快樂小藥師 Im pharmacist nichts glücklich

Release Date:  July 1, 2009

Acute respiratory distress syndrome (ARDS) and its less severe form, acute lung injury (ALI), are a leading cause of respiratory failure in hospitalized intensive-care patients requiring mechanical ventilation. Both conditions involve systemic inflammation and hypoxemia characterized by bilateral pulmonary infiltrates in the absence of elevated left atrial pressure; however, they differ in the degree of hypoxemia. ARDS, which is characterized by a more severe hypoxemia, is associated with greater morbidity and mortality. These disorders were first described in 1967 by Ashbaugh and Petty in patients presenting with abrupt onset of clinically significant hypoxemia refractory to treatment, decreased lung compliance, and diffuse pulmonary infiltrates on chest radiograph.¹

An estimated 10% to 15% of patients are admitted to intensive care with ALI or ARDS (ALI/ARDS) or develop one of these disorders during their hospital stay.² The estimated annual incidence in the United States is 79 cases per 100,000 population for ALI and 59 cases per 100,000 population for ARDS. The incidence of ALI/ARDS increases with advancing age and varies according to cultural, demographic, seasonal, and socioeconomic differences. Despite advances in supportive care and respiratory support, these disorders are associated with a mortality rate between 40% and 70%. The mortality associated with ALI/ARDS usually is not due to respiratory failure, but rather is caused by multiple organ dysfunction syndrome (MODS), as the pulmonary dysfunction of ALI/ARDS usually precedes MODS.^3-6

DIAGNOSIS

The current definitions of ALI and ARDS were developed by the American-European Consensus Conference Committee in 1994 and are based on clinical and radiologic findings.^7,8 Both disorders are characterized by acute development of bilateral pulmonary infiltrates on chest radiograph and a pulmonary capillary wedge pressure (PCWP) of less than 18 mmHg or the absence of clinically evident left atrial hypertension. ALI and ARDS differ in the degree of respiratory failure, defined as the ratio of the partial pressure of arterial oxygen (PaO₂) to the fraction of inspired oxygen, or PF ratio. ALI is diagnosed by a PF ratio of less than 300 mmHg; ARDS is diagnosed by a PF ratio of less than 200 mmHg. Differentiation of ALI/ARDS from other disorders that cause hypoxemia and pulmonary edema is difficult since there is no definitive radiographic feature or laboratory value to diagnose (TABLE 1).⁹

The PCWP differentiates pulmonary edema of cardiogenic versus noncardiogenic origin. A PCWP greater than 18 mmHg signifies that pulmonary edema seen on chest radiograph is of cardiac origin, but measurement requires insertion of a pulmonary-artery catheter. In the absence of a catheter, echocardiography may be used to evaluate the source of the pulmonary edema. Brain natriuretic peptide (BNP), a marker of heart failure, has been studied for differentiation between cardiogenic and noncardiogenic pulmonary edema.¹⁰ In a study of 80 patients identified as having cardiogenic pulmonary edema or ALI/ARDS, investigators found that a low BNP concentration (less than 200 pg/mL) was strongly associated with a diagnosis of ARDS (91%).

Another diagnostic criterion for ALI/ARDS is bilateral infiltrates on chest radiograph.^7,8 It is difficult to distinguish between acute and chronic pulmonary changes from this criterion. The current American-European Consensus definition does not designate a time period for acute pulmonary changes, nor does it specify acute versus chronic abnormalities. A common finding in chronic pulmonary conditions such as bronchiectasis,pulmonary fibrosis, asbestosis, and lymphangitic carcinoma is bilateral opacities on chest radiograph, making it difficult to differentiate them. Chronic obstructive pulmonary disease may be distinguished from ALI/ARDS by a flatter diaphragm in these patients, with lung fields appearing blacker and hyperinflated on chest radiograph.

PATHOPHYSIOLOGY

ALI/ARDS is a complication that arises when another condition produces a severe, progressive form of systemic inflammatory response. Development of ALI/ARDS is associated with both direct and indirect lung injury (TABLE 2) resulting in alveolar damage. Within 72 hours of injury, pathophysiologic changes that lead to the development of inflammation and coagulation—similar to sepsis syndrome—cause alveolar barrier disruption. Patients with sepsis are at greatest risk for developing ALI/ARDS.^4,10,11 The alveolar damage results in pulmonary edema, pulmonary hypertension, ventilation-perfusion mismatching, and, if the damage is long-standing, pulmonary fibrosis. All of these components lead to a worsening exchange of gas in the lungs.^11-13 ALI/ARDS comprises three main overlapping phases: exudative, proliferative, and fibrotic; there is also a recovery phase (TABLE 3). The exudative phase is caused by the initial inflammatory response, which is followed by a repair process (proliferative phase), after which the patient either begins the recovery phase or progresses to the fibrotic phase.

