosanoids, and cytokines/chemokines (e.g., tumor necrosis factor-a [TNF-a], interleukin-1 [IL-1], IL-6, IL-8, and other cytokines), as well as antiinflammatory substances such as IL-10, IL-11, cytokine receptor antagonists, anticytokine autoantibodies, antioxidants, and antiproteases.51 Release of some of these mediators may be induced by the mechanical ventilation that is often required in such cases, and these mediators may play a role in inducing the systemic inflammatory response syndrome and multiorgan failure.52 If there is an imbalance in favor of the inflammatory mediators, the mediators act as primers and secretagogues for neutrophils and other monocytes/macrophages, resulting in aggregation and embolization of these cells in the pulmonary vasculature. (b) The neutrophils adhere to the endothelium by way of specific receptors on the neutrophils (integrins and L-selectin) and receptors on the endothelium (intercellular adhesion molecule-1 [ICAM-1] and E- and P-selectin) and release injurious oxidants, proteolytic enzymes, and arachidonic acid metabolites, resulting in endothelial cell dysfunction and destruction and in denudation of the endothelial side of the basement membrane. Endotoxin may also injure endothelial cells directly. Increased permeability of the alveolocapillary membrane allows plasma to enter the interstitial spaces of the lung and, ultimately, the alveoli. (c) The second site of injury is the alveolar epithelium. Neutrophils penetrate the alveolocapillary membrane and, along with activated macrophages, release oxidants and proteolytic enzymes. As a result, type I pneumocytes die, denuding the alveolar side of the basement membrane. Macrophages produce procoagulant substances, such as tissue factor and factor VII, that produce fibrin, and the alveolus becomes filled with proteinaceous exudate and cellular debris. (d) In response to the death of the type I pneumocytes, type II pneumocytes, under the control of growth factors (keratinocyte growth factor [KGF], hepatocyte growth factor [HGF], and granulocyte-monocyte colony-stimulating factor [GM-CSF] from macrophages), begin to proliferate and attempt to cover the denuded basement membrane. If the injury to the epithelial cells and the basement membrane is severe, progressive interstitial and intra-alveolar fibrosis ensues. Fibroblasts, which are controlled by growth factors (transforming growth factor-p [TGF-p], platelet-derived growth factor [PDGF], and insulinlike growth factor [IGF]) derived from macrophages, invade the exudate, where they proliferate and synthesize collagen (type I), elastin, and other new matrix components. The normal lung architecture is progressively replaced at this point (approximately 2 weeks from onset) by fibrous tissue that severely impairs gas exchange.

Lung mechanics in ARDS is characterized primarily by a reduction in lung compliance (increased lung elastance); thus, high transpulmonary pressures are required to achieve normal tidal ventilation. Early in ARDS, when edema predominates, much of the distending pressure needed to inflate the lung is expended in opening collapsed alveoli. Indeed, lung compliance (i.e., the slope of the pressure-volume curve) may be in the normal range if it is measured after these collapsed alveoli have been opened. However, there is a significant reduction in compliance as the disease process evolves or when alveolar fibrosis becomes predominant. This apparent reduction may be caused by a diffuse thickening of the alveolocapillary membrane as a result of fibrosis or by the loss of a large percentage of the alve-olocapillary units that are available for ventilation. It has been suggested that in patients with ARDS, lung mechanics is best conceptualized by regarding the lung as being small rather than stiff.22 Increased airway resistance that responds to inhaled bronchodilators is also seen in ARDS.23

In addition to their effect on VD/VT, the pulmonary vascular changes in ARDS result in increased pulmonary vascular resistance and pulmonary hypertension.24 Indeed, the pulmonary arterial pressure is elevated in nearly all patients who have moderate to severe ARDS. The etiology of pulmonary hypertension in ARDS is likely to be multifactorial; however, a major underlying cause seems to be the presence of small pulmonary arterial thrombi. The pathogenesis of the thrombi in ARDS is unknown, but it is likely that they are formed in situ.

