Biomedical subjects

M Heinzelmann

Publications and source records attributed to M Heinzelmann.

At least 19 recordsLinked to original sources

PubMed2006

Quadriceps and patellar tendon rupture.

Ruptures of the patellar and/or quadriceps tendon are rare injuries that require immediate repair to re-establish knee extensor continuity and to allow early motion. We evaluated 36 consecutive patients with quadriceps or patellar tendon rupture between 1993 and 2000. There were 37 primary ruptures, 3 reruptures, 21 quadriceps and 19 patellar tendon ruptures. Follow up examination (>24 months postoperatively) included the patient's history, assessment of risk factors, clinical examination of both knees, isometric muscle strength measurements and three specific knee scores, Hospital for Special Surgery Score, Knee Society Score and Turba Score, and a short form SF-36. We evaluated 29 patients (26 men) with 33 ruptures (16 patellar tendon, 17 quadriceps tendon). Seven patients were lost to follow up. We found no difference between the range of motion and muscle strength when the injured leg was compared to the non-injured leg. Risk factors did not influence the four scores, patient satisfaction, pain, muscle strength or range of motion. Multiple injured patients had a significant reduction in muscle strength and circumference, however patient satisfaction did not differ to the non-multiple injured patient group.

Adult↗

PubMed2004

[The role of transarterial embolisation in the treatment of patients with abdominal injuries].

INTRODUCTION: The role of transarterial embolisation in patients with abdominal injuries is controversial. Some trauma centres advocate routine angiography, whereas others believe in restricted indications such as increasing haematomas or persistent/recurrent haematuria. METHOD: We prospectively studied 167 patients with blunt and penetrating abdominal trauma. We used restricted indications for angiography and embolisation. RESULTS: Eleven of 167 patients with abdominal trauma (7%) were treated with angiography and embolisation., Overall, three of 11 patients (27%) with angiography and embolisation were treated emergently and eight of them (73%) at an average of 7.3 days. There were no complications due to the embolisation procedure, and all bleeding could be stopped. CONCLUSION: Transarterial angiography and embolisation is an important and safe tool in the treatment of acute abdominal injury when used for restricted indications. We believe this should not be performed as a routine procedure, especially in unstable patients.

Abdominal Injuries↗

PubMed2004

[Shock trauma room management of the multiple-traumatized patient with skull-brain injuries. A systematic review of the literature].

This overview reviews the literature on multiply injured patients with traumatic brain injuries. Clinical trials were systematically collected (MEDLINE, Cochrane, and hand searches) and classified into evidence levels (1 to 5 according to the Oxford system).A detailed analysis of the literature of traumatic brain injuries has been elaborated by the Brain Trauma Foundation and has been published in the World Wide Web (http://www2.braintrauma.org/). The following procedures should be performed in the emergency room for multiply injured patients with traumatic brain injuries: (1) recording of precise history to identify risk factors for severe traumatic brain injury, (2) measurement of the Glasgow Coma Scale (GCS), pupillary reflex, and mean arterial pressure, (3) diagnostic evaluation with a CT scan, and (4) rapid surgical decompression if indicated.

Clinical Trials as Topic↗

PubMed2001

[Abdominal impalement injuries].

Impalement is an uncommon and spectacular injury, which combines aspects of both blunt and penetrating trauma. With reference to our own seven patients we discuss the initial management and the operative treatment of this rare injury. Further we demonstrate the imminent problems after impalement injuries such as removal of the impaled object, treatment of colon- and other abdominal organ injuries, and management of vascular injuries.

Abdominal Injuries↗

PubMed2001

Heparin binding protein (CAP37) differentially modulates endotoxin-induced cytokine production.