The exudative stage encompasses the first 4 to 7 days after symptom onset. It is characterized by increased permeability of both the alveolar epithelium and the endothelium, enhanced cytokine production, influx of plasma protein into alveoli, and loss of coagulation and fibrinolytic homeostasis. Neutrophils migrate to the damaged area and, with the assistance of activated alveolar macrophages, cause the release of proteases, oxidants, and leukotrienes and the activation of proinflammatory cytokines. These cytokines, which include interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha, contribute to endothelial damage. The damage results in exposure of the cell surface and the production of tissue factor and plasminogen activator inhibitor-1 (PAI-1). Procoagulant activity is increased as tissue factor activates the extrinsic clotting pathway, increasing the production of PAI-1 and downregulating the formation of activated protein C (APC). PAI-1 inhibits fibrinolysis, resulting in the formation of fibrin-rich hyaline membranes and intra-alveolar fibrin deposition.¹¹ Continuation of this process results in vascular obstruction and alterations in microvascular blood flow that may eventually lead to MODS and death.

This initial reaction is the immune system’s protective response to reduce lung injury. This immune response damages the lung endothelium, leading to a protein-rich pulmonary edema; it also damages the lung epithelium, resulting in a decreased surfactant production and a loss of normal fluid transport function, further complicating the pulmonary edema.¹¹ Accumulation of this protein-rich fluid in the alveoli causes the inactivation of surfactant, thereby reducing lung compliance and further contributing to the deterioration of pulmonary function. The resulting pulmonary damage leads to respiratory failure that, in the majority of cases, will require mechanical ventilation.

A large percentage of patients recover from the acute phase, but a good number of patients progress to the proliferative and fibrotic phases. Following the acute phase, pneumocyte proliferation and differentiation occur in response to injury to the alveolar components in an effort to restore the alveolar epithelial surface. During this phase, the alveolar lumen fills with mesenchymal cells and proliferating fibroblasts, and new blood vessels form. Loss of normal alveolar structure occurs, resulting in extensive pulmonary fibrosis and emphysematous lungs (fibrotic phase). This causes reduced lung compliance, poor gas exchange, and increased work to breathe.¹²

Resolution of ALI/ARDS involves the removal of protein-rich edema from the lungs, clearance of inflammatory cells, and restoration of normal alveolar function. Reduction of edema occurs through the active transport of sodium and chloride from the distal air spaces into the lung interstitium.¹⁴ This creates an osmotic barrier, and water will follow in order to maintain an isotonic condition. This process, which occurs early, has been associated with improved gas exchange and a better overall outcome in clinical studies. Both soluble and insoluble protein is removed from the distal air spaces by alveolar epithelial cells. Eventual restoration of the alveolar architecture is achieved by the proliferation of alveolar type II cells to line the basement membrane.

TREATMENT

The goal of treatment for ALI/ARDS is to prevent further lung injury, reduce lung edema, and maintain tissue oxygenation. Treatment may be nonpharmacologic or pharmacologic. Various therapies have been evaluated, but none has definitively demonstrated efficacy. Clinical trials targeting pharmacotherapies have failed to show a reduction in mortality. Currently, the only treatment with proven efficacy is the nonpharmacologic use of lung-protective mechanical ventilation.

Nonpharmacologic Therapy

Fluid-Management Strategies: An increase in lung capillary permeability leads to increased alveolar fluid and lung edema. Management of fluid status in ALI/ARDS patients is important because intravascular volume needs to be kept at a level that will not cause tissue hypoperfusion while still maintaining a dry or euvolemic state to prevent lung edema. Critically ill patients routinely are catabolic, resulting in hypoproteinemia and reducing the oncotic gradient. Edema formation may occur in these patients even at low hydrostatic pressures; thus the need for restricting fluids. In a randomized trial comparing liberal versus conservative fluid management in 1,000 patients with ALI, conservative management resulted in improved oxygenation, with a significant reduction in ventilator days (P <.0001) and ICU stay (P <.001).¹⁵ However, there was no significant difference in overall 60-day mortality, incidence or prevalence of shock, or requirement for dialysis. Patients who experienced shock were managed with early goal-directed therapy consisting of aggressive crystalloid resuscitation.

