Acute Respiratory Distress Syndrome-audio

Acute Respiratory Distress Syndrome: Introduction
Acute respiratory distress syndrome (ARDS) is a clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure. ARDS is caused by diffuse lung injury from many underlying medical and surgical disorders. The lung injury may be direct, as occurs in toxic inhalation, or indirect, as occurs in sepsis (Table R-1). The clinical features of ARDS are listed in Table R-2. Acute lung injury (ALI) is a less severe disorder but has the potential to evolve into ARDS (Table R-2). The arterial (a) PO2 (in mmHg)/FIO2 (inspiratory O2 fraction) <200 mmHg is characteristic of ARDS, while a PaO2FIO2 between 200 and 300 identifies patients with ALI who are likely to benefit from aggressive therapy.

Table R–1. Clinical Disorders Commonly Associated ARDS

Direct Lung Injury	Indirect Injury
Pneumonia	Sepsis
Aspiration gastric contents	Severe trauma
Pulmonary contusion	Multiple bone fractures
Near-drowning	Flail chest
Toxic inhalation injury	Head trauma
Burns
Multiple transfusions
Drug overdose
Pancreatitis
Postcardiopulmonary bypass
Table R–2. Diagnostic Criteria for ARDS

Oxygenation	Onset	Chest Radiograph	Absence Left Atrial Hypertension
ALI: ≤ mmHg

ARDS: mmHg	Acute	Bilateral alveolar or interstitial infiltrates	PCWP18 no clinical evidence increasedleft atrialpressure Abbreviations: ALI, acute lung injury; respiratory distress syndrome; FIO2, inspired O2 percentage; PaO2, arterial partial pressure O2;
PCWP, pulmonary capillary wedge pressure.
The annual incidences ARDS estimated be up 80 100,000 60 100,000, respectively. Approximately 10% all intensive care unit (ICU) admissions suffer failure, ~20% these meeting criteria ARDS.

Etiology

While many medical surgical illnesses have been associatedthe development mostcases (>80%) are caused by a relatively small number of clinical disorders, namely, severe sepsis syndrome and/or bacterial pneumonia (~40–50%), trauma, multiple transfusions, aspiration of gastric contents, and drug overdose. Among patients with trauma, pulmonary contusion, multiple bone fractures, and chest wall trauma/flail chest are the most frequently reported surgical conditions in ARDS, whereas head trauma, near-drowning, toxic inhalation, and burns are rare causes. The risks of developing ARDS are increased in patients suffering from more than one predisposing medical or surgical condition (e.g., the risk for ARDS increases from 25% in patients with severe trauma to 56% in patients with trauma and sepsis).

Several other clinical variables have been associated with the development of ARDS. These include older age, chronic alcohol abuse, metabolic acidosis, and severity of critical illness. Trauma patients with an acute physiology and chronic health evaluation (APACHE) II score ≥16 have a 2.5-fold increase in the risk of developing ARDS, and those with a score >20 have an incidence of ARDS that is more than threefold greater than those with APACHE II scores ≤9.

Clinical Course and Pathophysiology

The natural history of ARDS is marked by three phases—exudative, proliferative, and fibrotic—each with characteristic clinical and pathologic features (Fig. R-1).
Fig. R-1 : Diagram illustrating the time course for the development and resolution of ARDS. The exudative phase is notable for early alveolar edema and neutrophil-rich leukocytic infiltration of the lungs with subsequent formation of hyaline membranes from diffuse alveolar damage. Within 7 days, a proliferative phase ensues with prominent interstitial inflammation and early fibrotic changes. Approximately 3 weeks after the initial pulmonary injury, most patients recover. However, some patients enter the fibrotic phase, with substantial fibrosis and bullae formation.
Exudative Phase

