Long-term cognitive impairment after critical illness.

BACKGROUND: Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. METHODS: We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. RESULTS: Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months. CONCLUSIONS: Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.).

A randomized trial of the effects of nebulized albuterol on pulmonary edema in brain-dead organ donors.

Donor lung utilization rates are persistently low primarily due to donor lung dysfunction. We hypothesized that a treatment that enhances the resolution of pulmonary edema by stimulating the rate of alveolar fluid clearance would improve donor oxygenation and increase donor lung utilization. We conducted a randomized, blinded, placebo-controlled trial of aerosolized albuterol (5mg q4h) versus saline placebo during active donor management in 506 organ donors.The primary outcome was change in oxygenation arterial partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] from enrollment to organ procurement.The albuterol (n»260) and placebo (n»246)groups were well matched for age, gender, ethnicity,smoking, and cause of brain death. The change in PaO2/FiO2 from enrollment to organ procurement did not differ between treatment groups (p»0.54) nor did donor lung utilization (albuterol 29% vs. placebo 32%,p»0.44). Donors in the albuterol versus placebo groups were more likely to have the study drug dose reduced (13% vs. 1%, p<0.001) or stopped (8% vs. 0%,p<0.001) for tachycardia. In summary, treatment with high dose inhaled albuterol during the donor management period did not improve donor oxygenation or increase donor lung utilization but did cause tachycardia.High dose aerosolized albuterol should not be used in donors to enhance the resolution of pulmonary edema.

Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis.

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.

Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.

Correlation of oxygenation with vascular permeability-surface area but not with lung water in humans with acute respiratory failure and pulmonary edema.

We used a single-pass multiple tracer technique to measure cardiac output, extravascular lung water (EVLW) and lung vascular [14C]urea permeability-surface area (PSu) in 14 patients with acute respiratory failure and pulmonary edema. All patients had increased EVLW, but EVLW in the 10 surviving patients (0.26 +/- 0.06 SE ml/ml total lung capacity [TLC]) was not significantly different from that in the five patients who died (0.22 +/- 0.05). EVLW did not correlate with intravascular pressures or with alveolar-arterial oxygen pressure difference (A-aDO2). PSu was lower in surviving patients (0.50 +/- 0.16 SE ml/s X liter TLC) than in patients who died (3.44 +/- 0.36; P less than 0.05) and also lower than in previously reported data in patients with normal PSu. PSu correlated significantly with A-aDO2. Serial studies showed that PSu returned from a low value toward normal in a patient who survived but remained high in a patient who died. We conclude that the amount of edema in the lungs measured by indicator methods was not the principal determinant of either the magnitude of oxygenation defect or survival in the patients studied. We interpret the low PSu in surviving patients as decreased surface area and infer that the ability of the lung circulation to reduce perfusion of damaged and edematous areas was important in preserving oxygenation. A high PSu, presumably reflecting perfusion of areas with increased permeability, was a sign of especially poor prognosis. Multiple tracer techniques for measuring lung vascular PSu may help to define the pathogenesis and to evaluate therapies of acute lung injury in humans. Such measurements may be a more useful clinical tool than measurements of lung water in patients with acute respiratory failure and pulmonary edema.

N-acetylcysteine in experimental and clinical acute lung injury.