The use of crystalloids or colloids to resuscitate critically ill patients has been debated. Hypoproteinemia is a documented risk factor for the development of ALI/ARDS and mortality in critically ill patients. Clinical trials have demonstrated that the combination of a colloid (albumin) and furosemide improves oxygenation, fluid balance, and hemodynamics, but mortality is not reduced.¹⁶ The combination thus may be useful for improving pulmonary function in hypoproteinemic patients with ALI, but it cannot be routinely recommended without further studies.

Lung-Protective Mechanical Ventilation: Mechanical ventilation can be a source of further lung damage in ALI/ARDS: The injured part of the lung is unable to inflate, whereas the healthy portion of the lung is susceptible to overinflation and stretching.¹⁷ There is evidence that tidal volumes used in traditional ventilation (10-15 mL/kg) can damage the lungs. Low-tidal-volume ventilation leading to low plateau pressure is the only intervention to effectively reduce mortality in ALI/ARDS clinical trials by lessening injury to the lung and downregulating proinflammatory cytokines. Lowering the tidal volume to 6 mL/kg of ideal body weight while maintaining a plateau pressure of 30 cm of water or less is critical for a lung-protective ventilation strategy.Plateau pressure is the pressure following delivery of the tidal volume that prevents the patient from immediately exhaling; if this pressure is excessively elevated, overdistention of the lung may occur. Lung-protective ventilation allows for minimal barotrauma, which may result in an elevated partial pressure of carbon dioxide. This state, termed permissive hypercapnia, does not need to be corrected since it is more important to improve ventilatory function and the adverse effects are minimal. Patient-oxygenation goals are a PaO₂ of 55 to 80 mmHg and an oxygenation saturation between 88% and 95%.

A multicenter, randomized, controlled trial compared low tidal volume (6 mL/kg or less) with traditional tidal volume (12 mL/kg or less) in 861 ARDS patients.¹⁸ Significant reductions in hospital mortality rate (P = .007), days of mechanical ventilation (P = .007), and days free of nonpulmonary organ failure (P = .006) were seen in the low-tidal-volume group versus the traditional-tidal-volume group. The incidence of barotrauma was not statistically significant between the two groups, but a reduced inflammatory state was present in the low-tidal-volume group, as evidenced by a lower IL-6 concentration after the third day.

Additional ventilation strategies that have been studied in ALI/ARDS patients include high positive end-expiratory pressure ventilation, alveolar recruitment maneuvers, and prone positioning. None of these methods has proven effective for reducing mortality; they should be considered only as rescue therapy in severe hypoxemia.

Pharmacologic Therapy

Corticosteroids: Because of their anti-inflammatory properties, corticosteroids have long been studied for the treatment of all stages of ALI/ARDS, with variable success. Mechanisms by which corticosteroids would be effective in the treatment of ALI/ARDS include inhibition of inflammatory cytokines and reduction of collagen deposition.¹⁹ Corticosteroids inhibit pathways leading to the production of the inflammatory cytokines TNF-alpha, IL-1, IL-6, and IL-8 and are believed to switch on genes encoding for the anti-inflammatory mediators IL-10 and IL-1 receptor antagonists.

Clinical trials that examined the efficacy of corticosteroids in the early treatment (less than 3 days) of ALI/ARDS showed no decrease in mortality, and possibly even demonstrated a trend toward increased mortality.^20,21 These trials used high doses of methylprednisolone (30 mg/kg) every 6 hours for a duration of 24 to 48 hours. More recently, corticosteroids have been investigated for their efficacy in the fibrotic and proliferative phases of ALI/ARDS. A small multicenter, randomized, double-blind, controlled trial examined the use of methylprednisolone 2 mg/kg for 32 days versus placebo in patients with severe, late-phase ARDS who were on mechanical ventilation for more than 7 days.²² Patients receiving methylprednisolone had a marked reduction in hospital mortality compared with the placebo group (62% vs. 12%; P = .04). There was no significant difference in infection rates between the two groups. Limitations of this study include the small sample size and the crossover of four placebo patients to the treatment arm.

