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Biomedical subjects

L C Casey

Publications and source records attributed to L C Casey.

At least 19 recordsLinked to original sources
PubMed2000

Immunologic response to infection and its role in septic shock.

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.

Animals↗
PubMed1995

Medical effectiveness of esophageal balloon pressure manometry in weaning patients from mechanical ventilation.

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.

Aged↗
PubMed1993

Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome.

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.

Adolescent↗
PubMed1993

Suppression of the development of tumoricidal function in gamma interferon-treated human peripheral blood monocytes by lipopolysaccharide: the role of cyclooxygenase metabolites.

Bacterial lipopolysaccharide (LPS) is generally regarded as one of the most potent macrophage activators. Thus, LPS has been used as an obligatory second signal to stimulate macrophage cytotoxic function against a wide array of bacterial and neoplastic targets. In this study, however, we define conditions under which LPS can suppress the development of cytotoxic function in normal human peripheral blood monocytes. When monocytes were treated with a priming dose of gamma interferon (gamma-INF), followed 18-24 hr later by a triggering dose of LPS, significant cytotoxic function developed. However, when monocytes were treated with even minimal amounts of LPS during priming with interferon, the development of cytotoxic function following stimulation with a second, triggering dose of LPS was virtually abolished. This effect could be produced from 0 to 14 hr following the addition of gamma-INF. The inhibition of monocyte cytotoxicity which was produced by LPS treatment during priming was dose dependent and could not be overcome by modifying either the priming dose of gamma-IFN or the triggering dose of LPS. The suppression was largely overcome, however, by treatment with the cyclooxygenase inhibitor, indomethacin. The possibility that LPS-induced suppression of monocyte cytotoxicity was mediated by products of the cyclooxygenase pathway was supported further in this study by demonstrating that LPS stimulated the production of significant amounts of prostaglandin E2 (PGE2) from monocytes and that this was facilitated by gamma-IFN. In kinetics studies, it appeared that LPS suppression of monocyte activation was correlated temporally with a heightened sensitivity to suppression by exogenously added PGE2, a condition which was reduced greatly by the end of the priming phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Death↗
PubMed1993

Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure.

The clinical presentation of patients with multiorgan failure caused by septic conditions is very similar to that seen in patients with multiorgan failure after cardiopulmonary bypass. It has been hypothesized that the same mechanisms are at work in both instances. This commonality of presentation and mechanisms is denoted by the new term systemic inflammatory response syndrome. The systemic inflammation resulting from cardiopulmonary bypass is manifested by the development of adult respiratory distress syndrome. Overall mortality for this condition is high, and the absence of a specific therapy reflects the lack of understanding of the mechanisms involved. The risk factors associated with multiorgan failure include the age of the patient, the number of failed organs, and whether these organ failures persist or resolve. The release of a variety of inflammatory mediators has been implicated in the pathogenesis of sepsis. These include the cytokines (tumor necrosis factor, interleukin-1, interleukin-6), lipid and arachidonate metabolites, platelet-activating factor, and activation of the coagulation cascade. There seems to be marked synergy between these different mediators, suggesting that a combination of small amounts of them all may be more toxic than a large release of one by itself. During cardiopulmonary bypass, increased levels of circulating endotoxin have been associated with the activation of the complement system and increased levels of tumor necrosis factor. Interleukin-6 level has been shown to be elevated during bypass. The action of the inflammatory mediators to induce injury may be related to the activation of leukocytes and endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Reduced alveolar macrophage production of tumor necrosis factor during sepsis in mice and men.

BACKGROUND AND METHODS: Tumor 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 lipopolysaccharide 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 micrograms/mL). RESULTS: There 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 greater than .05). However, when stimulated with lipopolysaccharide in vitro, the pulmonary alveolar macrophages from nonseptic patients produced significantly (p less than .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 greater than .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 less than .01). When the murine pulmonary alveolar macrophages were stimulated with higher concentrations of lipopolysaccharide (0.1 to 10 micrograms/mL), pulmonary alveolar macrophages from lipopolysaccharide-injected mice produced less than 25.5% of the TNF produced by pulmonary alveolar macrophages from control mice. CONCLUSIONS: These 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.

Adult↗
PubMed1990

The in vitro development of cytotoxicity in response to granulocyte/macrophage-colony-stimulating factor or interferon gamma in the peripheral blood monocytes of patients with solid tumors: modulation by arachidonic acid metabolic inhibitors.