BACKGROUND AND OBJECTIVE: CAP37, also known as heparin-binding protein (HBP), is neutrophil-derived protein with multifunctional properties that include monocyte chemotaxis and the enhancement of LPS-induced tumor necrosis factor (TNF-alpha), IL-1, IL-6, and PGE2production from isolated monocytes, which suggest a generalized effect on LPS-induced monocyte activation. In this study, we tested whether HBP amplifies the release of other LPS-responsive cytokines from isolated human monocytes. METHODS: Freshly isolated monocytes from 5 healthy donors were stimulated for 24 h with saline, LPS (10 ng/ml), HBP (10 microg/ml), or a combination of LPS + HBP. Cytokine levels in the supernate were measured with ELISA. ANOVA and Fisher's posthoc test were used to determine significance (p < 0.05). Differential display was used to assess cellular mRNA levels. RESULTS: HBP alone induced the production of IL-8, macrophage inhibitory protein MIP-1alpha, and TNF-alpha. HBP increased the LPS-induced production of IL-8, MIP-1alpha, TNF-alpha, IL-1beta, but HBP did not increase the significant LPS-induced release of IL-10, monocyte chemoattractant protein MCP-1, and IL- 12. Differential display demonstrated that HBP induced an mRNA pattern that was different from the mRNA pattern induced by saline, LPS, or HBP + LPS, indicating multiple and different gene activation. CONCLUSIONS: We conclude that HBP is not a general amplificator of LPS-induced monocyte activation but rather a molecule that targets the production of a distinct set of mediators including pro-inflammatory cytokines such as TNF-alpha and IL-1beta, but not the anti-inflammatory cytokine IL-10, nor IL-12 and MCP-1. The exact intracellular signaling pathways remain unknown but include mechanisms that alter gene transcription.

Analysis of Variance↗

PubMed2000

Endotoxin and muramyl dipeptide modulate surface receptor expression on human mononuclear cells.

Endotoxin (lipopolysaccharide (LPS), 100 ng/ml) and muramyl dipeptide (MDP 100 ng/ml), two immunomodulatory bacterial cell wall products, were incubated with human whole blood, and the expression of receptors involved in antigen presentation, costimulation, and cell activation was investigated by use of flow cytometry. On monocytes, LPS and MDP increased surface expression of human leukocyte antigen-DR (HLA-DR), CD18, CD54 (intercellular adhesion molecule-1, ICAM-1), and CD86 (B7-2). On lymphocytes, LPS but not MDP increased HLA-DR expression after 18 h. The expression of CD28, CD49d/CD29, and CD106 (vascular cell adhesion molecule-1, VCAM-1) remained unchanged on both monocytes and lymphocytes. The early increase (1-6 h) of CD18 and ICAM-1 expression led us to hypothesize that CD18-dependent costimulatory signals were involved in the later (6 h) increase of monocyte HLA-DR expression. However, blocking studies using monoclonal antibodies against CD18 (IB4, 15 microg/ml) demonstrated that the LPS- and MDP-induced increase of HLA-DR and ICAM-1 expression on monocytes was not mediated through CD18. LPS induced the expression of the early activation marker CD69 by a CD14-dependent but CD18-independent mechanism, whereas MDP did not induce CD69 expression. Analysis of leukocyte subsets demonstrated that CD4(+) T-cells, CD8(+) T-cell, CD19(+) B-cells, CD56(+) natural killer (NK)-cells, and CD14(+) monocytes increased the expression of CD69 after stimulation with LPS. Collectively, these data demonstrate a stronger immunomodulatory effect of LPS compared with MDP which may, in part, explain the established difference of toxicity between these two bacterial cell wall products.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2000

Heparin binding protein increases survival in murine fecal peritonitis.