(Figure. R-2) In this phase, alveolar capillary endothelial cells and type I pneumocytes (alveolar epithelial cells) are injured, leading to the los of the normally tight alveolar barrier to fluid and macromolecules. Edema fluid that is rich in protein accumulates in the interstitial and alveolar spaces. Significant concentrations of cytokines (e.g., interleukin 1, interleukin 8, and tumor necrosis factor α) and lipid mediators (e.g., leukotriene B4) are present in the lung in this acute phase. In response to proinflammatory mediators, leukocytes (especially neutrophils) traffic into the pulmonary interstitium and alveoli. In addition, condensed plasma proteins aggregate in the air spaces with cellular debris and dysfunctional pulmonary surfactant to form hyaline membrane whorls. Pulmonary vascular injury also occurs early in ARDS, with vascular obliteration by microthrombi and fibrocellular proliferation (Fig. R-3).
Figure R-2 : A representative anteroposterior (AP) chest x-ray in the exudative phase of ARDS that shows diffuse interstitial and alveolar infiltrates, that can be difficult to distinguish from left ventricular failure.
Fig. R-3 : The normal alveolus (left-hand side) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right-hand side). In the acute phase of the syndrome (right-hand side), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines, interleukins 1, 6, 8, and 10 (IL-1, -6, -8, and -10) and tumor necrosis factor α (TNF-α), that act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including IL-1, -6, and -10. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of antiinflammatory mediators are also present in the alveolar milieu, including IL-1–receptor antagonist, soluble TNF-α receptor, autoantibodies against IL-8, and cytokines such as IL-10 and -11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF, macrophage inhibitory factor.
Alveolar edema predominantly involves dependent portions of the lung, leading to diminished aeration and atelectasis. Collapse of large sections of dependent lung markedly decreases lung compliance. Consequently, intrapulmonary shunting and hypoxemia develop and the work of breathing rises, leading to dyspnea. The pathophysiologic alterations in alveolar spaces are exacerbated by microvascular occlusion that leads to reductions in pulmonary arterial blood flow to ventilated portions of the lung, increasing the dead space, and to pulmonary hypertension. Thus, in addition to severe hypoxemia, hypercapnia secondary to an increase in pulmonary dead space is also prominent in early ARDS.

The exudative phase encompasses the first 7 days of illness after exposure to a precipitating ARDS risk factor, with the patient experiencing the onset of respiratory symptoms. Although usually present within 12–36 hours after the initial insult, symptoms can be delayed by 5–7 days. Dyspnea develops with a sensation of rapid shallow breathing and an inability to get enough air. Tachypnea and increased work of breathing frequently result in respiratory fatigue and ultimately in respiratory failure. Laboratory values are generally nonspecific and primarily indicative of underlying clinical disorders. The chest radiograph usually reveals alveolar and interstitial opacities involving at least three-quarters of the lung fields (Fig. R-2). While characteristic for ARDS or ALI, these radiographic findings are not specific and can be indistinguishable from cardiogenic pulmonary edema . Unlike the latter, however, the chest x-ray in ARDS rarely shows cardiomegaly, pleural effusions, or pulmonary vascular redistribution. Chest computed tomographic (CT) scanning in ARDS reveals extensive heterogeneity of lung involvement (Fig. R-4).
Fig. R-4 : A representative computed tomographic scan of the chest during the exudative phase of ARDS in which dependent alveolar edema and atelectasis predominate.
Because the early features of ARDS and ALI are nonspecific, alternative diagnoses must be considered. In the differential diagnosis of ARDS, the most common disorders are cardiogenic pulmonary edema, diffuse pneumonia, and alveolar hemorrhage. Less frequent diagnoses to consider include acute interstitial lung diseases [e.g., acute interstitial pneumonitis ], acute immunologic injury [e.g., hypersensitivity pneumonitis ], toxin injury (e.g., radiation pneumonitis), and neurogenic pulmonary edema.

Proliferative Phase

This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical ventilation during this phase. Despite this improvement, many still experience dyspnea, tachypnea, and hypoxemia. Some patients develop progressive lung injury and early changes of pulmonary fibrosis during the proliferative phase. Histologically, the first signs of resolution are often evident in this phase with the initiation of lung repair, organization of alveolar exudates, and a shift from a neutrophil- to a lymphocyte-predominant pulmonary infiltrate. As part of the reparative process, there is a proliferation of type II pneumocytes along alveolar basement membranes. These specialized epithelial cells synthesize new pulmonary surfactant and differentiate into type I pneumocytes. The presence of alveolar type III procollagen peptide, a marker of pulmonary fibrosis, is associated with a protracted clinical course and increased mortality from ARDS.