The results of this study prompted the enrollment of 180 patients meeting the diagnosis of ARDS into a larger multicenter trial.²³ Patients’ duration of ARDS onset was between 7 and 28 days. Patients in the treatment group demonstrated an improvement in ventilator-free days, shock-free days, and ICU-free days, as well as a slightly significant clinical improvement. Final analysis showed an increase in 60-day and 180-day mortality rates among patients enrolled more than 13 days after onset of ARDS, and patients treated with methylprednisolone were more likely to return to assisted ventilation after extubation (P = .006). An explanation for this may be that patients with ARDS of more than 13 days experience less fibroproliferation, leading to a poorer response to corticosteroids. Infection rates and occurrence of septic shock were lower in the corticosteroid arm, and the occurrence of neuromyopathy was high (P = .001) in both study groups.

A recent multicenter, placebo-controlled trial conducted by Meduri et al investigated the use of methylprednisolone in patients with an ARDS diagnosis of less than 72 hours.²⁴ The trial used a two-to-one randomization design. Patients received either placebo or methylprednisolone 1 mg/kg loading dose followed by an infusion of 1 mg/kg/day for days 1 through 14; 0.5 mg/kg/day for days 15 through 21; 0.25 mg/kg/day for days 22 through 25; and 0.125 mg/kg/day for days 26 through 28. The treatment group had significantly fewer days on mechanical ventilation (P = .01), greater improvement in PF ratios (P = .0006), and shorter length of ICU stay (P = .03). These results may be questionable owing to the small sample size (N = 91), the allowing of patients to cross over to the treatment arm if they failed to improve by days 7 and 9, and a greater percentage of patients in the control arm experiencing catecholamine-dependent shock.

Clinical trials support corticosteroids’ efficacy in improving gas exchange and reducing ventilation days and ICU stay, but fail to show an overall improvement in mortality. The use of corticosteroids early in the diagnosis of septic shock has been shown to reduce the incidence of ALI/ARDS.²⁵ The clinical role of corticosteroids in the treatment of ALI/ARDS remains uncertain, and its establishment will require additional large clinical trials.

Beta-Adrenergic Agonists: Beta-adrenergic agonists are beneficial in the treatment of ALI/ARDS because they promote the clearance of alveolar epithelial fluid. Clinical trials have shown that these agents reduce peak airway pressure, airflow pressure, and plateau pressures, which suggests a decrease in airflow resistance.²⁶ Two recent clinical trials evaluated the efficacy and safety of aerosolized albuterol (2,200 mcg/day) and IV albuterol (15 mcg/kg/h) in the treatment of patients with ALI/ARDS.^27,28 Both trials showed a trend toward reduced incidence of lung injury, but the IV formulation was associated with a high incidence of increased heart rate and supraventricular arrhythmias. Currently, there is not enough evidence to recommend the use of these agents in ALI/ARDS, except for those patients with bronchospasm and increased airway resistance.

Anticoagulants: The pathogenesis of ALI/ARDS is similar to that which occurs in severe sepsis, as both conditions involve abnormalities of coagulation and fibrinolysis. Coagulation is locally upregulated in the lung where fibrinolytic activity is depressed, which leads to fibrin deposition in the lung. Preliminary data indicate that anticoagulant interventions (tissue factor pathway inhibitor [TFPI], antithrombin III, and APC) that block the extrinsic coagulation pathway may protect against the development of pulmonary fibrin deposition, as well as lung dysfunction and acute inflammation.

Animal studies of TFPI and antithrombin therapies have consistently shown a decrease in lung injury and improved oxygenation; clinical studies in humans, however, have failed to show these results and demonstrate a higher incidence of bleeding. A phase II study of TFPI in patients with severe sepsis found a lower mortality rate in the subgroup of patients with ARDS, but a phase III study failed to validate this benefit.^29,30 The phase III study used a lower dose of TFPI (0.25 mg/kg/h for 96 hours) compared with the phase II study (0.25 to 0.5 mg/kg/h for 96 hours), and the phase III trial included patients with severe sepsis and coagulopathy (international normalized ratio 1.2 or greater). It is unknown whether the degree of coagulopathy or the lower dose of TFPI contributed to the lack of benefit to patients in the phase III trial. A low level of antithrombin in the lungs of patients with sepsis has been correlated with the development of ALI/ARDS, but the phase III study of antithrombin III in severe sepsis failed to show an improvement in pulmonary function.^1,11,31

