Quantification of organ dysfunction: seeking standardization.
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Critical Care↗
Biomedical subjects
G R Bernard
Publications and source records attributed to G R Bernard.
The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome.
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 10 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 pathologic 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.
Europe↗
Impact of a critical care pathway for unstable mechanically ventilated patients.
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Critical Care↗
The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.
BACKGROUND: In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS: From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS: In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS: In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.
Acidosis, Lactic↗
Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group.
OBJECTIVE: To test the effect of a novel bradykinin antagonist, deltibant (CP-0127), on survival, organ dysfunction, and other outcomes in patients with the systemic inflammatory response syndrome (SIRS) and presumed sepsis. DESIGN: Multicenter, randomized, placebo-controlled, double-blind, parallel, dose-ranging trial. Follow-up for 28 days or until death. SETTING: A total of 47 US referral hospitals. PATIENTS: A total of 504 patients with SIRS and documented evidence of infection plus either hypotension or dysfunction of 2 organ systems. INTERVENTIONS: Three-day continuous intravenous infusion of either placebo or 1 of 3 doses (0.3, 1.0, or 3.0 microg x kg(-1) x min(-1)) of deltibant. Concurrent therapy at the discretion of the treating physician. MAIN OUTCOME MEASURE: Risk-adjusted, 28-day, log-normal intent-to-treat survival analysis. Risk adjustment was performed using a study-specific risk model derived from the APACHE III database. RESULTS: Deltibant had no significant effect on risk-adjusted 28-day survival. In a posthoc analysis, risk-adjusted 7-day survival showed a nonsignificant trend toward improvement (P=.09). The 28-day risk-adjusted survival in the prospectively defined subset of patients with gram-negative infections showed a statistically significant improvement (P=.005). CONCLUSIONS: Deltibant may have some effect on survival in patients with SIRS and gram-negative sepsis; however, additional studies would be required to prove this.
APACHE↗
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.
Acetylcysteine↗
Right heart catheterization in acute respiratory failure.
OBJECTIVE: To review the literature addressing the use of the pulmonary artery catheter (PAC) in patients with respiratory failure. DATA SOURCE: All pertinent English language articles dealing with pulmonary artery catheterization in patients with respiratory failure were retrieved from 1983 through 1996. STUDY SELECTION: Articles were chosen for review if the use of pulmonary artery catheterization in patients with respiratory failure was studied or reviewed. DATA EXTRACTION: From the articles selected, information was obtained about changes in therapy and changes in outcome associated with PAC use in patients with respiratory failure. DATA SYNTHESIS: Evidence exists to suggest that use of the PAC in patients with respiratory failure often results in a change in diagnosis and therapy. Inadequate evidence exists to accurately determine benefit or harm from PAC use in patients with respiratory failure. CONCLUSION: The optimal role of the PAC as a diagnostic and monitoring device in different types of respiratory failure has not been clearly defined. Research is needed to determine the role of the PAC in very carefully defined groups of patients with respiratory failure.
Acute Disease↗
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.
Acetylcysteine↗
Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.
In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.
Adult↗
Applications of molecular biology and biotechnology: antibody therapy of sepsis.
The use of antibody therapy for the treatment of infections and inflammatory disease is well established. Unfortunately, clinical studies of antiendotoxin and anti-TNF monoclonal antibodies have failed to show clear physiological or survival benefit. Little information is available regarding the effect of antibodies to cytokines other than TNF in human sepsis. Limited pre-clinical data indicate that IL-6 antibodies may abrogate the effects of endotoxin infusion, but no human studies have been performed. Although both monoclonal and polyclonal antibodies have the potential to protect septic humans, at this time it is the polyclonal antibodies that have shown the greatest promise. Each type of antibody possesses specific advantages and limitations, the ultimate effectiveness of which will need to be proven in large randomized clinical trials.
Animals↗
Escherichia coli endotoxin-mediated endothelial injury is modulated by glutathione ethyl ester.
The mechanisms involved in endotoxin-induced endothelial injury are not fully understood. Oxidant stress is thought to play a role in cell damage after endotoxin exposure. Glutathione may ameliorate these affects. Glutathione ethyl ester (GSE) was used in bovine pulmonary artery endothelial cell (BPAEC) cultures to determine the potential for attenuation of endotoxin-induced injury. GSE (0.05-25 mM) was preincubated with BPAEC for 4 h before endotoxin exposure. Fresh media containing GSE and Escherichia coli endotoxin (0.05 microgram/mL) were then placed on the BPAEC and incubated for 18 h. GSE, at doses of 5 and 25 mM, attenuated endotoxin-induced injury, as reflected by a significant reduction in lactate dehydrogenase release. This was paralleled by a significant increase in endotoxin-stimulated prostaglandin E2 and prostacyclin release. Thus, GSE attenuates endotoxin-induced injury of BPAEC in culture and alters BPAEC prostaglandin metabolism.