The capacity of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) to elicit monocyte cytotoxicity in vitro in the peripheral blood monocytes of patients with solid tumors was investigated. The cytotoxicity elicited by IFN gamma was significantly reduced in cancer patient monocytes compared to normal monocytes. The cytotoxicity elicited by GM-CSF, however, was comparable between cancer patient monocytes and normal monocytes, but was lower than that induced by IFN gamma. Indomethacin, a cyclooxygenase inhibitor, significantly augmented IFN gamma-elicited cytotoxicity in cancer patient monocytes, but not in normal monocytes. In contrast, indomethacin augmented GM-CSF-elicited cytotoxicity in both cancer patient monocytes and normal monocytes. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was found to suppress cytotoxicity in response to IFN gamma and GM-CSF in both cancer patient monocytes and normal monocytes. The addition of leukotrienes to NDGA-treated cultures restored the development of cytotoxicity. Thus there are differences in the in vitro response of cancer patient monocytes and normal monocytes to distinct biological activators. Furthermore, these responses can be manipulated by agents that modulate arachidonic acid metabolism.

Adult↗
PubMed1989

Role of tumor necrosis factor in sepsis and acute lung injury.

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.

Animals↗
PubMed1986

Species variability in the cardiovascular and hematologic effects of zymosan-activated plasma infusion.

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)

Animals↗
PubMed1986

Rapid release and deactivation of plasminogen activators in human endothelial cell cultures in the presence of thrombin and ionophore A23187.

alpha-Thrombin, DFP-thrombin, and ionophore A23187 induce the rapid release (less than 5 minutes) of a variety of proteins, including t-PA forms (Mr 110 and 70 k, after SDS-PAGE) from primary cultures, and both t-PA and u-PA (Mr 90 and 54 k) from subcultured human HUVECs. All PA activity forms are rapidly decreased in the releasates by some unknown mechanism. gamma-Thrombin does not induce the release of PAs from cultured HUVECs.

Calcimycin↗
PubMed1986

Hemorrhagic hypotension increases plasma beta-endorphin concentrations in the nonhuman primate.

The role which beta-endorphin plays in the pathogenesis of hemorrhagic hypotension is controversial. In the present experiment, 20 ml/kg of blood was bled from ten healthy male baboons (Papio anubis) over 60 min and then retransfused over the next 30 min. We found that the mean plasma beta-endorphin level increased 109% above baseline (p less than .05) within 15 min after starting hemorrhage, and rapidly returned to a baseline concentration with retransfusion. We conclude that in a primate species, circulating endogenous opioid peptide concentrations increase rapidly in response to sublethal hemorrhagic hypotension and normalize with restoration of the baseline intravascular volume. These findings support the concept that endogenous opioid peptides may mediate the hypotension of shock states.

Animals↗
PubMed1986

Positive end-expiratory pressure increases plasma catecholamine levels in non-volume loaded dogs.

UNLABELLED: Positive end-expiratory pressure (PEEP) is commonly used in the treatment of critically ill patients whose sympathetic nervous system is stressed; however, PEEP's actions on sympathetic nervous system activity are unknown. We therefore measured the plasma noradrenaline response (an index of sympathetic nervous system activity) to graded doses of PEEP in nine mongrel dogs. After 30 minutes at each level of PEEP, plasma noradrenaline concentrations increased from baseline mean values of 300 (SD 108) pg/ml to 388 (SD 225) pg/ml (P less than 0.05) at 5 cm, 433 (SD 255) pg/ml (P less than 0.01) at 10 cm and 1194 (SD 882) pg/ml (P less than 0.01) at 20 cm water pressure of PEEP. The increases in plasma noradrenaline concentrations correlated inversely (r = -0.43, P less than 0.01) with PEEP-induced changes in cardiac output. Plasma adrenaline levels did not change significantly in response to 5 or 10 cm of PEEP; however, plasma adrenaline increased, while heart rate and mean arterial blood pressure fell, at 20 cm water pressure of PEEP (P less than 0.05). Within 15 minutes after discontinuation of PEEP, the plasma catecholamine concentrations returned to baseline levels. CONCLUSIONS: 1. PEEP significantly increases sympathetic nervous system activity in a rapid, dose-dependent, reversible manner; 2. the PEEP-induced increases in sympathetic activity may explain the reductions in organ blood flow which others have observed following the initiation of PEEP; 3. PEEP-related changes in sympathetic nervous system activity are a consequence of PEEP-induced reductions in cardiac output.

Animals↗
PubMed1985

The role of thromboxane in primate endotoxin shock.

UNLABELLED: Previous studies have suggested an important role of thromboxane (Tx) in the pathogenesis of endotoxin shock in the rat. The present study evaluated the role of thromboxane in an LD70 primate model of endotoxin shock by administering 6 mg/kg of endotoxin to three groups of animals that were pretreated with either saline (5 ml), OKY 1581 (2 mg/kg, 10 min prior), or imidazole (25 mg/kg/hr starting 30 min prior), groups I, II, and III, respectively. There were significant differences between the groups with respect to changes in MAP, PAP, and CO. OKY 1581 effectively blocked endotoxin-induced increase in plasma Tx. However, as a result of shunting of the endoperoxides into the prostacyclin pathway, there was a greater increase in plasma 6-keto PGF1 alpha, the stable hydrolysis product of prostacyclin. Imidazole augmented the formation of both prostacyclin and Tx. Despite the differences in plasma prostanoids, there was no difference between the groups with respect to changes in platelet or WBC counts, nor in survival: I (4/10); II (4/10); III (2/6). CONCLUSIONS: (i) endotoxin-induced neutropenia and decrease in the platelet count are not Tx mediated; (ii) Tx is not solely responsible for the decrease in CO during endotoxin shock; (iii) it is possible to prevent endotoxin-induced increase in the PAP by either blocking Tx formation or by increasing endogenous PGI2 production; and (iv) Tx may not be a major contributing factor in the mortality of endotoxin shock in baboons.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Effects of nonsteroidal anti-inflammatory drugs on renal function in septic dogs.

The effects of nonsteroidal anti-inflammatory drugs on renal function were studied in 15 chronically instrumented, unanesthetized beagles. In 9 dogs, bacterial peritonitis was induced by implanting in the peritoneal cavity a fibrin clot containing viable Escherichia coli. Six (control) dogs were subjected to laparotomy but were not implanted with an infected clot. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated using standard clearance methods. All measurements were performed after resuscitation with Ringer's lactate to a pulmonary capillary wedge pressure of 6 Torr. When measured 24 hr after laparotomy, there were no significant changes (relative to baseline) in GFR or ERPF in either the septic or control groups. In septic dogs, 60 min after the administration of either indomethacin (2 mg/kg) or ibuprofen (25 mg/kg), GFR decreased an average of 26 +/- 11 ml/min (P = 0.043) and ERPF decreased an average of 100 +/- 27 ml/min (P = 0.02). In controls, administration of indomethacin (2 mg/kg) did not significantly affect either GFR or ERPF. These results suggest that renal function should be carefully monitored in clinical trials of nonsteroidal anti-inflammatory drugs in septic patients.

Animals↗
PubMed1984

Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis.

This study investigates the role of prostaglandins (PG) in hyperdynamic sepsis. Thirteen chronically instrumented dogs were rendered septic by implanting in the peritoneal cavity a fibrin clot containing viable Escherichia coli. One day later, cardiac output (CO) increased from 2.80 +/- 0.22 to 3.72 +/- 0.32 l/min (p = 0.011); heart rate (HR) increased from 122 +/- 8 to 147 +/- 6 beats/min (p = 0.005); mean pulmonary artery pressure (PAP) increased from 15 +/- 1 to 19 +/- 1 mmHg (p = 0.003); mean systemic arterial pressure (MAP) decreased from 120 +/- 5 to 107 +/- 7 mmHg; and systemic vascular resistance (SVR) decreased from 44.1 +/- 2.6 to 29.3 +/- 1.9 mmHg/l/min (p less than 0.001). Sixty minutes after intravenous injection of indomethacin (2 mg/kg) or ibuprofen (25 mg/kg), CO decreased to 2.60 +/- 0.21 l/min (p less than 0.001); HR decreased to 118 +/- 5 beats/min (p less than 0.001); PAP decreased to 17 +/- 1 mmHg (p = 0.021); and SVR increased to 43.7 mmHg/l/min (p less than 0.001). In seven control dogs, laparotomy alone did not significantly affect any of these parameters. Infusion of indomethacin caused a slight increase in MAP (106 +/- 4 to 116 +/- 4 mmHg, p = 0.035) but otherwise did not alter hemodynamics. It is concluded that administration of indomethacin or ibuprofen restores normal hemodynamics in a canine model of high-output sepsis, probably by inhibiting PG synthesis.

6-Ketoprostaglandin F1 alpha↗