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L B Hinshaw

Publications and source records attributed to L B Hinshaw.

At least 19 recordsLinked to original sources
PubMed2000

Peritonitis in the baboon: a primate model which stimulates human sepsis.

The physiological, hemostatic, and immunological responses of 12 chronically instrumented conscious baboons with sepsis due to Escherichia coli peritonitis were compared with that of similarly instrumented controls. Chronic indwelling cannulae were placed in the aorta and pulmonary artery to monitor pressure, cardiac output, and obtain blood samples. At t = 0 a sterile or E. coli-laden fibrin clot containing 1.9-6.7 x 10(11) CFU/kg was introduced into the peritoneal cavity. The control animals were group 1 (n = 3). The animals with peritonitis were divided into three groups depending on their clinical response. Group 2 animals (n = 3) were clinically well at the time of sacrifice (day 14), group 3 (n = 4) survived but were obviously sick on day 14, and group 4 (n = 5) died of sepsis. Implantation of a sterile fibrin clot was well tolerated with little hemodynamic change and a transient minimal inflammatory response in group 1. Implantation of an E. coli-containing clot elicited a hyperdynamic cardiovascular response and evoked a marked inflammatory reaction and a disseminated intravascular coagulopathy. Five of 12 (42%) E. coli animals died from sepsis. In general, the physiological, hemostatic, and immunological disturbances tended to be greatest in these animals. Autopsy revealed residual peritoneal inflammation and varying degrees of inflammation in the lungs, adrenal, spleen, liver, and kidneys in all the animals that received E. coli with the inflammatory infiltrate increasing in severity from group 2 through group 4. Tissue necrosis was observed only in the latter group. We conclude that the cardiovascular, hemostatic, and immunological responses of baboons with sepsis due to E. coli peritonitis exhibit a variable course that resembles the clinical manifestations of gram-negative sepsis in humans.

Animals↗
PubMed1998

Lupus humoral autoimmunity induced in a primate model by short peptide immunization.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by humoral autoimmunity against the spliceosomal proteins, including Sm B/B'. In SLE patients with anti-Sm B/B' antibodies the proline rich sequence, PPPGMRPP, is the predominant Sm B/B' autoimmune epitope and appears to be an early target in the development of the anti-Sm B/B' response. METHODS: Two female baboons were immunized with the PPPGMRPP peptide from the Sm B/B' spliceosomal protein constructed on a MAP backbone in Freund's adjuvant. One female control baboon was immunized with Freund's adjuvant alone. Baboon sera were collected and assessed for antibody binding to the spliceosomal proteins and compared to SLE patient and control sera. RESULTS: Peptide immunized baboons developed antibodies to multiple regions of the Sm B/B' protein, as well as reactivity against other spliceosomal proteins. Consistent with serologic manifestations found in SLE, experimental baboons also acquired anti-nuclear antibodies, anti-nuclear ribonucleoprotein (nRNP) antibodies and, in one animal, anti-double stranded DNA antibodies. The control animal had none of these immunologic findings. CONCLUSIONS: Immunization with PPPGMRPP is capable of initiating a humoral autoimmune response in primates against the Sm, nRNP complex from which the peptide was derived. The additional autoantibody specificities generated in experimental animals are similar to those found in human SLE sera. This study is the first evidence of peptide induction of SLE humoral autoimmunity in a primate model.

Amino Acid Sequence↗
PubMed1998

Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli--a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli.

This study was designed to determine the effect of a delayed infusion (T+120 min) of alanyl tissue factor pathway inhibitor (ala-TFPI) on the response to LD100 E. coli. We hypothesized that baboons treated with a low dose of TFPI (5 mg/kg) which did not survive would exhibit thrombosis, infarction and hemorrhage of target tissues such as that seen in untreated animals infused with LD100 E. coli. Eight baboons were infused with 5 mg/kg of ala-TFPI over a 10 h period beginning immediately after a 2 h infusion of LD100 E. coli (experimental group). Four baboons were infused with E. coli followed by a 10 h infusion of saline (control group). Of the 12 baboons, the 11 non-survivors (TFPI = 7 out of 8; controls = 4 out of 4) were evaluated for the extent of thrombosis, necrosis, hemorrhage, and congestion of target tissues and for changes in clinical chemical parameters. We expected that failure to protect would correlate with failure to inhibit thrombosis of target tissue (8). Surprisingly ala-TFPI significantly inhibited thrombosis, hemorrhage and necrosis of adrenal and renal tissues and attenuated the rise in creatinine in the 7 treated non-survivors. The lungs of these non-survivors, however, exhibited intra-alveolar fibrin and a mild degree of hemorrhage and edema. We concluded that low doses of ala-TFPI begun as late as T+120 in minutes failed to protect against the lethal effects of LD100 E. coli in spite of completely preventing thrombosis and hemorrhage in target organs, and that thrombosis, infarction and hemorrhage of adrenal and renal tissue are not part of the lethal chain of events in this IV model of E. coli sepsis.