Animals↗
Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.
OBJECTIVE: To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness. DESIGN: Systematic literature review; prospective cohort study. SETTING: Surgical intensive care unit (ICU) of a tertiary-level teaching hospital. PATIENTS: All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of < 5%, whereas a value of 4 represented marked functional derangement and an ICU mortality rate of > or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices. CONCLUSIONS: This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)
Humans↗
Sepsis trials. Intersection of investigation, regulation, funding, and practice.
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Clinical Trials as Topic↗
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.
Animals↗
Pivot/Remote: a distributed database for remote data entry in multi-center clinical trials.
1. INTRODUCTION. Data collection is a critical component of multi-center clinical trials. Clinical trials conducted in intensive care units (ICU) are even more difficult because the acute nature of illnesses in ICU settings requires that masses of data be collected in a short time. More than a thousand data points are routinely collected for each study patient. The majority of clinical trials are still "paper-based," even if a remote data entry (RDE) system is utilized. The typical RDE system consists of a computer housed in the CC office and connected by modem to a centralized data coordinating center (DCC). Study data must first be recorded on a paper case report form (CRF), transcribed into the RDE system, and transmitted to the DCC. This approach requires additional monitoring since both the paper CRF and study database must be verified. The paper-based RDE system cannot take full advantage of automatic data checking routines. Much of the effort (and expense) of a clinical trial is ensuring that study data matches the original patient data. 2. METHODS. We have developed an RDE system, Pivot/Remote, that eliminates the need for paper-based CRFs. It creates an innovative, distributed database. The database resides partially at the study clinical centers (CC) and at the DCC. Pivot/Remote is descended from technology introduced with Pivot [1]. Study data is collected at the bedside with laptop computers. A graphical user interface (GUI) allows the display of electronic CRFs that closely mimic the normal paper-based forms. Data entry time is the same as for paper CRFs. Pull-down menus, displaying the possible responses, simplify the process of entering data. Edit checks are performed on most data items. For example, entered dates must conform to some temporal logic imposed by the study. Data must conform to some acceptable range of values. Calculations, such as computing the subject's age or the APACHE II score, are automatically made as the data is entered. Data that is collected serially (BP, HR, etc.) can be displayed graphically in a trend form along with other related variables. An audit trail is created that automatically tracks all changes to the original data, making it possible to reconstruct the CRF to any point in time. On-line help provides information on the study protocol as well as assistance with the use of the system. Electronic security makes it possible to lock certain parts of the CRF once it has been monitored. Completed CRFs are transmitted to the DCC via electronic mail where it is reviewed and merged into the study database. Questions about subject data are transmitted back to the CC via electronic mail. This approach to maintaining the study database is unique in that the study data files are distributed among the CC and DCC. Until a subject's CRF is monitored (verified against the original patient data residing in the hospital record), it logically resides at the CC where it was collected. Copies are transmitted to the DCC and are only read there. Any pre-monitoring changes must be made to the data at the CC. Once the subject's CRF is monitored, it logically moves to the DCC, and any subsequent changes are made at the DCC with copies of the CRF flowing back to the CC. 3. DISCUSSION. Pivot/Remote eliminates the need for paper forms by utilizing portable computers that can be used at the patient bedside. A GUI makes it possible to quickly enter data. Because the user gets instant feedback on possible error conditions, time is saved because the original data is close at hand. The ability to display trended data or variables in the context of other data allows detection of erroneous conditions beyond simple range checks. The logical construction of the database minimizes the problem of managing dual databases (at the CC and DCC) and keeps CC personnel in the loop until all changes are made.
Computer Communication Networks↗
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.
Clinical Protocols↗
Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee.
The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity rate, mortality rate (10% to 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 who wish to know the true incidence and outcome of 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 to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.
Clinical Trials as Topic↗
Significance of glutathione in lung disease and implications for therapy.
Glutathione is a tripeptide that contains an important thiol (sulfhydryl) group within the central cysteine amino acid. Glutathione is involved in numerous vital processes where the reducing potential of the thiol is used. Several lung disorders are believed to be characterized by an increase in alveolar oxidant burden, potentially depleting alveolar and lung glutathione. Low glutathione has been linked to abnormalities in the lung surfactant system and the interaction between glutathione and antiproteases in the epithelial lining fluid of patients. Normal levels of intracellular glutathione may exert a critical negative control on the elaboration of proinflammatory cytokines. The increase of intracellular reactive oxygen species is believed to correlate with the activation of NF-kappa B, a transcription activator linked to the elaboration of several cytokines. There is now sufficient data to strongly implicate free radical injury in the genesis and maintenance of several lung disorders in humans. This information is substantial and will help the development of clinical studies examining a variety of inflammatory lung disorders.
Acetylcysteine↗