Magnetic Double-J-Stent Removal Without General Anaesthesia in Children.

OBJECTIVES: To show the feasibility of magnetic double-J-stent (mDJS) removal without general anaesthesia in infants and children. METHODS: A retrospective analysis of mDJS removals was conducted between February 2018 and July 2020 in a cohort of 32 consecutive paediatric patients. Only patients with unilateral ureteric stenting were included. Stent retrieval was performed in an outpatient setting. In males the junction of the retrieval-catheter and the mDJS was confirmed by transabdominal ultrasound. All patients were followed-up for 4-12 weeks after stent removal. RESULTS: Thirty-two patients (54% males) were included. Median age was 3.8 years (range 1 month - 15 years). Ureteral stents remained in place for a median of 67.5 days (range 2 days - 6 months). General anaesthesia was necessary in one single patient due to expressed patient's and caregiver's wish. Thirty-one patients had stent removal without need for general anaesthesia. Thereof, nitrous oxide was used in 12 patients (37.5%), fentanyl in 3 patients (9.4%), midazolam in 3 patients (9.4%), and 17 patients (53.1%) did not need sedation at all. Seven patients (21.9%) being 8 months or younger had received peroral saccharosis. No complications occurred during stent removal. Retrieval was successful at first catheterization in 30 patients (93.8%). Two male patients needed a second catheterization (6.3%). CONCLUSION: The use of magnetic DJS is safe in the paediatric population and spares general anaesthesia during removal in almost all patients.

Valvular endocarditis due to Mycobacterium tuberculosis.

Granulomas due to Mycobacterium tuberculosis are rarely observed in valvular structures. When observed, they are associated with disseminated tuberculosis in immunocompromised patients. We report the first case of tuberculous valvular endocarditis isolated in an immunocompetent patient. The patient had severe mitral valve regurgitation due to a perforation of the anterior leaflet of the mitral valve. M. tuberculosis was cultured from the vegetations and no other tuberculous foci were identified. This case exemplifies the protean manifestations of M. tuberculosis infections.

Isoniazid levels in the bronchoalveolar lavage fluid of patients with pulmonary tuberculosis.

Isoniazid (INH) is one of the most important first line drugs in the treatment of tuberculosis. We utilized high performance liquid chromatography with a hydrazone extraction technique to measure INH in bronchoalveolar lavage (BAL) fluid specimens from six patients with active pulmonary tuberculosis. We found BAL fluid INH levels to be similar to 2-h peak serum levels. The concentration of INH in BAL fluid from lobes with infiltrate was similar to the concentration of INH in BAL fluid from lobes without infiltrate (0.062 microgram/ml and 0.073 microgram/ml, respectively). After adjusting for protein concentration in the BAL fluid, INH levels in lobes with infiltrate were threefold lower than in lobes without infiltrate. The correlation between the concentration of INH in serum and BAL fluid approached significance after correcting for protein (lobes with infiltrate, r2 = 0.60 (p = 0.07); lobes without infiltrate, r2 = 0.50 (p = 0.12). INH penetrates into bronchoalveolar fluid, and concentrations of INH in the BAL fluid suggest that assessment of the INH serum concentration is adequate to evaluate bioavailability of the drug in patients with pulmonary tuberculosis.

Potent CD14-mediated signalling of human leukocytes by Escherichia coli can be mediated by interaction of whole bacteria and host cells without extensive prior release of endotoxin.

How invading microorganisms are detected by the host has not been well defined. We have compared the abilities of Escherichia coli and lipopolysaccharides (LPS) purified from these bacteria to prime isolated neutrophils for phorbol myristate acetate-stimulated arachidonate release, to trigger respiratory burst in 1% blood, and to increase steady-state levels of tumor necrosis factor alpha mRNA in whole blood. In all three assays, bacteria were > or = 10-fold more potent than equivalent amounts of LPS and could trigger maximal cellular responses at ratios as low as one bacterium per 20 to 200 leukocytes. Both E. coli and LPS-triggered responses were enhanced by LPS-binding protein and inhibited by an anti-CD14 monoclonal antibody and the bactericidal/permeability-increasing protein (BPI). However, whereas O polysaccharide did not affect the potency of isolated LPS, intact E. coli carrying long-chain LPS (O111:B4) was less potent than rough E. coli (J5). Furthermore, material collected by filtration or centrifugation of bacteria incubated under conditions used to trigger arachidonate release or chemiluminescence was 5- or 30-fold less active, respectively, than whole bacterial suspensions. Extracellular BPI (not bound to bacteria) inhibited bacterial signalling, but BPI bound to bacteria was much more potent. Taken together, these findings indicate that E. coli cells can strongly signal their presence to human leukocytes not only by shedding LPS into surrounding fluids but also by exposing endotoxin at or near their surface during direct interaction with host cells.

Central venous catheter placement in patients with disorders of hemostasis.

OBJECTIVE: To define the incidence of bleeding complications from central venous access procedures performed by a critical care service in patients with disorders of hemostasis. DESIGN: Prospective, consecutive sample, collection of clinical data. SETTING: University teaching hospital. PATIENTS: Seventy-six consecutive patients with disorders of hemostasis who required central venous access for clinical management between October 1992 and October 1993. MEASUREMENTS: Age, sex, clinical diagnosis, most recent platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were recorded from the medical record of patients with known coagulation or platelet abnormalities. The site of central venous catheter placement, the number of needle passes necessary to complete the procedure, and the occurrence of complications were reported by the critical care attending physician performing or supervising the procedure. RESULTS: One hundred four central venous access procedures were performed on 76 patients with disorders of hemostasis. Seventy-three percent of catheters were placed in patients with platelet counts less than 100,000/mL and 40% of catheters were placed in patients with abnormalities of PT, aPTT, or both. Thirteen percent of patients had abnormalities of both platelets and coagulation profile. There were no serious complications. Bleeding complicated 7 (6.5% of the procedures; 5 patients had bleeding from the skin (from the suture sites in four), and 2 patients developed small periosteal hematomas. All patients with bleeding complications had thrombocytopenia with mean platelet counts of 22,000/mL and a range of 6,000 to 37,000/mL. Most patients with platelet counts in this range did not have clinically evident bleeding. CONCLUSIONS: Central venous access procedures can be done safely in patients with disorders of hemostasis by skilled physicians who frequently perform these procedures. Patients most likely to experience bleeding from these procedures are patients with severe thrombocytopenia. In this series, only a single patient, with a platelet count of 6,000/mL, required therapeutic blood product administration.

Antibacterial proteins of granulocytes differ in interaction with endotoxin. Comparison of bactericidal/permeability-increasing protein, p15s, and defensins.

Bactericidal/permeability-increasing protein (BPI), antibacterial 15-kDa protein isoforms (p15s), and defensins (neutrophil peptides or NPs) are granule-associated antibacterial proteins of polymorphonuclear leukocytes (PMN) that have both direct and synergistic growth inhibitory activity against Gram-negative bacteria. In this study, we have compared in vitro the abilities of these antibacterial proteins, alone and in combination, to inhibit the endotoxic activity of isolated LPS and whole bacteria. All three proteins blocked endotoxin activity in: 1) the Limulus amoebocyte lysate assay, 2) priming of PMN for enhanced arachidonate release, and 3) stimulating leukocyte oxidase activity in 1% blood. However, the proteins differ markedly in both relative potency (BPI >> p15s = NP1) in the presence of the plasma LPS-binding protein and in the range of LPS chemotypes that can be inhibited. BPI potently neutralizes LPS of any chemotype, but p15s and defensins are less active against long-chain (S-type) LPS. In whole blood ex vivo, the p15s and NP1 are approximately 1000-fold less potent than BPI, but at subinhibitory doses act in synergy with BPI to inhibit the TNF-inducing activity of a serum-resistant encapsulated strain of Escherichia coli (K1/r). The anti-endotoxic effects of p15 and NP1 against E. coli K1/r in whole blood appear secondary to growth arrest, because, in marked contrast to BPI, they are not evident against nonviable bacteria (pretreated with antibiotic) nor isolated LPS. Thus, BPI stands out for its ability to inhibit isolated or bacterial LPS under physiologic conditions. However, p15s and defensins may also contribute to suppression of endotoxic signaling by Gram-negative bacteria via synergistic (with BPI) growth inhibition upon extracellular release of these proteins from PMN during inflammation.

Bacterial lipopolysaccharide primes human neutrophils for enhanced release of arachidonic acid and causes phosphorylation of an 85-kD cytosolic phospholipase A2.

Production of leukotriene B4 (LTB4) by human neutrophils (PMN) in response to different stimuli is increased after pretreatment with lipopolysaccharides (LPS). We have analyzed the steps in arachidonic acid (AA) metabolism affected by LPS by examining release of AA and its metabolites from [3H]AA prelabeled PMN. Pretreatment of PMN for 60 min with up to 1 microgram/ml of LPS alone had no effect, but release of [3H]AA was stimulated up to fivefold during subsequent stimulation with a second agent. In the absence of LPS-binding protein (LBP), priming was maximal after pretreatment of PMN with 10 ng of LPS/ml for 60 min; in the presence of LBP maximal priming occurred within 45 min at 0.1 ng of LPS/ml and within 15 min at 100 ng of LPS/ml. Treatment of PMN with 10 ng of LPS/ml also increased uptake of opsonized zymosan by up to 60%. Phospholipids are the source of released [3H]AA. No release was observed from [14C]oleic acid (OA)-labeled PMN suggesting that phospholipolysis may be specific for [3H]AA-labeled phospholipid pools. Cytosol from PMN primed with LPS contains two to three times the phospholipase A2 (PLA2) activity of control PMN, against 1-palmitoyl-[2-14C]arachidonoyl-phosphatidylcholine. This activity is Ca2+ dependent and dithiothreitol resistant. LPS priming is accompanied by reduced migration during SDS-PAGE of an 85-kD protein, identified as a cytosolic PLA2. The extent and kinetics of this effect of LPS on cPLA2 parallel the priming of [3H]AA release, both depending on LPS concentration either with or without LBP. These findings suggest that priming by LPS of AA metabolism by PMN includes phosphorylation of an AA-phospholipid-selective cytosolic PLA2 that is dissociated from activation until a second stimulus is applied.

The bactericidal/permeability increasing protein of neutrophils is a potent antibacterial and anti-endotoxin agent in vitro and in vivo.

The Bactericidal/Permeability Increasing protein (BPI) is a major constituent of the azurophilic granules of human and rabbit polymorphonuclear leukocytes (PMN). The cDNA of the highly conserved protein has been isolated from man, rabbit and cow. The ca. 50 kDa BPI and a ca. 25 kDa bioactive N-terminal fragment are cytotoxic only for Gram-negative bacteria (GNB). This target-cell specificity reflects the strong attraction of the highly cationic protein for the negatively charged lipopolysaccharides (LPS) in the bacterial envelope. Native and recombinant (r) holo-BPI and the N-terminal fragment (rBPI-23) bind with high affinity (apparent Kd 1-10 nM) to all forms of isolated LPS so far examined, and inhibit the numerous biological effects of LPS in vitro (including in whole blood ex vivo) as well as in animals. Under the same conditions the antibacterial activities of holo-BPI and rBPI-23 against GNB with rough chemotype LPS are the same, but against serum-resistant and smooth chemotype GNB rBPI-23 is up to 30-fold more potent than holo-BPI. Holo-BPI and rBPI-23 protect mice, rats and rabbits against lethal cytotoxic effects of LPS and in some cases against lethal inoculations with live GNB.

Leukotriene B4 and interleukin-8 in human immunodeficiency virus-related pulmonary disease.

STUDY OBJECTIVE: To investigate the pathogenesis of lung injury in Pneumocystic carinii pneumonia and nonspecific interstitial pneumonitis (NIP), common pulmonary complications of human immunodeficiency virus (HIV) infection. The efficacy of corticosteroid therapy in P carinii pneumonia and the observation that bronchoalveolar lavage (BAL) neutrophilia predicts a poor prognosis support the premise that the lung injury of P carinii pneumonia is due to the host's inflammatory response to the infection. DESIGN: In vitro measurements on previously collected BAL fluid samples. SETTING: The Clinical Center of the National Institutes of Health, a research hospital and tertiary care referral center. PATIENTS: Five normal volunteers, 5 asymptomatic HIV-positive patients, 10 HIV-positive patients with NIP (5 asymptomatic and 5 with respiratory symptoms), and 19 HIV-positive patients with P carinii pneumonia. MEASUREMENTS AND RESULTS: BAL leukotriene B4 (LTB4), interleukin 8 (IL-8), and phospholipase A2 (PLA2) were measured. IL-8 and PLA2 were elevated in patients with P carinii pneumonia, and IL-8 correlated with BAL fluid absolute neutrophil count. LTB4, IL-8, and PLA2 levels were elevated in patients with NIP; LTB4 and PLA2 levels correlated with absolute neutrophil count, and IL-8 correlated with alveolar-arterial oxygen pressure difference. IL-8 was elevated in the asymptomatic HIV-positive patients, and there was a trend toward elevation of PLA2 in this group. CONCLUSION: IL-8 appears to play a role in the pathogenesis of lung injury in P carinii pneumonia and may be the principal neutrophil chemotaxin in this disease; PLA2 may also be involved in the pathogenesis of P carinii pneumonia. Both LTB4 and IL-8 may be involved in the recruitment of neutrophils and subsequent lung injury of NIP. These data suggest that there are varying mechanisms by which inflammatory cells are recruited to the lung in different HIV-related lung diseases.

Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components.

The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including tumor necrosis factor-alpha (TNF alpha) and IL-1 beta. We have demonstrated that Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM), mycobacterial heat shock protein-65 kD, and M. tuberculosis culture filtrate, devoid of LPS as assessed by the Amebocyte Lysate assay, stimulate the production of TNF alpha and IL-1 beta proteins and mRNA from mononuclear phagocytes (THP-1 cells). The effect of LAM on the release of these cytokines was specific, as only LAM stimulation was inhibited by anti-LAM monoclonal antibody. Interestingly, we found that LAM and Gram-negative bacterial cell wall-associated endotoxin LPS may share a similar mechanism in their stimulatory action as demonstrated by inhibition of TNF alpha and IL-1 beta release by monoclonal antibodies to CD14. Anti-CD14 monoclonal antibody MY4 inhibited both TNF alpha and IL-1 beta release with LAM and LPS but no effect was observed with other mycobacterial proteins. An isotype antibody control did not inhibit release of cytokines under the same experimental conditions. M. tuberculosis and its components upregulated IL-1 beta and TNF alpha mRNAs in THP-1 cells. Nuclear run-on assay for IL-1 beta demonstrated that LAM increased the transcription rate. The induction of IL-1 beta was regulated at the transcriptional level, in which these stimuli acted through cis-acting element(s) on the 5' flanking region of the IL-1 beta genomic DNA. M. tuberculosis cell wall component LAM acts similarly to LPS in activating mononuclear phagocyte cytokine TNF alpha and IL-1 beta release through CD14 and synthesis at the transcriptional level; both cytokines are key participants in the host immune response to tuberculosis.

Therapeutic trial of lipid X in a canine model of septic shock.

Three groups of dogs were given lipid X (0, 1, or 10 mg/kg) every 8 h for for seven doses, starting simultaneously with the intraperitoneal placement of Escherichia coli-containing fibrin clots. All animals developed bacteremia, hypotension, and a pattern of decreased left ventricular ejection fraction characteristic of septic shock (P = .01). Survival rates and survival times were not significantly different between treatment groups (P > .2). In a similar experiment, higher doses of lipid X resulted in a significantly decreased survival time compared with concurrent controls (P = .04). Animals receiving lipid X did not differ from controls in serial determinations of temperature, hemodynamic measurements, or laboratory parameters (except serum total protein). Although lipid X has antiendotoxin effects, no benefit could be demonstrated in this antibiotic-treated, gram-negative bacillary-infected model of septic shock. These data do not support a therapeutic role for lipid X in the treatment of gram-negative sepsis.

Antagonism of lipopolysaccharide-induced priming of human neutrophils by lipid A analogs.

Lipid X, a monosaccharide precursor of the lipid A component of LPS, has been found to antagonize LPS-induced priming of human neutrophils in a manner consistent with competitive inhibition. In this investigation, the inhibition of neutrophil priming by lipid A analogs was found to be specific for LPS-induced priming. Priming of neutrophils by TNF, IL-8, and C5a were all unaffected by increasing concentrations of 3-aza-lipid X-4-phosphate (compound 3), a monosaccharide LPS-antagonist. Unlike lipid X, the pattern of antagonism exhibited by some monosaccharide LPS-antagonists was noncompetitive-like. The relationship between the chemical structure and inhibition pattern was found to be complex and not simply related to the type of acyl linkage at the C-3 position of the glucosamine backbone. Lipid A analogs were found to antagonize calcium ionophore A23187-stimulated leukotriene B4 (LTB4) production from LPS-primed neutrophils in a pattern of inhibition qualitatively similar to that seen with FMLP-stimulated O2- production. Resting and FMLP-stimulated (peak) cytosolic-free calcium levels did not differ significantly between unprimed and LPS-primed neutrophils, (p = 0.67 and p = 0.97, respectively). Furthermore, antagonism of LPS-mediated priming by 3-aza-lipid X-4-phosphate (compound 3) could not be explained by changes in intracellular calcium flux despite marked inhibition of O2- production (p less than 0.0001). Thus, lipid A analogs antagonize only LPS-induced priming and the pattern of inhibition is dependent on the chemical structure. Inhibition of LPS-induced priming by lipid A analogs may involve an early step in the signal transduction pathway common to both O2- and LTB4 generation, but independent of intracellular calcium concentration.