Fibrotic Phase

While many patients with ARDS recover lung function 3–4 weeks after the initial pulmonary injury, some will enter a fibrotic phase that may require long-term support on mechanical ventilators and/or supplemental oxygen. Histologically, the alveolar edema and inflammatory exudates of earlier phases are now converted to extensive alveolar duct and interstitial fibrosis. Acinar architecture is markedly disrupted, leading to emphysema-like changes with large bullae. Intimal fibroproliferation in the pulmonary microcirculation leads to progressive vascular occlusion and pulmonary hypertension. The physiologic consequences include an increased risk of pneumothorax, reductions in lung compliance, and increased pulmonary dead space. Patients in this late phase experience a substantial burden of excess morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase of ARDS is associated with increased mortality.

Treatment: Acute Respiratory Distress Syndrome

General Principles

Recent reductions in ARDS/ALI mortality are largely the result of general advances in the care of critically ill patients . Thus, caring for these patients requires close attention to (1) the recognition and treatment of the underlying medical and surgical disorders (e.g., sepsis, aspiration, trauma); (2) minimizing procedures and their complications; (3) prophylaxis against venous thromboembolism, gastrointestinal bleeding, aspiration, excessive sedation, and central venous catheter infections; (4) prompt recognition of nosocomial infections; and (5) provision of adequate nutrition.

Management of Mechanical Ventilation

See also in chapter Mechanical Ventilator Support. Patients meeting clinical criteria for ARDS frequently fatigue from increased work of breathing and progressive hypoxemia, requiring mechanical ventilation for support.

Ventilator-Induced Lung Injury

Despite its life-saving potential, mechanical ventilation can aggravate lung injury. Experimental models have demonstrated that ventilator-induced lung injury appears to require two processes: repeated alveolar overdistention and recurrent alveolar collapse. Clearly evident by chest CT (Fig. R-4), ARDS is a heterogeneous disorder, principally involving dependent portions of the lung with relative sparing of other regions. Because of their differing compliance, attempts to fully inflate the consolidated lung may lead to overdistention and injury to the more “normal” areas of the lung. Ventilator-induced injury can be demonstrated in experimental models of ALI, with high tidal volume (VT) ventilation resulting in additional, synergistic alveolar damage. These findings led to the hypothesis that ventilating patients suffering from ALI or ARDS with lower VTs would protect against ventilator-induced lung injury and improve clinical outcomes.

A large-scale, randomized controlled trial sponsored by the National Institutes of Health and conducted by the ARDS Network compared low VT (6 mL/kg predicted body weight) ventilation to conventional VT (12 mL/kg predicted body weight) ventilation. Mortality was significantly lower in the low VT patients (31%) compared to the conventional VT patients (40%). This improvement in survival represents the most substantial benefit in ARDS mortality demonstrated for any therapeutic intervention in ARDS to date.

Prevention of Alveolar Collapse

In ARDS, the presence of alveolar and interstitial fluid and the loss of surfactant can lead to a marked reduction of lung compliance. Without an increase in end-expiratory pressure, significant alveolar collapse can occur at end-expiration, impairing oxygenation. In most clinical settings, positive end-expiratory pressure (PEEP) is empirically set to minimize FIO2 and maximize PaO2. On most modern mechanical ventilators, it is possible to construct a static pressure–volume curve for the respiratory system. The lower inflection point on the curve represents alveolar opening (or “recruitment”). The pressure at this point, usually 12–15 mmHg in ARDS, is a theoretical “optimal PEEP” for alveolar recruitment. Titration of the PEEP to the lower inflection point on the static pressure–volume curve has been hypothesized to keep the lung open, improving oxygenation and protecting against lung injury. Three large randomized trials have investigated the utility of PEEP-based strategies to keep the lung open. In all three trials, improvement in lung function was evident but there were no significant differences in overall mortality. Until more data become available on the clinical utility of high PEEP, it is advisable to set PEEP to minimize FIO2 and optimize PaO2 . Measurement of esophageal pressures to estimate transpulmonary pressure may help identify an optimal PEEP in some patients.