OBJECTIVE: To test the effectiveness of recombinant heparin-binding protein (HBP), a neutrophil-derived multifunctional protein with monocytic-specific properties, in fecal peritonitis and polymicrobial sepsis. DESIGN: Prospective, controlled animal trial. SETTING: Animal research laboratory. SUBJECTS: Swiss Webster mice challenged with cecal ligation and puncture (CLP) and treated with recombinant HBP and 60 mg/kg cefoxitin twice a day. INTERVENTIONS: HBP was administered to mice at different concentrations and different intervals before and after CLP. Rat albumin (1%) was administered to control animals. MEASUREMENTS AND MAIN RESULTS: MORTALITY RATE: Survival was increased in mice pretreated intraperitoneally 24 hrs before CLP with 10 microg or 100 microg of HBP without cefoxitin (p = .01, Cox-Mantel log-rank test). Compared with control animals, survival was increased significantly (from 5% to 47%, p = .014) in mice that received cefoxitin and 50 microg ip HBP immediately after CLP, followed by continuous administration of HBP (12 microg/24 hrs). Intravenous administration of HBP (0.1, 1, and 10 microg) at the time of CLP showed an opposite dose effect; low doses (0.1 microg) prolonged early survival, whereas high dose (10 microg) shortened survival (p = .036). Compared with control animals, overall survival was not different. CHEMOTAXIS: Cytospin preparations from peritoneal exudate cells (PECs) 48 hrs after administration of 10 microg and 100 microg ip HBP demonstrated a 1.7-fold increase in the total number of macrophages compared with carrier control (p < .05). PHAGOCYTOSIS: A flow cytometric in vitro assay demonstrated that administration of 10 microg ip HBP alone did not enhance phagocytosis of fluorescent Escherichia coli in PECs. However, 24-hr pretreatment with 10 microg of HBP followed by CLP increased phagocytosis in PECs 1.8-fold compared with the control CLP group (p = .04). RECEPTOR EXPRESSION: CD16/CD32w expression in PECs did not change after HBP or CLP. CD11b and CD18 expression in PECs was increased significantly after CLP compared with PECs from non-CLP-challenged animals (p < .05). Pretreatment with 10 microg of HBP did not further enhance CD11b/CD18 expression in PECs. CONCLUSIONS: Recombinant HBP increases survival in murine fecal peritonitis. The mechanisms by which HBP reduces septic death are not fully understood, but they include monocyte chemotaxis and increased phagocytosis of E. coli by PECs. Our data suggest that the inflammatory response induced by CLP is important for the effect of HBP to enhance phagocytosis.

Animals↗

PubMed1999

Endocytosis of heparin-binding protein (CAP37) is essential for the enhancement of lipopolysaccharide-induced TNF-alpha production in human monocytes.

Heparin-binding protein (HBP), also known as CAP37, is a proteolytically inactive serine protease homologue that is released from activated granulocytes. However, HBP is not a biologically inactive molecule but rather a multifunctional protein with properties that include the enhancement of LPS-induced TNF-alpha production from monocytes. We have previously demonstrated that HBP is internalized in monocytes. In the current study, we hypothesize that HBP is internalized in monocytes via endocytosis, and this internalization is an important mechanism by which HBP enhances LPS-induced TNF-alpha release. Using whole blood from healthy donors and flow cytometry, we found that colchicine (0.1-10 mM), cytochalasin D (1000 microM), NH4Cl (10-50 mM), and bafilomycin A1 (0.1-3 microM) significantly reduced the affinity of FITC-HBP for CD14-positive monocytes. Using isolated human monocytes and ELISA, we found that colchicine (0.1 mM), cytochalasin D (30 and 300 microM), NH4Cl (30 mM), and bafilomycin A1 (1 microM) significantly reduced the effect of HBP (10 microg/ml) to enhance LPS (10 ng/ml)-induced TNF-alpha release after 24 h. These findings demonstrate that internalization of HBP in monocytes is essential for the enhancement of LPS-induced TNF-alpha release. Transport of HBP to an activating compartment depends on intact F-actin polymerization and endosomal acidification, an important mechanism for endosomal protein sorting and trafficking.

Adjuvants, Immunologic↗

PubMed1999

Differences between bacterial species shown by simultaneous assessment of neutrophil phagocytosis and generation of reactive oxygen intermediates in trauma patients.

HYPOTHESIS: Previous studies on alterations in phagocytosis and bacterial killing after trauma have yielded conflicting results. We hypothesize that these changes are variable, depending on the species of bacteria used to assay these variables. DESIGN: Blood samples from patients were assayed by means of flow cytometry for phagocytosis and reactive oxygen intermediate generation. Several common clinical pathogens were used: Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Results were compared with those from controls. SETTING: Regional level I trauma center. PATIENTS: Ten consecutive patients were studied with E. coli and K. pneumoniae. Five of these were also studied with S. aureus. Patients were 18 years of age or older, with an Injury Severity Score of 16 or more. Patients who were taking corticosteroids before hospital admission or who were administered corticosteroids before blood was drawn were not studied. Isolated head injuries or limb fractures were also excluded. Controls consisted of healthy volunteers. MAIN OUTCOME MEASURES: The ingestion of bacteria by neutrophils and the generation of reactive oxygen intermediates. RESULTS: After trauma, phagocytosis of E. coli was enhanced, whereas ingestion of K. pneumoniae was depressed. Ingestion of S aureus remained unchanged. The generation of reactive oxygen intermediates was depressed after incubation with E. coli and unchanged with K. pneumoniae, but enhanced with S. aureus. CONCLUSIONS: Neutrophil response to trauma is dependent on which bacterial species the cell is attempting to kill. This may, in part, explain why only a limited number of bacterial species cause a significant proportion of early infections after trauma.