Clinically, lung injury is characterized by one or more of the following: altered gas exchange, dyspnea, decreased static compliance, and nonhydrostatic pulmonary edema. Although many antioxidants have been investigated in in vitro systems and in animal models, only some are at the developmental stage, or safe for clinical trials. Considerable evidence has recently accumulated supporting the hypothesis that leukocyte activation involves release of large quantities of highly reactive oxygen radicals, and hydrogen peroxide is partially responsible for diffuse microvascular and tissue injury in septic patients. Granulocyte depletion in animal models reduces the degree of fall in dynamic lung compliance and the increase in airflow resistance, lymph flow, and hypoxemia secondary to endotoxin administration. We hypothesized that the partial benefit derived from granulocyte depletion was due to the effective removal of a major source of oxygen radicals. Among the list of free radical scavengers, N-acetylcysteine stands out, because of its established usefulness in at least one human disease thought to be secondary to free radical organ damage (acetaminophen or paracetamol overdose). It is an extremely safe agent with a wide toxic-therapeutic window. An increasing number of animal studies indicate efficacy for this agent in the prevention and therapy of lung injury involving toxic oxygen species. We developed a randomized, double-blind protocol for the study of intravenous N-acetylcysteine in patients with established adult respiratory distress syndrome (ADRS). Results of this trial are preliminary. Nevertheless, they indicate that plasma and red cell glutathione levels are decreased in ADRS patients, and that N-acetylcysteine increases plasma cysteine as well as plasma and red cell glutathione. There are also indications that cardiopulmonary physiology is favorably affected by such therapy including improvements in chest radiograph edema scores, pulmonary vascular resistance, static compliance, oxygen delivery, and oxygen consumption.

Pulmonary edema. Pathophysiologic mechanisms and new approaches to therapy.

Since the first report by Ashbaugh and Petty in 1967 categorizing patients with acute respiratory failure and labelling the process the adult respiratory distress syndrome (ARDS), this illness has been recognized with increasing frequency. Adult respiratory distress syndrome now afflicts more than 150,000 people a year and the mortality remains in the 70 percent range in spite of significant advances in critical care medicine. As a consequence, research in the area of acute lung injury has intensified resulting in the elucidation of many of the pathophysiologic mechanisms operative in the process. As long as the mortality of ARDS remains high, research of this kind will be needed especially with regard to clinical trials of pharmacologic agents which have appeared promising in the laboratory. An aggressive approach, possibly utilizing multiple drug regimens, seems justified considering the morbidity and mortality with which are dealing. Until success is achieved, supportive intensive care with diligent attention to oxygen and ventilator management, infection control, and fluid therapy will be the mainstay of treatment for ARDS.

Airway complications from free-basing cocaine.

The majority of the deaths due to fires result from smoke inhalation, hypoxia, and systemic toxicity. Lower airway injury from chemical byproducts carried in the smoke is less frequent and thermal injury to the lower airways is a rare occurrence. We report a case of severe thermal injury to the conducting airways due to either inhalational injury or to intratracheal ignition of the ether vehicle used in free-basing cocaine resulting in severe reactive airways disease and tracheal stenosis requiring reconstructive surgery.

Effects of intravenous amphotericin B infusion on hemodynamics and airway mechanics in awake sheep.

To gain a better understanding of the adverse pulmonary response to amphotericin B administration reported in humans, we examined the effects of this agent in the chronically instrumented awake sheep. We measured pulmonary artery and left atrial pressures (Ppa and Pla), lung lymph flow (Qlymph), dynamic lung compliance (Cdyn), resistance to airflow across the lung (RL), lymph thromboxane B2 (TxB2), lymph 6-keto-PGF1 alpha, peripheral leukocyte counts, and arterial blood gases. After at least one hour of stable baseline (BL) observation, amphotericin B (Fungizone, Squibb, 1 mg/kg) was infused intravenously over 1 h. Measurements were continued for 3 h after the start of infusion. Amphotericin caused an immediate decrease in Cdyn nadiring at 55 percent of BL and an increase in Ppa from 21 +/- 1 mm Hg at BL to 44 +/- 4 at 30 minutes. RL increased to 5.5-fold over BL by 30 minutes into infusion, and lung lymph TxB2 concentrations were increased tenfold compared with BL by the end of the 1-h infusion (p less than 0.05). In this same time interval, there were increases in Qlymph (1.5 ml/15 min at BL to 4.9 +/- 0.8), but 6-keto-PGF1 alpha concentrations did not reach maximum until 2 h after the start of infusion. There was a decrease in peripheral leukocyte count and PaO2 (80 +/- 3 mm Hg at BL to 69 +/- 4 at 1 h) that returned to BL over the remaining 2 h. The temporal relationship of the TxB2 peak with these pathophysiologic changes and previous data describing the effects of thromboxane in the sheep lung suggest that a component of these alterations is due to thromboxane release. We conclude that several pulmonary system abnormalities occur following amphotericin infusion in sheep and that these findings provide a better physiologic basis for explaining the human pulmonary response to amphotericin.