Many patients with ARDS have certain markers of accelerated intravascular coagulation.25 However, despite the apparent importance of thrombosis in producing pulmonary hypertension, it has not been determined whether traditional anticoagu-lation benefits patients with ARDS.

Treatment

The treatment of ARDS includes addressing the precipitating cause of ARDS, general ICU support (e.g., nutrition), prevention of complications in the ICU (e.g., stress ulcer prophylaxis), and management of edema26 [see Table 4]. Ventilatory and car-diorespiratory issues in the management of respiratory failure in patients with ARDS are discussed in detail elsewhere [see 14:VIII Respiratory Failure].

Treatment of the cause of ARDS, when feasible, should be instituted as soon as possible. For example, in patients with ARDS that is associated with sepsis, appropriate antibiotics should be started immediately, and the source of the infection should be identified and treated (e.g., abscesses should be drained).

The initial management in the ICU should include several general measures. Prevention of stress ulceration and associated gastrointestinal bleeding, as well as prevention of deep vein thrombosis and pulmonary embolism, is indicated. Activated protein C (drotrecogin alfa [activated]), an endogenous protein with antithrombotic, profibrinolytic, and anti-inflammatory properties, should be administered to patients with sepsis who are not at risk for bleeding.27 In septic patients with adrenal insufficiency, replacement doses of corticosteroids are indicated.28 Attempts to reduce nosocomial infection, particularly ventilator-associated pneumonia, through the use of topical and systemic antibiotics have had favorable results,29 but concerns about the induction of resistant organisms have made this type of therapy controversial. Enteral feeding is indicated if the GI tract is functioning; otherwise, parenteral nutrition should be provided. Special enteral formulations enriched with "immunonutrients" (e.g., arginine, glutamine, omega-3 fatty acids, and nucleotides) have been found to reduce length of hospital stay, infection rates, and duration of mechanical ventilation, but not mortality.30

The treatment of ARDS is focused on reducing existing pulmonary edema, preventing further edema, and modifying the evolution of the disease. Once the patient is hemodynamically stable, fluid restriction, diuresis (possibly with albumin infusion), or both are indicated.31 Numerous attempts have been made to reduce the inflammatory response in ARDS. Except in patients with relative adrenal insufficiency, use of corticosteroids early in the course of disease has no beneficial effect; however, steroids given 7 to 14 days later may modify the fibroprolifera-tive phase.32 Numerous other agents have not been found to modify the disease process or improve outcome [see Table 4].33,34

Outcome

Although the prognosis of patients with ARDS is related to the degree of lung injury, other parameters more accurately predict outcome; this is not surprising, because ARDS is frequently part of a systemic inflammatory response syndrome. The cause of the syndrome is often unclear, but the possibilities include bronchopneumonia, translocation of bacterial products across the intestine, and persistent release of endogenous mediators in the absence of ongoing infection. Sepsis, which is often associated with vasodilatation that is unresponsive to vasoconstrictors, is the most common cause of death during the course of illness. As a result of state-of-the-art ventilatory-sup-port techniques, respiratory failure is the cause of death in less than 20% of cases—a fact that highlights the importance of dysfunction of other organ systems (e.g., hemodynamic failure with refractory shock or progressive renal failure) in causing morbidity and mortality. Data suggest that the outcome of patients with ARDS may be improving, possibly because of improvements in therapy.10,19

One way to predict mortality is by the number of organ systems that fail. Mortality increases with the number of failing organs and the number of days of failure [see Figure 3].35 There is a further increase in mortality in patients who are older than 65 years. For example, in patients younger than 65 years who have single-organ malfunction for 5 days, mortality is 27%, whereas in patients with single-organ malfunction who are older than 65 years, mortality is 48%. Likewise, the failure of two organs for 2 days results in a 47% mortality in patients younger than 65 years and a 73% mortality in patients older than 65 years. The failure of three or more organs for 5 days in patients of any age is associated with a 97% mortality.35 These data provide a useful guide for decision making for patients with catastrophic illness and their families.