Adolescent↗

PubMed1999

Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in experimental peritonitis.

Neutrophil (PMN) migration into the peritoneal cavity in response to fecal peritonitis is an important mechanism of host defense against bacterial invasion. We show that the murine C-X-C (PMN-specific) chemokine, macrophage inflammatory protein-2 (MIP-2), on intraperitoneal injection in mice, causes PMN migration into the peritoneum. MIP-2 mRNA and protein were expressed by peritoneal leukocytes after cecal ligation and puncture (CLP) in mice and neutralization of MIP-2 reduced peritoneal PMN migration. A prerequisite for neutrophil-endothelial adhesion and subsequent migration from the circulation is selectin-mediated rolling. Pretreatment of mice with an anti-P-selectin antibody before intraperitoneal injection of MIP-2 significantly reduced peritoneal PMN migration. However, there are no reports that a C-X-C chemokine can up-regulate endothelial selectins. We postulated that MIP-2, when injected intraperitoneally, interacts with a cell that is known to release factors that up-regulate endothelial selectins. A likely candidate is the mast cell, which contains histamine and tumor necrosis factor alpha (TNF-alpha), and both of these factors induce selectins. Intraperitoneally injected MIP-2 caused an early significant increase in peritoneal TNF-alpha, whereas histamine levels were unaffected. In a subsequent experiment, mast cell-deficient mice and their normal controls were then injected intraperitoneally with MIP-2 or underwent CLP. Significantly fewer PMNs migrated into the peritoneal cavity in the mast cell-deficient mice after MIP-2 injection or CLP. Thus, our findings indicate that mast cells and MIP-2 are necessary for PMN migration into the peritoneum in response to intra-abdominal infection, and that MIP-2 appears to facilitate this through an increase in TNF-alpha release.

Animals↗

PubMed1999

Neutrophils and renal failure.

In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils' ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2-integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis.

Animals↗

PubMed1999

Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-alpha production in human monocytes.

OBJECTIVE: To determine whether heparin or the low-molecular-weight heparin enoxaparin alter lipopolysaccharide (LPS)-induced monocyte activation. SUMMARY BACKGROUND DATA: Heparin is widely used in clinical practice to inhibit the coagulation cascade. However, heparin also is a naturally occurring glucosaminoglycan and a pleiotropic immunomodulator that binds to a variety of proteins. LPS is a component of gram-negative bacteria and is thought to be responsible for many of the deleterious effects seen in sepsis. The binding of LPS to CD14 induces a signaling cascade that results in the release of many inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha). METHODS: Monocytes from healthy volunteers were isolated and cultured in the presence of saline, LPS (10 ng/ml), heparin (0.1 to 1000 microg/ml), or enoxaparin (0.1 to 1000 microg/ml). In blocking experiments, cells were pretreated for 60 minutes with the monoclonal anti-CD14 antibody MY4 (10 microg/ml) or with isotype-matched control IgG2 (10 microg/ml). TNF-alpha values were measured with enzyme-linked immunosorbent assay. Significance was assessed with analysis of variance. RESULTS: Heparin (10 to 1000 microg/ml) and enoxaparin (1000 microg/ml) significantly enhanced LPS-induced TNF-alpha release. Heparin (1000 microg/ml) or enoxaparin (1000 microg/ml) did not produce TNF-alpha in the absence of LPS. Blockade of CD14 abrogated both LPS-induced TNF-alpha release and the effect of heparin or enoxaparin to enhance LPS-induced TNF-alpha release. CONCLUSIONS: The effect of heparin to enhance LPS-induced TNF-alpha release is a biologic phenomenon that reveals a novel and potentially important host defense mechanism during endotoxemia and sepsis. Binding of LPS to CD14 is necessary to induce this phenomenon, suggesting that both heparin and enoxaparin induce signaling mechanisms that are downstream from the initial binding of LPS on CD14.