Animals↗
PubMed1996

Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of TNF-alpha.

Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli challenge was administered (n=4). LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity. These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.

Animals↗
PubMed1996

Sepsis/septic shock: participation of the microcirculation: an abbreviated review.

OBJECTIVE: An overview of the importance of understanding mechanisms occurring in the microcirculation during septic and endotoxic shock. The thesis of the paper is to place emphasis on this important vascular network to ultimately benefit the patient. DATA SOURCES: Early descriptions of vascular reactions to endotoxin which suggest that the microcirculation is a major site of attack during shock. More recent studies were sought out and examined as to their possible impacts on the microcirculation. STUDY SELECTION: Early comprehensive studies concerning vascular reactions in the microcirculation during shock were selected. Subsequent studies identified from the mainstream scientific medical literature describe the actions of blood, cells, and the emerging significant role of the vascular endothelium among other factors. A consensus view is identified, pointing to the causes of a malfunctioning microcirculation during shock. DATA EXTRACTION: Data gathered from reports in the mainstream, well-established basic and clinical literature, from reviews and forum reports, from studies by well-established investigators, and from more recent reports of excellent quality. DATA SYNTHESIS: The microcirculation undergoes massive alterations during sepsis/septic shock. There are numerous changes, including slowing of capillary blood flow due to depressed perfusion pressure as a result of systemic pressure reduction and local arteriolar constriction. Observations suggest that the microcirculation is shut off early in severe sepsis, allowing the effects of hypoperfusion and attacks by microorganisms to prevail in their destructive capabilities. Widespread capillary dilation may ultimately occur. However, with blood flow diverted through some arteriovenous channels, important areas of capillary exchange are bypassed. Decreased capillary blood flow during shock results from failure to allow normal passage of cellular elements, including erythrocytes and neutrophils. This defect occurs, in part, because of decreased perfusion pressure, decreased deformability of red and white cells, constricted arterioles, circulating obstructive fragments (including hemoglobin), and plugging of microvessels with "sludge." Other factors are adherence of cells to capillary and venular epithelial membranes creating increased resistance to flow, loss of fluid through abnormal transcapillary exchange, differential vascular resistance changes between various beds (e.g., intestinal vs. muscle), and the relative absence of regulatory neurohumoral control of small vessel segments of the circulation. During sepsis/septic shock, endothelial cells are reported to modulate vascular tone, control local blood flow, influence the rate of leakage of fluids and plasma proteins into tissues, modulate the accumulation and extravasation of white cells into tissues, and influence white cell activation. As a result of the predominance of many destructive factors, a subsequent round of tissue damage may occur. Because of prolonged capillary vascular stasis, deficient flow, and factors released from injured cells, the microcirculation becomes a trap for uncontrolled bacterial growth enhanced by sustained hypoxemia, acidosis and toxemia. These events may combine to contribute to the loss of normal cell integrity and death of the host. CONCLUSIONS: The purpose of this review is to draw the readers' attention to the growing list of adverse factors occurring in the microcirculation during sepsis/septic shock. A further aim is to point to the realization of the complexity of factors which may contribute to the importance of a well-functioning microcirculation.

Animals↗
PubMed1996

Comparison of the capacity of rhTNF-alpha and Escherichia coli to induce procoagulant activity by baboon mononuclear cells in vivo and in vitro.

The procoagulant activity of mononuclear cells (MNCs) may play an important role in the disseminated intravascular coagulation seen in septic shock. This study compares the capacity of Escherichia coli (E. coli) and recombinant human TNF-alpha (rhTNF-alpha) to induce procoagulant activity by baboon MNCs. In vivo studies showed that MNC procoagulant activity was significantly increased at T + 120 min after LD100 E. coli infusion into baboons. Most of this procoagulant activity was attributable to tissue factor. In contrast, a bolus infusion of rhTNF-alpha (150 micrograms/kg) and a monoclonal antibody to activated protein C (2 mg/kg) did not induce any increase of MNC procoagulant activity at T + 120 min even though the plasma TNF-alpha level was 10 times higher than that seen following infusion of E. coli. In vitro studies showed that E. coli at concentrations comparable to that observed in the vivo study and LPS at a concentration of 2.5 ng/mL induced more intense tissue factor expression by both human and baboon monocytes than rhTNF-alpha in the concentrations ranging from 10 to 1,000 ng/mL. These results suggest that TNF-alpha alone is not sufficient to induced noticeable MNC procoagulant activity, at least, in the early stage of this septic shock model.

Animals↗
PubMed1995

Functional assay of plasma antithrombin using polyethylene glycol (PEG) defibrinated plasma.

Polyethylene glycol(PEG) was used to precipitate fibrinogen to prepare defibrinated plasma in the two stage clotting assay of antithrombin activity. Five percent PEG-8000 precipitated fibrinogen from plasma without loss of antithrombin activity in the defibrinated plasma. Fibrin degradation products(FDP) as high as 640 ug/ml did not interfere the two stage clotting assay using PEG defibrinated plasma possibly because part of FDP was precipitated by PEG in the process of plasma defibrination. The two stage clotting assay was very sensitive to the changes of antithrombin activity in the range of 60%-100% of normal level. The assay was reproducible and correlated with chromogenic assay. The decrease of plasma antithrombin activity in a baboon septic shock model was demonstrated with this assay.

Animals↗
PubMed1994

Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock.

Excessive coagulation is a typical response to the vascular injury occurring in gram negative sepsis. This study evaluated the pharmacological effects of the use of a recombinant Escherichia coli derived form of tissue factor pathway inhibitor (ala-TFPI) in a baboon model of septic shock. Several doses of ala-TFPI were administered either 30 or 120 min after the initiation of a lethal intravenous infusion of E. coli into baboons. Treatment at 30 min with either 2.7 or 7.4 mg/kg of ala-TFPI resulted in the same survival rates and attenuation of both the coagulation response and cellular injury, as measured by clinical chemistry. When administration of ala-TFPI was delayed for 120 min, a dose of ala-TFPI protein continued to provide a benefit to survival. Ala-TFPI reduced the drop in mean systemic arterial pressure compared to control baboons in addition to partially attenuating the coagulopathic response. Baboons given ala-TFPI also maintained lower levels of plasma interleukin-6 (IL-6) and thrombin-antithrombin. These results suggest that the site of action of the protein may involve the later stage components of the coagulation and inflammatory pathways.

Animals↗
PubMed1994

Study of septic shock in the non-human primate: relationship of pathophysiological response to therapy with anti-TNF antibody.

Therapy with anti-TNF antibody is reported to be effective in preventing morbidity and mortality in baboons given lethal infusions of Escherichia coli. Treated animals survived, and organ histopathology was absent when antibody was administered early after lethal infusions of E. coli. The present study explored the relationship between antibody dosage, pathophysiology, and survivability from shock. When antibody dose was decreased lungs, kidneys, adrenals, spleen, and liver were injured as shown by increased vascular congestion, hemorrhage, edema, and necrosis of tissues. Survival was also affected. All animals treated with 15 mg/kg antibody survived as reported earlier; less than 60% survived with 7.5 mg/kg; 9% survived with 5.0 mg/kg, and all died with 1.5 mg/kg. Serum concentrations of interleukin-6 (IL-6) increased markedly as dose of antibody decreased. The increases in concentrations of IL-6 were associated with increases in morbidity and mortality following E. coli administration.

Adrenal Glands↗
PubMed1994

Retrospective description and experimental reconstitution of three different responses of the baboon to lethal E. coli.

This paper is divided into a retrospective descriptive section in which we report on three distinctly different and spontaneous responses of the baboon to LD100 Eschericia coli observed over the last 6 years. This section is followed by an experimental section in which we reproduce the immediate and delayed responses based on hypothetical mechanisms. In the descriptive section, we arbitrarily divided all the non-survivor animals on which we had sufficient data into three groups based on duration of survival (i.e., 12 hr or less, immediate, 12 to 30 hr, intermediate, and 30 hr or more, delayed). The natural history and pathophysiology of the 12 hr or less group matched that of capillary leak syndrome with a rapid fall in blood pressure, rise in hematocrit, massive edema, and congestion with leukocyte sequestration in both lung and liver, with only limited adrenal cortical hemorrhage. The 12 to 30 hr group matched the natural history of a consumptive hemorrhagic diatheses with a biophasic blood pressure response, limited change in hematocrit, a severe consumptive coagulopathy, severe adrenal cortical hemorrhage, and a moderate renal cortical tubular necrosis, but limited renal cortical thrombosis. The greater than 30 hr group matched the natural history of a microvascular thrombotic (hemolytic uremic) syndrome with a stable blood pressure, a fall in hematocrit associated with a massive renal cortical thrombosis with a severe medullary, and cortical tubular necrosis. We did not analyze these groups further (i.e., type of intervention etc.) once we found that time of survival correlated with a unique clinical syndrome, because based on these observations, we hypothesized that we could reproduce the immediate capillary leak and pulmonary failure, and the delayed microvascular thrombosis and renal failure syndromes experimentally. We reproduced the immediate (< 12 hr) and delayed (> 30 hr) responses by infusion of either tumor necrosis factor or C4b binding protein with sublethal E. coli. This provides models of the immediate and delayed as well as the intermediate responses to E. coli for study of mechanism and the efficacy of therapeutic interventions.

Animals↗
PubMed1993

Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine.

OBJECTIVES: The goals of this study were: a) to evaluate the efficacy of controlled, continuous arteriovenous hemofiltration in improving morbidity and mortality rates in an immature swine model of Staphylococcus aureus-induced septicemia; b) to determine if ultrafiltrate from septic animals contained mediators that produce pathophysiologic changes observed in untreated S. aureus septic pigs. DESIGN: Prospective, randomized, controlled study with age-matched controls. SETTING: U.S. Department of Agriculture-licensed biomedical research facility. SUBJECTS: Sixty-five weaned Poland-China swine (4 to 6 wks of age; 5 to 10 kg). INTERVENTIONS: Part 1: Animals received a lethal dose of live S. aureus (8 x 10(9) colony-forming units/kg) over 1 hr. The three treatment groups included: hemofiltration group 1 (eight filtered, eight nonfiltered animals), plasma filtration fraction = 5.5%; hemofiltration group 2 (six filtered, six nonfiltered animals), filtration fraction = 16.6%; and hemofiltration group 3 (six filtered, six nonfiltered animals), filtration fraction = 33.4%. A control, nonseptic group of animals (n = 4) was filtered to obtain "clean" ultrafiltrate (hemofiltration group 4). Part 2: Sterile ultrafiltrate concentrate batches obtained from each group of filtered, septic animals were concentrated and infused into healthy, nonseptic pigs (reinfusion groups 1 through 3). MEASUREMENTS AND MAIN RESULTS: Physiologic, biochemical, and hematologic variables were measured in all animals every 1 to 3 hrs. Overall length of survival was also recorded. In hemofiltration groups 1 through 3, filtered animals survived significantly longer than matched, nonfiltered (sham-filtered) animals. Increments in survival time increased directly with filtration fraction. Ultrafiltrate concentrate from septic pigs produced death (LD41) and disease similar to those rates observed in untreated S. aureus-septic pigs. Infusion of clean ultrafiltrate concentrate produced no response. CONCLUSIONS: Continuous arteriovenous hemofiltration significantly improved survival rates in swine with S. aureus-induced sepsis. Resultant ultrafiltrate concentrate contained mediators responsible for some pathophysiologic responses observed in this animal model.

Age Factors↗
PubMed1993

Preclinical review of anti-tumor necrosis factor monoclonal antibodies.

OBJECTIVE: To review the preclinical evidence for the role of tumor necrosis factor (TNF) in the pathogenesis of septic shock and to assess the preclinical efficacy of anti-TNF therapies for this clinical problem. DATA SOURCES: The international English language literature from 1986 to the present formed the basis of this review. MEDLINE was used to identify pertinent in vitro and animal studies pertaining to the pathobiology of TNF and the use of anti-TNF therapies, with special emphasis on antibody approaches. STUDY SELECTION: Those studies that focused on the mechanisms of action of TNF, its role in the inflammatory cascade, and the potential uses of anti-TNF therapies were emphasized. Investigations that described animal and human results served as the primary database. DATA EXTRACTION: Animal studies were selected based on the relevance of the model to the pathogenesis of the human clinical sepsis syndrome. Where they provided supportive evidence, patient studies were selected on the basis of study design. DATA SYNTHESIS: The administration of anti-TNF antibodies in baboons, monkeys, and other species that were administered lethal doses of bacteria or endotoxin suggest that this approach may limit organ damage and decrease the mortality rate caused by the septic shock syndrome. Therapy with anti-TNF monoclonal antibodies is reviewed. CONCLUSIONS: Bacterial challenge induces the release of TNF (among other mediators), which exerts both physiologic and toxic effects that may ultimately lead to organ dysfunction and death. New anti-TNF therapies such as anti-TNF antibodies appear to attenuate the injurious effects of TNF and promote survival in otherwise lethal septic shock animal models, suggesting a similar benefit might be obtained in the treatment of human septic shock.

Animals↗
PubMed1993

Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.

This study was designed to test the hypothesis that tissue factor pathway inhibitor (TFPI) plays a significant role in vivo in regulating coagulation that results from exposure of blood to tissue factor after vascular injury as in the case of gram negative sepsis. Highly purified recombinant TFPI (6 mg/kg) was administered either 30 min or 4 h after the start of a lethal intravenous Escherichia coli infusion in baboons. Early posttreatment of TFPI resulted in (a) permanent seven-day survivors (5/5) with significant improvement in quality of life, while the mean survival time for the controls (5/5) was 39.9 h (no survivors); and (b) significant attenuations of the coagulation response and various measures of cell injury, with significant reductions in pathology observed in E. coli sepsis target organs, including kidneys, adrenals, and lungs. TFPI administration did not affect the reduction in mean systemic arterial pressure, the increases in respiration and heart rate, or temperature changes associated with the bacterial infusion. TFPI treated E. coli infected baboons had significantly lower IL-6 levels than their phosphate buffered saline-treated controls, however tumor necrosis factor levels were similarly elevated in both groups. In contrast to the earlier 30-min treatment, the administration of TFPI at 4 h, i.e., 240 min, after the start of bacterial infusion resulted in prolongation of survival time, with 40% survival rate (2/5) and some attenuation of the coagulopathic response, especially in animals in which fibrinogen levels were above 10% of normal at the time of TFPI administration. Results provide evidence for the significance of tissue factor and tissue factor pathway inhibitor in bacterial sepsis, and suggest a role for blood coagulation in the regulation of the inflammatory response.

Animals↗
PubMed1992

Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody.

A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.

Animals↗
PubMed1991

Sequential renal alterations in septic shock in the primate.

This is a descriptive sequential study of the response of the baboon to LD100 Escherichia coli. The response was found to consist of three stages based on electron microscopic, physiologic, and clinical laboratory data. This study associates the inflammatory, coagulant, and cell injury (stage 1-3) responses with markers of activation of inflammatory cells (tumor necrosis factor) and of the vascular endothelium (tissue plasminogen activator). This work also shows that in contrast to the underlying parenchymal cells of the organ, the vascular endothelium remains intact throughout the response to LD100 E. coli. The possible role of the vascular endothelium in mediation of events at both its luminal (blood) and antiluminal (parenchymal) surfaces is discussed.

Animals↗
PubMed1991

Survival factors in a canine septic shock model.

Physiological indicators of tissue perfusion in a canine septic shock model have been examined. An early death (ED) group and a combined late death and survivor group (LDS) were defined and the corresponding data compared. It was found that the LDS group had less reductions in mean systemic arterial pressure (P less than 0.05), transcutaneous oxygen pressure (P less than 0.05), and red blood cell deformability (P less than 0.001); a smaller increase in hematocrit (P less than 0.05); and a lower concentration of white blood cells (P less than 0.05), relative to the ED group, at 6 hr after an infusion of Escherichia coli organisms. These results suggest that dogs in the LDS group have better tissue perfusion than those in the early death ED group. Post-treatment of dogs with pentoxifylline did not improve survival time or enhance flow factors.

Animals↗
PubMed1990

Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group.

Sepsis, an important cause of hospital mortality, continues to be a diagnostic and therapeutic challenge. To define more clearly the impact of encephalopathy on the course of sepsis, the various clinical signs of sepsis, blood culture results, and mortality rates were examined in relation to mental status in septic patients. Patients were classified as having an acutely altered mental status due to sepsis (AAMS), preexisting altered mental status (PAMS), or normal mental status (NMS). Twenty-three (307/1333) percent of the study patients had an acutely altered sensorium secondary to sepsis. Patients with AAMS had a higher mortality (49%) than patients with PAMS (41%) or patients with NMS (26%) (p less than .000001). Multivariate analysis disclosed that altered mental status, hypothermia, hypotension, thrombocytopenia, and the absence of shaking chills were independent predictors of increased mortality in the sepsis syndrome. Patients with Gram-negative bacteremia (28%) were as likely to have AAMS as patients with Gram-positive bacteremia (25%) or patients with negative blood cultures (23%). In summary, alterations in mental status are common in septic patients, and are associated with significantly higher mortality.

Bacterial Infections↗