In summary, the invasion of bacteria across mucosal surfaces is met with a vigorous host response that includes complement, antibody formation (thymus-independent and eventually thymus-dependent), phagocytosis, production of antibacterial peptides and proteins, the production of cytokines that result in activation of phagocytes and endothelial cells to attract more phagocytes, and the formation of fibrin to limit the spread of infection. The best summary of immune response to infection was written by Lewis Thomas in 1974.

Reduction in cardiovascular events with 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (HMG-CoA RIs) has been attributed to their anti-inflammatory properties,1 and these agents lower a non-specific inflammatory marker, C-reactive protein.2 Macrophages and T lymphocytes interact with endothelial cells and release cytokines which regulate vascular tone, plaque stability, and thrombogenesis. We investigated whether pravastatin modified production of pro-inflammatory cytokines.

An unusual case of a self-inflicted intracardiac injury with a sewing needle caused a pneumothorax. Fewer than ten cases of needles in the heart have been reported in the recent medical literature; none of these cases was associated with presence of a pneumothorax. The literature regarding self-inflicted injury with needles in the heart is reviewed.

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.

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.

Background and MethodsTumor necrosis factor (TNF) has been implicated as a major humoral mediator of sepsis and endotoxin shock. TNF is secreted by cells of the reticuloendothelial system, including alveolar macrophages. Alveolar macrophage TNF production has been postulated to play a pathogenetic role in the development of adult respiratory distress syndrome (ARDS) in sepsis. To evaluate alveolar macrophage production of TNF during sepsis and endotoxin shock, we studied the effects of sepsis and/or in vivo lipopolysac-charide on the in vitro production of TNF by pulmonary alveolar macrophages. Human pulmonary alveolar macrophages were obtained by bronchoalveolar lavage from six septic and five nonseptic patients, cultured in the presence or absence of lipopolysaccharide (1 ng/mL), and assayed for TNF activity in a bioassay using fibroblast lysis. A murine model of sepsis was also utilized to study pulmonary alveolar macrophage TNF production under more controlled conditions. Normal mice were given ip injections of either lipopolysaccharide or saline. After 2 hrs, pulmonary alveolar macrophages were obtained and cultured in saline or various concentrations of lipopolysaccharide (0.001 to 10 μg/mL). ResultsThere was no difference in baseline TNF activity, expressed as per cent lysis at 1:10 dilution, between pulmonary alveolar macrophages from control and septic patients (35.7 ± 5.5% vs. 24.4 ± 9.3%, respectively) (p > .05). However, when stimulated with lipopolysaccharide in vitro, the pulmonary alveolar macrophages from nonseptic patients produced significantly (p < .01) more TNF (82.8 ± 3.6%) than did pulmonary alveolar macrophages from patients with the septic syndrome (35.2 ± 3.8%). Similar findings were obtained using the murine sepsis model. The baseline TNF activity in pulmonary alveolar macrophages from control mice was 22.9 ± 7.0% (mean ± SEM) and from lipopolysaccharide-injected mice was 26.8 ± 3.3% (p > .05). Stimulation with 1 ng/mL lipopolysaccharide in vitro produced an increase in TNF activity in both groups, but the increase was greater in the control mice (68.1 ± 5.7%) than in the lipopolysaccharide-injected mice (47.5 ± 5.3%) (p < .01). When the murine pulmonary alveolar macrophages were stimulated with higher concentrations of lipopolysaccharide (0.1 to 10 ug/mL), pulmonary alveolar macrophages from lipopolysaccharide-injected mice produced <25.5% of the TNF produced by pulmonary alveolar macrophages from control mice. ConclusionsThese studies indicate that sepsis and endotoxin injection result in a rapid decrease in the ability of pulmonary alveolar macrophages from both humans and mice to produce and secrete TNF in response to lipopolysaccharide. We speculate that a downregulation of TNF production or of macrophage responsiveness to lipopolysaccharide has occurred. These results suggest that sustained TNF production by macrophages is not required for lung injury in sepsis.

TNF is a small protein secreted by activated monocytes and macrophages that mediates the in vivo effects of endotoxin. When injected into experimental animals, TNF reproduces the picture of septic or endotoxin shock. In addition, antibodies to TNF protect animals against the deleterious effects of IV injections of either LPS or live bacteria. Specifically, the available evidence suggests that TNF may be necessary for the organ injury and failure seen in sepsis. However, TNF probably is not the final common pathway to shock and tissue injury. Inhibition of cyclooxygenase is protective from the lethal effects of both LPS and TNF infusion, suggesting that prostanoids play an important, and perhaps more proximal role in the generation of tissue injury. In addition, TNF is produced and cleared from the blood-stream within a short period of time after an LPS stimulus, suggesting that TNF sets into motion a chain of events that may be self-perpetuating even in the absence of further TNF stimulus. In the near future, the treatment of sepsis may involve the administration of antibodies both to TNF and to LPS. Cyclooxygenase inhibitors should also begin to play a role in the therapy of sepsis. In the more distant future it is likely that we will be able to manipulate the state of activation of genes that code for TNF to exert some control over its production and secretion. It is perhaps within our grasp to finally reduce the morbidity and mortality of this lethal condition.

The anaphylatoxins have been implicated in the pathogenesis of endotoxin shock and the adult respiratory distress syndrome. Both endotoxin and zymosan activate the complement pathway. Because there are marked species differences in the cardiovascular and hematologic effects of endotoxin infusion, the purpose of this study was to compare the effects of zymosan-activated plasma (ZAP) infusion in dogs, sheep, and baboons. ZAP was infused (0.11 ml/kg/min for 60 min) into dogs (n = 5), baboons (n = 5), and sheep (n = 3). The infusion of ZAP resulted in significant changes in heart rate (HR) (P less than 0.03), mean arterial pressure (MAP) (P less than 0.002), pulmonary artery pressure (PAP) (P less than 0.004), cardiac index (CI) (P less than 0.034), and extra vascular lung water (EVLW) (P less than 0.001). A specific difference between the species' response to ZAP infusion was present when evaluating the effect of ZAP on MAP (P less than 0.02), HR (P less than 0.003). EVLW (P less than 0.001), platelet count (P less than 0.01), and white blood cell count (P less than 0.01). The main species differences in the changes in MAP, HR, and platelet count were an increase in MAP, decrease in HR, and decrease in platelet count that occurred in dogs. The species difference in the WBC count was the result of ZAP-induced neutropenia in sheep versus a leukocytosis in dogs. Unlike dogs and baboons, sheep developed an increase in EVLW. Like endotoxin, the cardiovascular and hematologic effects of ZAP infusion are species dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

1.1. The archidonic acid prostaglandin system participates in shock-like states.2.2. Indomethacin improves the survival by inhibition of the prostaglandin system and by attenuating the circulatory dysfunction.3.3. Lidocaine improves the survival in endotoxin shock, but the exact mechanism is unclear.4.4. Lidocaine increases prostacyclin levels in subhuman primates during endotoxin shock and in normal rats.5.5. Lidocaine may exert its beneficial effects in shock-like states by altering arachidonate metabolism.