Oxygenation can also be improved by increasing mean airway pressure with “inverse ratio ventilation.” In this technique, the inspiratory (I) time is lengthened so that it is longer than the expiratory (E) time (I:E > 1:1). With diminished time to exhale, dynamic hyperinflation leads to increased end-expiratory pressure, similar to ventilator-prescribed PEEP. This mode of ventilation has the advantage of improving oxygenation with lower peak pressures than conventional ventilation. Although inverse ratio ventilation can improve oxygenation and help reduce FIO2 to ≤0.60 to avoid possible oxygen toxicity, no mortality benefit in ARDS has been demonstrated. Recruitment maneuvers that transiently increase PEEP to “recruit” atelectatic lung can also increase oxygenation, but a mortality benefit has not been established.

In several randomized trials, mechanical ventilation in the prone position improved arterial oxygenation, but its effect on survival and other important clinical outcomes remains uncertain. Moreover, unless the critical-care team is experienced in “proning,” repositioning critically ill patients can be hazardous, leading to accidental endotracheal extubation, loss of central venous catheters, and orthopedic injury. Until validation of its efficacy, prone-position ventilation should be reserved for only the most critically ill ARDS patients.

Other Strategies in Mechanical Ventilation

Several additional mechanical ventilation strategies that utilize specialized equipment have been tested in ARDS patients, most with mixed or disappointing results in adults. These include high-frequency ventilation (HFV) [i.e., ventilating at extremely high respiratory rates (5–20 cycles per second) and low VTs (1–2 mL/kg)]. Partial liquid ventilation (PLV) with perfluorocarbon, an inert, high-density liquid that easily solubilizes oxygen and carbon dioxide, has revealed promising preliminary data on pulmonary function in patients with ARDS but also without survival benefit. Lung-replacement therapy with extracorporeal membrane oxygenation (ECMO), which provides a clear survival benefit in neonatal respiratory distress syndrome, may also have utility in select adult patients with ARDS.

Data in support of the efficacy of “adjunctive” ventilator therapies (e.g., high PEEP, inverse ratio ventilation, recruitment maneuvers, prone positioning, HFV, ECMO, and PLV) remain incomplete, so these modalities are not routinely used.

Fluid Management

See also in Approach to patient with critical Illness. Increased pulmonary vascular permeability leading to interstitial and alveolar edema rich in protein is a central feature of ARDS. In addition, impaired vascular integrity augments the normal increase in extravascular lung water that occurs with increasing left atrial pressure. Maintaining a normal or low left atrial filling pressure minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance, improves pulmonary mechanics, shortens ICU stay and the duration of mechanical ventilation, and is associated with a lower mortality in both medical and surgical ICU patients. Thus, aggressive attempts to reduce left atrial filling pressures with fluid restriction and diuretics should be an important aspect of ARDS management, limited only by hypotension and hypoperfusion of critical organs such as the kidneys.

Glucocorticoids

Inflammatory mediators and leukocytes are abundant in the lungs of patients with ARDS. Many attempts have been made to treat both early and late ARDS with glucocorticoids to reduce this potentially deleterious pulmonary inflammation. Few studies have shown any benefit. Current evidence does not support the use of high-dose glucocorticoids in the care of ARDS patients.

Other Therapies

Clinical trials of surfactant replacement and multiple other medical therapies have proved disappointing. Inhaled nitric oxide (NO) can transiently improve oxygenation but does not improve survival or decrease time on mechanical ventilation. Therefore, the use of NO is not currently recommended in ARDS.

Recommendations

Many clinical trials have been undertaken to improve the outcome of patients with ARDS; most have been unsuccessful in modifying the natural history. The large number and uncertain clinical efficacy of ARDS therapies can make it difficult for clinicians to select a rational treatment plan, and these patients’ critical illnesses can tempt physicians to try unproven and potentially harmful therapies. While results of large clinical trials must be judiciously administered to individual patients, evidence-based recommendations are summarized in Table R-3, and an algorithm for the initial therapeutic goals and limits in ARDS management is provided in Fig. R-5.