Anticoagulants↗

PubMed1999

Posterior elbow dislocation with associated vascular injury after blunt trauma.

BACKGROUND: Injury of the brachial artery is a rare (5-13%) but serious complication after closed elbow dislocation without associated fractures. METHOD: Retrospective analysis of long-term results (mean, 4.1 years) in four patients. RESULTS: All patients underwent emergency repair of the arterial injury within 2.5 hours. In three patients, a reversed saphenous vein graft was used; in one patient the artery was sutured. This latter patient needed another operation with interposition of a reversed saphenous graft, because the primary anastomosis occluded. The capsule and the collateral ligaments were immediately reconstructed in three patients because of instability. No patient showed claudication of the arm. In three patients, a sensory deficiency of median nerve persisted. Average range of motion was 128 degrees of flexion (120-135 degrees) and an extension deficit of 7.5 degrees (15-0 degrees). CONCLUSION: Primary repair of vascular injury after closed elbow dislocation with vein graft and immediate reconstruction of ligamentous injuries results in good long-term functional outcome.

Adult↗

PubMed1999

Quantification of phagocytosis in human neutrophils by flow cytometry.

Phagocytosis represents a central element of the host response to microbial invasion. We describe a flow cytometric method for measuring the kinetics of phagocytosis of two bacteria by human polymorphonuclear leukocytes (PMNs). Over a 60-min period, isolated human PMNs were exposed to Staphylococcus aureus (rapidly phagocytosed) and Klebsiella pneumoniae (slowly phagocytosed). This method distinguished adherent from ingested bacteria by quenching fluorescein isothiocyanate-labeled extracellular bacteria with ethidium bromide. This further allowed the exclusion of dead, highly permeable, and subsequently bright-red fluorescent PMNs. Our experiments with two different bacteria, various PMN-to-bacteria ratios (1:1, 1:10, 1:100), and different individuals proved that 1) flow cytometric analysis is accurate and useful for characterizing phagocytosis, 2) adherent bacteria can be distinguished from ingested bacteria after quenching with ethidium bromide, and that 3) phagocytosis kinetics of two bacteria with different onsets of phagocytosis can be determined by flow cytometry and the assessment of a score that quantifies phagocytosis.

Bacterial Adhesion↗

PubMed1999

[Role of laparoscopy in the management of acute appendicitis].

Minimal invasive surgery had a considerable impact on common surgical techniques and has almost replaced established operative procedures such as cholecystectomy. However, the laparoscopic approach for the treatment of acute appendicitis is still not very popular. We discuss the role of laparoscopy for appendectomy and include three studies from our institution (University Hospital Zürich, Switzerland) and prospective studies reported in the literature. We conclude that laparoscopic appendectomy, when compared with the open approach, has the following advantages for the diagnosis and treatment of acute appendicitis. (1) Diagnostic laparoscopy is an effective and relatively atraumatic tool to investigate the abdominal cavity, which results in a sensitivity of almost 100%. This allows for accurate decision making, which is especially advantageous in young women and obese patients. (2) Prospective studies demonstrate that laparoscopic appendectomy is at least as good as open appendectomy and that the laparoscopic approach results in a reduced postoperative infection rate. (3) The similar complication rate after laparoscopic appendectomy, when performed by residents rather than staff surgeons, underlines the feasibility and teaching potential of this minimal invasive procedure.

Acute Disease↗

PubMed1998

Heparin-binding protein (CAP37) is internalized in monocytes and increases LPS-induced monocyte activation.

