N-Acetylcysteine Enhances Recovery From Acute Lung Injury in Man – Subjects and Protocol
Acute lung injury characterized by a high-permeability, low-pressure pulmonary edema can develop following a number of predisposing diseases resulting in different degrees of respiratory insufficiency. Patients with mild-to-moderate injury could, within this continuum, represent an interesting subset to evaluate a therapeutic approach of lung dysfunction. The pathogenesis of acute lung injury and its severest form, the adult respiratory distress syndrome (ARDS), involves a number of mechanisms and mediators. Toxic oxygen radicals of intra-cellular as well as extracellular origin seem to play an important role. Oxygen metabolites such as superoxide anion (O0’r), hydrogen peroxide (H70,), hydroxyl radical ( OH), and hypochlorous acid (HOCl) cause increased vascular permeability in endothelial cell monolayers, in isolated lungs, and in vivo.u In human ARDS, increased oxidant activity has been observed in expired breath or in bronchoalveolar lavage (BAL) fluid as well as in granulocytes and red blood cells. In addition, patients with ARDS seem to have a marked deficiency of the tripeptide antioxidant glutathione (GSH) in the extracellular epithelial lining fluid of the lower respiratory tract. Glutathione acts as an antioxidant for H202. The GSH deficiency observed in ARDS could favor oxidative stress, thus allowing functional and/or morphologic damage in the lower respiratory tract, including an overshooting inflammatory reaction and epithelial and endothelial lesions resulting in pulmonary edema. N-acetylcysteine (NAC) is a GSH agonist, and previous studies have demonstrated that NAC administration increases GSH levels in red blood cells, granulocytes, and plasma of patients with ARDS.
Increasing GSH levels in the early phases of acute lung injury with NAC could reduce or limit the extent of epithelial and endothelial damage and improve the clinical course. N-acetylcysteine has been used at high dosages in the treatment of paracetamol intoxication and was well tolerated.
The purpose of the present study was to assess the effects of NAC on the development of ARDS and mortality in patients with mild-to-moderate acute lung injury associated with known risk factors predisposing to ARDS. Other important end points, such as duration of ventilatory support, FIo2 requirements, and the clinical course of respiratory function were identified at the end of the investigation and analyzed.
During a 12-month period, patients with risk factors known to predispose to the development of ARDS (see below), and presenting with mild-to-moderate acute lung injury, were included in the trial in the four participating intensive care units (ICUs) in Switzerland (Geneva, Lausanne, Basel, Locarno).
In order to collect patients with comparable lung dysfunction for a pharmacologic treatment regimen, we used the expanded definition suggested by Murray et al, and only considered patients presenting with an initial lung injury score (LIS) between 0.1 and 2.5. Patients with cardiogenic pulmonary edema and/or chronic heart failure were excluded on the basis of medical history, results of clinical examination, and the use of a pulmonary artery catheter in all unclear situations. The following predisposing factors for the development of ARDS were considered.
Sepsis, defined as proposed by Bone, was clinical evidence of infection, ie, respiratory rate above 20 cycles/min or minute ventilation over 10 L/min if mechanically ventilated, heart rate more than 90 beats/min, core or rectal temperature outside the range of 35.5° to 38.0°C, a white blood cell count above 12,000 or below 4,000/ц] or 20 percent or more immature cells plus evidence of altered organ perfusion (ie, acute change in mental status, PaOg/FIc^ less than 280, plasma lactate concentration greater than upper limit of normal, and urine output below 0.5 nil/kg of body weight for at least 1 h).