If patients survive the acute illness that causes ARDS, the prognosis for return of lung function is good. Factors associated with poor pulmonary functional outcome are severity of ARDS, lowest measured compliance, and duration of positive pressure ventilation.10 Lung function improves rapidly over the first several weeks, then more slowly over a period of as long as 2 years. Common symptoms and signs include exertional dyspnea, cough, wheezing, and persistent rales. Pulmonary function tests may demonstrate the presence of restrictive disease; obstructive disease, often with increased airway reactivity; or decreased diffusing capacity. CT may show a persistent reticular pattern in 85% of patients.36 One year or more after the onset of ARDS, more than 75% of patients either have normal respiratory function or suffer only mild impairment. However, many will suffer neuropsychological sequelae such as impaired memory, attention, and concentration; decreased mental-processing speed; or all four effects.37 Patients also experience reduced quality of life because of impaired physical functioning that results from muscle wasting and weakness.

Table 4 Treatments of ARDS That Do Not Involve Ventilation26

Treatment

Purpose

Evidence Grade

Is This Treatment Recommended?

Stress ulcer prophylaxis

Prevent stress ulcers and GI bleeding

A (studied in ICU patients)

Yes, gastric acid neutralization allowable

Prophylaxis of deep vein thrombosis and pulmonary embolism

Prevent deep vein thrombosis and pulmonary embolism

A (studied in ICU patients)

Yes

Activated protein C

Antithrombotic, profibrinolytic, anti-inflammatory

B

Yes, for patients with sepsis without risk of hemorrhage

Corticosteroids, replacement doses

Relative adrenal insufficiency

B

Yes, for patients with sepsis with relative adrenal insufficiency

Topical plus systemic prophylactic antibiotics

Prevent nosocomial infections

A (studied in ICU patients)

Controversial; evidence favors

Enteral nutrition

Prevent malnutrition

Ungraded

Yes, if GI function satisfactory

Parenteral nutrition, with low carbohydrate and high fat

Prevent malnutrition

Ungraded

Yes, when GI function inadequate

Immune-enhancing nutritional formulations (e.g., omega-3 fatty acids)

Alter immune system and prostenoids

B

Controversial; evidence favors

Early fluid restriction and/or diuresis, possibly with albumin infusion

Prevent or reduce edema

B

Yes, if hemodynamically stable, trial under way

Corticosteroids (high dose) early in course of disease

Reduce inflammation

A

No

Corticosteroids (high dose) late in course of disease

Prevent or reduce intra-alveolar fibroproliferation

B

Controversial; one randomized clinical trial reports benefit when given at 7-14 days; large randomized clinical trial is in progress

Exogenous surfactant

Prevent alveolar collapse

B

No; no trials under way

Acetylcysteine, procysteine

Antioxidant

B

No

Ketoconazole

Inhibit thromboxane and leukotriene synthesis

A

No

Ibuprofen, other NSAIDs

Reduce inflammation

B

No

Alprostadil (prostaglandin E1)

Inhibit neutrophil activity

B

No

Pentoxifylline, lisofylline

Inhibit cytokine secretion

A

No

Antiendotoxin and anticytokines

Prevent ARDS

A

No

Inhaled nitric oxide

Improve V/Q balance; reduce hypoxemia

A

No

Nebulized prostacyclin (epoprostenol)

Improve V/Q balance; reduce hypoxemia

C

No

Inhaled beta-adrenergic agonists

Reduce airway resistance, speed edema resorption

D

Yes

ARDS—acute respiratory distress syndrome

GI—gastrointestinal

NSAIDs—nonsteroidal anti-inflammatory drugs

Q—perfusion

V—ventilation

Next post:

Previous post: