Staphylococcus aureus is an important oral bacterium that enters the bloodstream following dental procedures, causing bacteremia. Infectious endocarditis occurs due to the invasion of blood-borne pathogens into the endocardium. S. aureus is the most frequently isolated bacterium in Gram-positive sepsis, and shock and coagulation disorders are common and potentially fatal consequences of sepsis. Staphopains are the most abundant proteases among extracellular proteolytic enzymes produced by staphylococci, and their virulence activities related to the pathophysiology of S. aureus bacteremia have been elucidated.Staphopain A (ScpA)—not staphopain B (SspB)—releases bradykinin, and the two staphopains synergistically release a novel kinin, Leu-Met-Lys-bradykinin, directly from human plasma kininogens. These kinins cause vascular leakage. ScpA, similar to the two kinins, lowers blood pressure in guinea pigs in a bradykinin B2-receptor-dependent manner when administered intra-arterially, and produces septic shock symptoms in them. Kinin generation from human plasma by ScpA is enhanced in the presence of SspB, strongly suggesting a shock induction by the bacterial proteases. Staphopains, SspB being threefold more potent than ScpA, truncate fibrinogen by preferentially cleaving this coagulation factor at the C-terminal region of the Aα chain, which results in loss of fibrinogen clottability, thereby causing bleeding tendency. Staphopains showed a degradation activity for type I collagen similar to that observed in ScpA-mediated skin destruction, indicating that they participate in S. aureus-induced endocardium destruction.Staphopains are potent virulence factors and are potentially involved in the onset of septic shock, coagulation disorders, and infectious endocarditis that occurs in S. aureus bacteremia.

Dellinger, R. Phillip MD, FCCM; Bone, Roger C. MD, FCCM, PhD (Honorary) Author Information

Diagnosis of nosocomial sinusitis in critically ill patients.-New developments in understanding pathogenesis of sepsis.-Noninvasive ventilation is safe and effective means of support.

Pulmonary radiographs are essential adjuncts to the evaluation and diagnosis of suspected pulmonary disease. In the intensive care unit, radiographs are useful to confirm correct positioning of diagnostic and therapeutic devices. Patterns seen on the radiograph may be within broadly normal limits or may be interpreted as abnormal, especially when placed in the clinical context of a specific patient's problem. The description abnormal can be related to both nonspecific and specific radiographic patterns of disease. Nonspecific radiographic patterns of disease include location of disease, temporal course of disease, pleural abnormalities, hyperinflation, extra-alveolar air, atelectasis, bronchiectasis, and vascular disease. Specific radiographic patterns of disease are discrete anatomic structures seen on a radiograph, for example, cavitary and cystic disease. The interpretation of nonspecific and specific radiographic patterns is useful in diagnosis, selection of treatment, and monitoring of the course of disease and the patient's response to treatment.

compensatory anti-inflammatory response syndrome

Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest. Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory antiinflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.

Objective: To devise alternatives to randomized, controlled, clinical trials that clinicians and research experts might find acceptable for approval of devices used in critical care medicine.Data Sources: The Coalition for Critical Care Excellence (Coalition) of the Society of Critical Care Medicine organized a consensus conference in which recognized critical care researchers gave testimony to a panel of experts regarding the process for testing and approval of monitoring devices.Data Selection: The expert panel used testimony from the presenters as the basis of discussions on the testing and approval process. Guiding principles and specific recommendations were made based on the testimony given.Main Results: The panel determined the main constituents of the medical device approval process to be the Food and Drug Administration (FDA), the research and clinical community, and the device manufacturers. Distinctions were made between monitoring and interventional device categories, This document addresses only monitoring devices, Potential alternatives to randomized, blinded, controlled study designs for device testing are: a) nonblinded, randomized, management protocol-driven study; b) crossover study (n-of-one design); c) cluster-randomization (randomized by care unit); d) case-matched controls; e) mixed design; f) on/off design (before-after); and g) historical controls.Conclusions: The panel agreed on the following major recommendations: a) the FDA should accelerate publication of specific guidances for physiologic monitoring products with the assistance of the Coalition (priorities and content); b) more multidisciplinary research should be incorporated into new device studies; c) commonly accepted clinical tools may not need to be tested for clinical utility-these accepted tools should be identified by the Coalition; and d) an independent council of researchers and clinicians should make themselves available to serve as consultants to manufacturers regarding appropriate study design for the testing of devices.

OBJECTIVE:To determine the efficacy of a new respiratory monitor, which uses esophageal balloons, in aiding clinicians attempting to wean patients from mechanical ventilation.DESIGN:Prospective study of patients who were deemed ready to be weaned after having required mechanical ventilation for a minimum of 3 days. Each of the patients served as his or her own control.SETTING:University medical intensive care unit.PATIENTS:The series consisted of 23 consecutive patients who were ready to wean from mechanical ventilation.INTERVENTIONS:Before the onset of the study, two weaning strategies were developed. One strategy involved using clinically available weaning parameters. The other strategy involved using esophageal balloon data that was recorded via a new respiratory monitor. Each of the weaning strategies resulted in the development of a scoring system that could be rigidly adhered to and which determined, without bias, to what extent the patient could be weaned each day. Rigid criteria were also developed to determine whether the weaning trial was successful or not. The two strategies were then compared to determine the ability of the strategy to shorten ventilatory time.MEASUREMENTS AND MAIN RESULTS:Each patient was evaluated daily by the two weaning protocols. At each weaning step, the two protocols were compared with respect to degree of aggressiveness and tolerance of the weaning maneuver by the patient. A protocol was judged superior if it resulted in more aggressive weaning without increased patient intolerance. The clinicians evaluating the patient with the clinical protocol could accelerate or retard the number of weaning steps by one step, based on the patient's clinical state and the clinician's experience. There was no such freedom in the esophageal protocol. The major finding was that in 40.5% of the instances, the protocol involving the esophageal balloon resulted in more aggressive weaning without patient intolerance. In 11.6% of the cases, the clinical protocol was more aggressive. Both protocols predicted the same number of weaning steps 39.8% of the time. In all these instances, the patient tolerated the weaning suggested. The use of data from the esophageal protocol resulted in weaning the patients 1.68 days faster than the use of data from the clinical protocol.CONCLUSIONS:The respiratory monitor, using esophageal balloon technology, is effective in that it can provide the clinician with data that can result in more aggressive weaning from mechanical ventilation without an increase in patient intolerance. The duration of mechanical ventilation can be shortened when these data are applied via a rigidly controlled weaning strategy.

Several stains have emanated from the classic work of Hanker et al. which provide highly visable and electron opaque end products. These allow back-scattered electron imaging (BEI) and visualization of polymerized 3, 3'-diaminobenzidine (DAB) or p-phenylenediamine/pyrocatechol (PPD/PC) on endogenous enzyme or nonenzyme hemoproteins, or visualization of exogenous horseradish peroxidase (HRP) transported in tissue or attached to cells, or immunoperoxidase localized to tissue antigen or receptor sites. Additionally, the Giammara-Hanker PATS reaction (Pat.Appl. No. 08/225,058), originally used to show biomacromolecules or structures such as glycogen, basement membranes, reticular fibers or lipopolysaccharide, appears to be a positive stain for Gram (-) bacteria, including spirochetes, as well as for neutrophils and activated macrophages. The PATS reaction also demonstrates sites of calcification in tissues and certain calcium compounds by both light and electron microscopy. Likewise, an improved FETS reaction uses silver as an electron opaque Feulgen-type reaction for DNA and demonstrates DNA in bacteria and Candida albicans as well as other cellular nuclei.

Objective.-To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhlL-1ra) in the treatment of sepsis syndrome.Study Design.-Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial.Population.-A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo.Outcome Measure.-Twenty-eight-day all-cause mortality.Results.-There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n=893; generalized Wilcoxon statistic, P=.22) or among patients with shock at study entry (n=713; generalized Wilcoxon statistic, P=.23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n=563; linear dose-response, P=.009). Retrospective analysis demonstrated an increase In survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n=580; linear dose-response, P=.005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n=411; linear dose-response, P=.002).Conclusions.-There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

OBJECTIVES:To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome. DESIGN:Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra. SETTING:Twelve academic medical center intensive care units in the United States. PATIENTS:Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo. INTERVENTIONS:Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. MEASUREMENTS AND MAIN RESULTS:A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated. CONCLUSIONS:This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.

OBJECTIVE:To determine whether plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and lipopolysaccharide are detectable in patients when they first present with the sepsis syndrome and to determine whether levels correlate with patient survival.DESIGN:Prospective study comparing patients with the sepsis syndrome, critically ill patients without sepsis, and normal healthy volunteers.SETTING:Tertiary care hospital affiliated with a medical school.PATIENTS:The study included 97 consecutive patients on a medical service who met the criteria for the sepsis syndrome; 20 critically ill patients without sepsis who were in the medical intensive care unit; and 20 healthy volunteers who served as comparison groups.MEASUREMENTS:Plasma tumor necrosis factor-alpha, IL-1 beta, interleukin-6, and endotoxin (lipopolysaccharide) levels were measured when a patient was first identified as having the sepsis syndrome. Survival was defined as being alive 30 days after the sepsis syndrome was diagnosed.RESULTS:Fifty-four percent of patients with the sepsis syndrome had detectable levels of TNF-alpha (median, 26 pg/mL; range, nondetectable to 1000 pg/mL); 37% had detectable levels of IL-1 (median, 20 pg/mL; range, nondetectable to 2850 pg/mL); 80% had detectable levels of IL-6 (median, 415 pg/mL; range, nondetectable to 2380 pg/mL); and 89% had detectable levels of lipopolysaccharide (median, 2.6; range, nondetectable to 12.5 endotoxin units [EU]/mL). In all cases levels were higher than those in critically ill patients without sepsis and normal healthy controls (P < 0.001 for all comparisons). Plasma levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were detectable in patients regardless of culture status. The IL-6 level was 69% (95% CI, 30% to 108%) higher in patients who died compared with those who survived. The scores for the individual levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were summed to arrive at a total lipopolysaccharide-cytokine score, and mortality increased with lipopolysaccharide-cytokine score (P < 0.001).CONCLUSIONS:Patients with the sepsis syndrome have detectable levels of circulating TNF-alpha, IL-1, IL-6, and lipopolysaccharide independent of culture-documented infection. Lipopolysaccharide and cytokines may play a pathogenic role in sepsis, and the combination of several elevated factors may be important in determining patient survival.

PULMONARY embolism cannot be diagnosed on clinical grounds; it can only be suspected. In addition, pulmonary embolism often develops in patients who have other conditions that could explain some or all of the symptoms. For example, viral pneumonia may produce symptoms remarkably similar to those of pulmonary embolism. Additional testing is therefore needed to identify those patients who actually do have embolic disease. Angiography is the gold standard for diagnosis, but this invasive test is associated with risk factors of its own. Thus, the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) investigators wisely sought a less invasive method to determine which patients could be spared the risk of angiography. Specifically, they studied the current role of ventilation/perfusion (Ve/Pe) scanning in the diagnosis of pulmonary embolic disease. When these investigators issued their report, they stressed that for the best results, Ve/Pe scan findings should be combined with an assessment of the

In the 26 years since Ashbaugh et al.1 first described the adult respiratory distress syndrome (ARDS), we have progressed considerably in our understanding of the pathogenesis of this disorder. Unfortunately, we have made much less progress in our ability to improve its outcome. In this issue of the Journal, Rossaint et al. describe a new treatment for ARDS -- inhaled nitric oxide2. Their results may represent an important advance in therapy for ARDS.ARDS may sometimes result from direct injury to the lungs (for example, from aspiration of gastric contents, pneumonia, or inhalation of a toxic substance); it may . . .

Incapacitating respiratory distress was the presenting manifestation of a choreiform movement disorder. Because the patient also had asthma, respiratory distress was at first mistakenly attributed to this condition. Despite vigorous asthma management, there was no improvement. However, once the neurologic condition was recognized, use of specific therapy (haloperidol and reserpine) resulted in rapid and sustained remission of respiratory symptoms.

Rush-Presbyterian-St. Luke's Medical Center Chicago, IL Address requests for reprints to: Roger C. Bone, MD, Rush-Presbyterian-St. Luke's Medical Center, 1753 West Congress Parkway, Chicago, IL 60612.

OBJECTIVE:To formulate recommendations for the development of early intensive care unit (ICU) discharge criteria for low-risk monitor patients.DESIGN:Literature review of published reports over the period 1966 to 1991 pertaining to ICU discharge criteria.PATIENTS:Studies identifying patients admitted to ICUs who could be characterized as low risk. Patient populations of interest included adults (> or = 18 years of age) with low-risk medical or mixed medical/surgical conditions; cardiac care unit and burn patients were excluded.MEASUREMENTS AND MAIN RESULTS:Of 1,492 articles identified as being pertinent to ICU discharge, only 2 studies (by the same group of investigators) were found that distinguished low-risk populations among medical and mixed medical/surgical ICU patients. The physiologic component of the Acute Physiology and Chronic Health Evaluation (APACHE) was used in both of these studies to ascertain the degree of risk. No studies were found that compared outcomes of low-risk patients remaining in the ICU after 24 h with those transferred to other hospital locations.CONCLUSIONS:Objective methods (such as APACHE III) should be used to identify low-risk patients at 24 h post-ICU admission. A multicenter study should be conducted to compare outcomes on patients identified as low risk who are randomly assigned to alternative hospital locations for treatment versus those assigned to continued ICU treatment until routine ICU discharge. Mortality and quality of life data should be used as outcome measures (prior to ICU admission and 6 months post-ICU discharge).

Gram-negative sepsis is an increasingly common problem, with up to 300, 000 cases occurring each year in the United States alone. Despite the ongoing development of new antibiotics, mortality from gram-negative sepsis remains unacceptably high. To stimulate earlier therapeutic intervention by physicians, a new set of broad definitions has been proposed to define the systemic inflammatory response characteristic of sepsis. In this review, the signs and symptoms of this progressive, injurious process are reviewed and its management is discussed, as are the mechanisms by which bacterial endotoxin triggers the biochemical events that lead to such serious complications as shock, adult respiratory distress syndrome, and disseminated intravascular coagulation. These events often occur even when appropriate antimicrobial therapy has been instituted. An increased understanding of the structure of endotoxin and its role in the development of sepsis, together with advances in hybridoma technology, has led to the development of monoclonal antibodies that bind to endotoxin and significantly attenuate its adverse effects. These agents promise to substantially reduce the morbidity and mortality associated with gram-negative sepsis.