Current guidelines for the management of severe sepsis recommend the use of APC in sepsis-induced ALI/ARDS.²⁵ An analysis of clinical trials of APC for sepsis-induced ALI/ARDS found reduced mortality rates, improved recovery of respiratory function, and shortened duration of mechanical ventilation, but the utility of APC in patients without sepsis-induced ARDS is unknown.³²

Vasodilators: Clinical trials of both nonselective (nitroprusside, hydralazine) and selective (nitric oxide [NO], prostaglandin E₁, prostacyclin) vasodilators have demonstrated a short-term improvement in oxygenation and a reduction in pulmonary vascular resistance, but no long-term reduction in mortality.⁹NO is the most studied of the vasodilators owing to its anti-inflammatory properties and its ability to cause selective pulmonary vasodilation. A meta-analysis concluded that NO did not affect mortality, duration of ventilation, or ventilator-free days.³³ NO was found to be associated with improvements in the PF ratio and the oxygenation index, but its effects were transient and did not persist beyond 24 to 48 hours. NO’s place in therapy may be as a rescue agent in patients with acute hypoxemia not responsive to traditional therapy.

Surfactant: The accumulation of protein-rich fluid in the alveoli leads to inactivation of pulmonary surfactant, contributing to alveolar collapse and a deterioration in pulmonary function. The administration of exogenous surfactant to treat patients with ALI/ARDS was first reported in the late 1980s. Small clinical trials in humans showed promising trends toward improved physiologic endpoints, but a large, randomized trial found no significant improvements in oxygenation or mortality.^34,35 In trials, surfactant therapy has continued to fall short in improvement of oxygenation, but a possible trend toward a dose-dependent improvement in 28-day mortality has been indicated. The benefit of surfactant therapy in ALI/ARDS, therefore, remains unknown and awaits further clinical study.

Immunonutrition: Regarding nutritional support, there is a growing interest in targeting enteral products that decrease endogenous inflammatory mediator release in ALI/ARDS patients. A recent meta-analysis found that diets supplemented with omega-3 fatty acid (eicosapentaenoic acid) in combination with gamma-linolenic acid caused a significant reduction in risk of mortality, risk of developing new organ failures, time on mechanical ventilation, and ICU stay.³⁶ This diet was well tolerated, as evidenced by a low occurrence of gastrointestinal adverse effects compared with the control group.

Additional Therapies: Various pharmacologic therapies have been investigated for the reduction of pulmonary damage in ALI/ARDS. Agents studied include ketoconazole, pentoxifylline, and N-acetylcysteine (NAC), but none of these therapies has demonstrated a reduction in mortality.^37-39Ketoconazole, a synthetic imidazole with anti-inflammatory properties, was evaluated in a randomized, double-blind, placebo-controlled study of 234 patients with ALI/ARDS.³⁷ The study concluded that although ketoconazole was safe, it did not improve lung function or reduce mortality or duration of mechanical ventilation. The vasodilator pentoxifylline was studied in a pilot trial involving six patients with severe ARDS.³⁸ The trial concluded that large doses of IV pentoxifylline induced small hemodynamic changes without any worsening of pulmonary gas exchange. NAC has been studied based on its antioxidant properties, which provide protective effects against acute pulmonary injury. A double-blind, placebo-controlled study of 48 patients found that treatment with IV NAC (70 mg/kg) decreased the number of days of ALI without affecting overall mortality.³⁹ Future experimental therapies include agents to enhance edema clearance, stimulate repair pathways, inhibit proinflammatory transcription factors, and target inflammatory cytokines.

THE PHARMACIST’S ROLE

The pharmacist, as part of the health care team, can assist in improving outcomes by optimizing the treatment administered to patients diagnosed with ALI/ARDS. Mechanical ventilation, the only intervention that has shown a mortality benefit in ALI/ARDS, requires monitoring of sedation, analgesia, and oxygenation. The pharmacist can be influential in the development of protocols that include sedation scales for appropriate titration of sedation and analgesia, sedation vacations, addition of a beta-agonist in airway resistance, and prevention of pneumonia through using a 30-degree angle at the head of the bed. Additionally, the pharmacist can assist the health care team in appropriate antimicrobial selection if sepsis is the underlying cause of ALI/ARDS.

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