Previous studies have shown that the neutrophil-derived heparin-binding protein (HBP), also known as CAP37 or azurocidin, potentiates the LPS-induced release of proinflammatory cytokines (TNF-alpha, IL-1, and IL-6) from isolated human monocytes. To date, the mechanisms by which HBP enhances LPS-induced monocyte activation have not been elucidated, and it is not known whether HBP also increases the LPS-induced production of other bioactive substances. We studied human monocytes activated by recombinant human HBP and LPS and their interaction with the LPS receptor CD14. We hypothesized that the stimulatory effect of HBP on the LPS-induced release of proinflammatory mediators from monocytes was mediated by specific binding of HBP to monocytes, which resulted in an up-regulation of CD14. Our results demonstrated that HBP alone (10 microg/ml) stimulated the production of TNF-alpha from isolated monocytes. In addition, HBP had an additive effect on LPS-induced production of TNF-alpha and PGE2, suggesting a generalized monocyte activation. We used flow cytometry to demonstrate that HBP had a high affinity to monocytes but not to the LPS receptor CD14, and experiments performed at 4 degrees C indicated an energy-dependent step in this process. Confocal microscopy showed that monocytes internalize HBP within 30 min. These data suggest that mechanisms other than increased CD14 expression are responsible for the enhanced release of TNF-alpha or PGE2 in response to HBP and LPS.

Adjuvants, Immunologic↗

PubMed1998

Heparin binding protein (CAP37) is an opsonin for Staphylococcus aureus and increases phagocytosis in monocytes.

Heparin binding protein (HBP), also known as cationic antibiotic protein (CAP37) or azurocidin, is stored in azurophilic granules of neutrophils and is released to the extracellular space when granulocytes phagocytose Staphylococcus aureus. We investigated whether extracellular HBP also has the potential to increase phagocytosis of S. aureus by other phagocytes. We used flow cytometry to characterize the binding of HBP to S. aureus and to simultaneously measure phagocytosis and superoxide production of opsonized S. aureus in monocytes and granulocytes. Our results demonstrate that HBP is a strong opsonin for S. aureus, and that monocytes, but not granulocytes, increase phagocytosis of HBP-treated S. aureus. However, HBP-treated S. aureus increases the production of superoxide in both monocytes and granulocytes as compared with untreated S. aureus. These findings support the role of granulocytes in the afferent limb of inflammation and demonstrate that HBP, when released from activated granulocytes, potentiates bacterial uptake in monocytes and enhances the potential of microbial killing in monocytes and granulocytes.

Antimicrobial Cationic Peptides↗

PubMed1998

Continuous antibiotic treatment for experimental abdominal sepsis: effects on organ inflammatory cytokine expression and neutrophil sequestration.

BACKGROUND: Tumour necrosis factor (TNF) alpha and interleukin (IL) 1 beta are produced in the lung after peritonitis and may contribute to neutrophil-mediated organ injury. It was hypothesized that, during experimental peritonitis, continuous rather than intermittent antibiotic therapy would reduce lung expression of TNF-alpha and IL-1 beta messenger RNA (mRNA) and neutrophil sequestration. METHODS: After caecal ligation and puncture, mice received either intermittent or continuous cefoxitin, or continuous metronidazole or aztreonam. Cytokine mRNAs were determined by reverse transcription differential polymerase chain reaction and lung neutrophil content by myeloperoxidase (MPO) assay. RESULTS: Continuous cefoxitin reduced median (interquartile range (i.q.r.)) lung IL-1 beta mRNA expression ((ratio to beta-actin): continuous 0.18 (0.14-0.34), intermittent 0.46 (0.44-0.49), saline 0.43 (0.38-0.53), P < 0.05) and median (i.q.r.) lung MPO content (continuous 22.5 (9.7-40), intermittent 65 (57.5-76), saline 47 (41-64), P < 0.05) compared with intermittent therapy and saline controls. Continuous infusion was also associated with reduced bacteraemia (P < 0.05) but not serum TNF-alpha or endotoxin levels. Both continuous metronidazole and aztreonam reduced lung MPO concentration (P < 0.05) and TNF-alpha and IL-1 beta mRNA expression (P < 0.05) compared with those in saline controls. These effects were dependent on a reduction in the number of susceptible bacteria rather than serum TNF-alpha or endotoxin levels. CONCLUSION: The stimulus for organ inflammatory cytokine production and neutrophil sequestration during peritonitis is the level of bacteraemia present, which is more effectively controlled with continuous antibiotic therapy.

Animals↗