Effect of bronchodilators on lung mechanics in the acute respiratory distress syndrome (ARDS).

The acute respiratory distress syndrome (ARDS) is a disorder of diffuse lung injury secondary to a wide variety of clinical insults (eg, sepsis) and is manifested by impaired oxygenation, pulmonary edema, and decreased static and dynamic compliance. More recently, airflow resistance has been shown to be increased in humans with ARDS. We designed a prospective, randomized, placebo-controlled, crossover trial to determine the presence and reversibility of increased airflow resistance in ARDS. We studied eight mechanically ventilated patients with ARDS (criteria: PaO2 < or = 70 mm Hg with FIO2 < or = 0.4; diffuse bilateral infiltrates; and pulmonary artery wedge pressure < or = 18 mm Hg). Each was intubated with a No. 8.0 orotracheal tube. We measured dynamic compliance (Cdyn), static compliance (Cstat), airflow resistance across the lungs (RL), shunt fraction (Qs/Qt on FIO2 = 1.0), minute ventilation (VE), PaO2/PAO2, and dead space to tidal volume ratio (VD/VT). Patients were blindly assigned to receive either metaproterenol (1 mL 0.5% in 3 mL saline solution) or saline solution (4 mL) aerosolized over 15 min 6 h apart and in random order so that patients served as their own controls. Metaproterenol significantly reduced RL, peak and plateau airway pressure, and increased Cdyn. Metaproterenol tended to increase PaO2/PAO2, but had no effect on pulmonary shunt or dead space ventilation. We conclude that the increase in airflow resistance of ARDS is substantially reversed by aerosolized metaproterenol without affecting dead space. These data suggest that abnormalities of RL are at lest partially due to bronchospasm.

Comparison of the pulmonary dysfunction caused by cardiogenic and noncardiogenic pulmonary edema.

We designed a series of experiments to compare the pulmonary dysfunction observed in models of cardiogenic and noncardiogenic pulmonary edema in chronically instrumented awake sheep. Cardiogenic pulmonary edema was induced by inflating the balloon of a Foley catheter surgically positioned in the mitral valve orifice causing increased left atrial pressure (increases PLA). Noncardiogenic pulmonary edema was induced by intravenous infusion of Perilla ketone (PK). Calculated microvascular pressure remained constant during PK infusion but increased from 9.4 +/- 0.7 to 42.8 +/- 2.4 cm H2O during increases PLA. Comparable increases in lung lymph flow (QL) were observed in the two protocols (five to seven times baseline). Pulmonary edema as quantified by chest radiograph scores increased from 0 (normal) to 2.9 +/- 0.5 and 3.4 +/- 0.1 in the PK and increases PLA groups, respectively. Room air alveolar to arterial oxygen pressure difference (P[A-a]O2) increased from 24 +/- 3 to 46 +/- 7 mm Hg in the PK group and from 23 +/- 4 to 56 +/- 6 mm Hg in the increases PLA group. Dynamic compliance of the lungs (Cdyn) expressed as the percentage of the baseline value decreased to 53 +/- 7 and 50 +/- 7% in the PK and increases PLA groups, respectively. Resistance to airflow across the lungs (RL) increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 cm H2O.L-1.sec-1 in the PK group and from 1.4 +/- 0.3 to 4.2 +/- 1.1 in the increases PLA group. Significant correlations were observed between changes in the severity of pulmonary edema observed on chest radiographs, Cdyn, delta P(A-a)O2, and QL in both the increases PLA groups. We conclude that similar degrees of pulmonary edema, regardless of the mechanism, are associated with similar changes in QL, Cdyn, and delta P(A-a)O2. Hydrostatic pulmonary edema appeared to cause greater changes in RL than that resulting from increased microvascular permeability.