Table R–3. Evidence-Based Recommendations for ARDS Therapies

Treatment	Recommendation*
Mechanical ventilation:	
Low tidal volume	A
Minimize left atrial filling pressures	B
High-PEEP or “open lung”	C
Prone position	C
Recruitment maneuvers	C
ECMO	C
High-frequency ventilation	D
Glucocorticoids	D
Surfactant replacement, inhaled nitric oxide, and other anti-inflammatory therapy (e.g., ketoconazole, PGE1, NSAIDs)	D
*A, recommended therapy based on strong clinical evidence from randomized clinical trials; B, recommended therapy based on supportive but limited clinical data; C, indeterminate evidence: recommended only as alternative therapy; D, not recommended based on clinical evidence against efficacy of therapy.
Abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; NSAIDs, nonsteroidal anti-inflammatory drugs; PEEP, positive end-expiratory pressure; PGE1, prostaglandin E1.
Fig. R-5 : Algorithm for the initial management of ARDS. Clinical trials have provided evidence-based therapeutic goals for a stepwise approach to the early mechanical ventilation, oxygenation, and correction of acidosis and diuresis of critically ill patients with ARDS.
Prognosis

Mortality

Recent mortality estimates for ARDS range from 26 to 44%. There is substantial variability, but a trend toward improved ARDS outcomes appears evident. Of interest, mortality in ARDS is largely attributable to nonpulmonary causes, with sepsis and nonpulmonary organ failure accounting for >80% of deaths. Thus, improvement in survival is likely secondary to advances in the care of septic/infected patients and those with multiple organ failure.

Several risk factors for mortality to help estimate prognosis have been identified. Similar to the risk factors for developing ARDS, the major risk factors for ARDS mortality are also nonpulmonary. Advanced age is an important risk factor. Patients >75 years of age have a substantially increased mortality (~60%) compared to those <45 (~20%). Also, patients>60 years of age with ARDS and sepsis have a threefold higher mortality compared to those <60. Preexisting organ dysfunction from chronic medical illness is an important additional risk factor for increased mortality. In particular, chronic liver disease, cirrhosis, chronic alcohol abuse, chronic immunosuppression, sepsis, chronic renal disease, any nonpulmonary organ failure, and increased APACHE III scores have also been linked to increased ARDS mortality. Several factors related to the presenting clinical disorders also increase the risk for ARDS mortality. Patients with ARDS from direct lung injury (including pneumonia, pulmonary contusion, and aspiration; Table R-1) have nearly twice the mortality of those with indirect causes of lung injury, while surgical and trauma patients with ARDS, especially those without direct lung injury, have a better survival rate than other ARDS patients.

Surprisingly, there is little value in predicting ARDS mortality from the PaO2/FIO2 ratio and any of the following measures of the severity of lung injury: the level of PEEP used in mechanical ventilation, the respiratory compliance, the extent of alveolar infiltrates on chest radiography, and the lung injury score (a composite of all these variables). However, recent data indicate that an early (within 24 hours of presentation) elevation in dead space and the oxygenation index may predict increased mortality from ARDS.

Functional Recovery in ARDS Survivors

While it is common for patients with ARDS to experience prolonged respiratory failure and remain dependent on mechanical ventilation for survival, it is a testament to the resolving powers of the lung that the majority of patients recover nearly normal lung function. Patients usually recover their maximum lung function within 6 months. One year after endotracheal extubation, more than one-third of ARDS survivors have normal spirometry values and diffusion capacity. Most of the remaining patients have only mild abnormalities in their pulmonary function. Unlike the risk for mortality, recovery of lung function is strongly associated with the extent of lung injury in early ARDS. Low static respiratory compliance, high levels of required PEEP, longer durations of mechanical ventilation, and high lung injury scores are all associated with worse recovery of pulmonary function. When caring for ARDS survivors, it is important to be aware of the potential for a substantial burden of emotional and respiratory symptoms. There are significant rates of depression and posttraumatic stress disorder in ARDS survivors.

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