A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome.

A simple multiple system organ failure (MSOF) score may predict mortality of patients who have sepsis syndrome. Using an MSOF scoring system, we prospectively determined the presence or absence of respiratory, cardiovascular, renal, hepatic, gastrointestinal, hematologic, and neurologic organ failure on day 1 of sepsis syndrome in 154 consecutive patients who had sepsis syndrome in the ICU of a tertiary care, teaching hospital. We used 30-day hospital mortality as the primary outcome variable. Overall 30-day mortality was 34 percent. There was a strong linear association between number of organ system failures and 30-day mortality (p < 0.0001). Mortality was 20 percent in patients who had less than 3 organ system failures (n = 111) and 70 percent in patients who had 3 or more organ system failures (n = 43). Survival was assessed using the Cox proportional hazards model and was found to be significantly different (p < 0.01) between the two groups defined by the aforementioned dichotomy after adjustment for age and sex using time to death as the primary outcome. The increase in relative risk of death associated with 3 or more organ system failures was 2.77 (95 percent confidence interval, 2.74 to 2.83). Using logistic regression, the adjusted odds ratios (OR) for covariates most predictive of mortality were hematologic (OR = 6.2), neurologic (OR = 4.4), hepatic (OR = 3.4), cardiovascular (OR = 2.6), and age (1.05 per year). The logistic model using the seven organ system failures and age as covariates accurately predicted outcome 75 percent of the time with a sensitivity of 51 percent and specificity of 87 percent. In conclusion, a simple scoring system tabulating the number of organ system failures present on day 1 of sepsis syndrome predicts the mortality of patients who have sepsis syndrome with reasonable accuracy.

Low levels of protein C are associated with poor outcome in severe sepsis.

STUDY OBJECTIVE: To investigate whether protein C levels predict 30-day mortality rate, shock status, duration of ICU stay, and ventilator dependence in patients with sepsis. DESIGN: Retrospective analysis of a subset of a previously published, prospective, randomized, double-blind, placebo-controlled trial ("Effects of Ibuprofen on the Physiology and Survival of Patients With Sepsis" [ISS]). SETTING: A multicenter study performed in the United States and Canada (seven sites). PATIENTS: Seventy hospitalized patients with acute severe sepsis and failure in one or more organs at entry into the ISS trial. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained from all patients at baseline and at 20, 44, 72, and 120 h after the initiation of study drug (ibuprofen or placebo) infusion. Data obtained at these times included platelet count, prothrombin time, and partial thromboplastin time. The results described in this article are based on a subset of the total ISS population for whom additional coagulation assays were performed on the blood samples obtained at baseline and 44 h. These assays included protein C antigen, D-dimer, and fibrinogen levels. A total of 63 of the 70 patients (90%) studied in this report had acquired protein C deficiency at entry to the ISS trial (baseline). The presence and severity of acquired protein C deficiency were associated with poor clinical outcome, including lower survival rate, higher incidence of shock, and fewer ICU-free and ventilator-free days. CONCLUSIONS: Acquired protein C deficiency may be useful in predicting clinical outcome in patients with sepsis. Clinical studies are warranted to determine whether the replacement of protein C in sepsis patients may improve outcome.

A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group.

OBJECTIVE: To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine; Clintec Technologies Inc; Chicago [OTZ]) on these levels and on common physiologic abnormalities, and organ dysfunction associated with ARDS. DESIGN: Randomized, double-blind, placebo-controlled, prospective clinical trial. SETTING: ICUs in five clinical centers in the United States and Canada. PATIENTS: Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation. INTERVENTION: Standard care for ARDS and I.V. infusion, every 8 h for 10 days, of one of the following: NAC (70 mg/kg, n=14), OTZ (63 mg/kg, n=17), or placebo (n=15). MAIN RESULTS: Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period (47% and 49% increases from baseline values for NAC and OTZ, respectively). There was no difference in mortality among groups (placebo, 40%; NAC, 36%; OTZ, 35%). However, the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups (NAC/OTZ [+]14%; placebo [-]6%). CONCLUSIONS: Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this.

Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

The American-European Consensus Conference on ARDS, part 2. Ventilatory, pharmacologic, supportive therapy, study design strategies and issues related to recovery and remodeling.

The acute respiratory distress syndrome (ARDS) continues as a contributor to the morbidity and mortality of patients in intensive care units throughout the world, imparting tremendous human and financial costs. During the last ten years there has been a decline in ARDS mortality without a clear explanation. The American-European Consensus Committee on ARDS was formed to re-evaluate the standards for the ICU care of patients with acute lung injury (ALI), with regard to ventilatory strategies, the more promising pharmacologic agents, and the definition and quantification of pathological features of ALI that require resolution. It was felt that the definition of strategies for the clinical design and coordination of studies between centers and continents was becoming increasingly important to facilitate the study of various new therapies for ARDS.

Effects of nitroprusside on lung mechanics and hemodynamics after endotoxemia in awake sheep.

We examined the effects of intravenous sodium nitroprusside (NP) infusion on pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), and alveolar-arterial O2 pressure gradient (PAO2-PaO2) (room air) after endotoxemia in awake sheep. NP infused 2.5 h after endotoxin administration immediately reduced mean Ppa from 30 +/- 3 to 17 +/- 3 (SE) cmH2O, PVR from 6.3 +/- 0.7 to 4.8 +/- 0.5 cmH2O.l-1.min, and RL from 340 +/- 48 of base line to 205 +/- 73% and increased Cdyn from 54 +/- 5 of base line to 80 +/- 14% without affecting PAO2--PaO2. Ppa and lung mechanics returned immediately to preinfusion levels when NP was stopped. In vitro experiments with NP showed a dose-dependent relaxation of preconstricted pulmonary artery and vein, carbachol-preconstricted sheep tracheal strips, and bronchial rings. We conclude that NP reverses pulmonary hypertension and lung mechanics abnormalities after endotoxin and that this is due to effects of NP on airway and vascular smooth muscle. The return of these abnormalities after NP cessation suggests the continued presence of vascular and airway-constricting factors late after endotoxin. The lack of effect of NP on blood oxygenation suggests that deleterious effects on hypoxic vasoconstriction are offset by improved lung mechanics.

Pharmacotherapy of sepsis.

During the past few years, many promising new agents for the treatment of sepsis have been studied to varying degrees in vitro as well as in vivo in animals and humans. Although there is a relative plethora of animal data, full-scale clinical trials of size sufficient to yield clear answers are rare. Many of the agents appear to hold promise based on preliminary data in animals or from small human studies, and some are undergoing multicenter clinical investigation. At present, however, none of the agents discussed clearly has shown survival benefit when administered to patients with sepsis. Certainly, none can be recommended as standard therapy, and others such as glucocorticoids should be avoided. Nevertheless, the pharmacotherapy of sepsis remains an area of intense research, and ongoing clinical trials as well as continuing basic research into the pathophysiologic mechanisms of sepsis yet may yield a well-studied drug that offers survival benefit to patients with sepsis.

Acute respiratory distress syndrome. Potential pharmacologic interventions.

Remarkable progress has been made in the past 10 years with regard to understanding the interplay of potent physiologic mediators in patients with acute lung injury. Because there are so many mediators and the interaction of these agents is complex, true insight into the process has been slow in coming. Clinical studies in ARDS, as well as sepsis, the leading cause of ARDS, have increased in number, size, and quality over this same period. Although none of these studies has produced an accepted new therapy for ARDS, each has laid the groundwork for more efficient and more elegant studies of the problem. The stage is now set for the real advances to be brought forward and put to rigorous, efficient clinical testing.

Septicemia and lung injury.

The results of investigations undertaken by the authors which deal with the functional and structural changes in the lungs resulting from gram-negative bacterial endotoxemia and the mechanisms of these changes are analyzed. The authors emphasize the major roles played by granulocytes and metabolites of arachidonic acid in mediating endotoxin-induced lung injury.