Human neutrophil-derived histamine-releasing activity (HRA-N) causes the release of serotonin but not arachidonic acid metabolites from rat basophilic leukemia cells.

The effects of neutrophil-derived histamine-releasing activity (HRA-N) on arachidonic acid (AA) metabolism is unknown. Human basophils exposed to HRA-N released 25% of total histamine but no leukotriene C4 (LTC4). To confirm this phenomenon, rat basophilic leukemia (RBL) cells were exposed to HRA-N as well as anti-IgE, or calcium ionophore A23187. RBL cells incubated with A23187 released 44% of available serotonin and 59 and 124 pmol/10(6) cells of prostaglandin D2 (PGD2) and LTC4, respectively. Anti-IgE stimulation resulted in 34% serotonin release and the generation of 34 pmol PGD2 per 10(6) cells and 72 pmol LTC4 per 10(6) cells. In contrast, HRA-N (2 U/ml) induced 20% serotonin release, 4 pmol PGD2 per 10(6) cells, and 0.6 pmol LTC4 per 10(6) cells. Neither increasing the dose nor the incubation time of HRA-N enhanced the generation of AA metabolite. Additionally, the spectrum of AA metabolites generated by RBL cells in response to those agents was examined by reverse-phase high-performance liquid chromatography. RBL cells stimulated with A23187 released PGD2, LTB4, and its isomers, LTC4, and 5-hydroxyeicosatetraenoic acid. In contrast, HRA-N stimulation resulted in only minimal PGD2 generation and no other discernable AA metabolites. Thus, HRA-N causes selective release of serotonin without inducing AA metabolites. These data suggest that HRA-N activates mast cells through a unique pathway.

Systemic complications of fluid resuscitation.

Fluid administration in critically ill individuals is frequently a major component of their therapy. There are important effects on blood pressure and maintenance of cardiac output and oxygen delivery, as detailed elsewhere in this text. There are also potentially negative side effects of this therapy, which have been less well defined. Edema of the gastrointestinal tract has been well described, primarily with crystalloid infusions. Gastrointestinal edema may have very complicated effects on albumin kinetics, fluid flux, and ion flux. It may lead to development of ileus. Increased nasogastric tube output may be incorrectly construed as unremitting obstruction rather than a result of the aforementioned changes and increased crystalloid loads. The relationships of intestinal edema to intestinal absorptive function and diarrhea are less clear. At present, changes in type of fluid infusion or correction of serum albumin level to normal cannot be uniformly recommended. The myocardium, although showing evidence of edema with crystalloid infusion, may appear to benefit from colloidal, osmotically active suspensions in the all too few studies that have been done. To date, there is no study giving evidence of clinically different outcome using a variety of fluids that cause, reduce, or prevent this edema. The presence or absence of myocardial edema may be important in patients who demonstrate decreased ventricular function during sepsis or other disorders in which aggressive fluid administration is routine. Edema of the skin has been associated primarily with decreased oxygen tension. Other studies have shown an association with impaired wound healing or increased risk of infection. A direct causal relationship can only be inferred. We are left with a sense that aggressive fluid resuscitation with crystalloid, although improving oxygen delivery, may have other deleterious effects on organ systems, such as the gastrointestinal tract, myocardium, and integument. The edema resulting from crystalloid administration may lessen or negate the benefits of increased oxygen delivery. Care needs to be taken in interpreting any alteration in organ function with respect to the fluid type and volume being administered. An alternative choice of therapy is lacking at present. The role of colloid has not been as well investigated as that of crystalloid and further study is warranted before any benefits become clear.

Platelet-activating factor stimulates eicosanoid production in cultured feline tracheal explants.

Eicosanoids have been shown to be major mediators of airway inflammation. Platelet-activating factor (PAF), a potent bronchoconstrictor and stimulator of respiratory mucous secretion, may mediate some of its effects via eicosanoid production. To explore eicosanoid generation by cultured feline tracheal explants, eicosanoids were measured following PAF stimulation. After labeling the explants with [3H]arachidonic acid, supernatant from control and PAF treated explants was fractionated by reverse phase high-performance liquid chromatography (HPLC). The resulting elution pattern suggested the release of arachidonic acid (AA), 15-hydroxyeicosatetraenoic acid (HETE), leukotriene (LT)B4, C4, prostaglandin (PG) D2/E2/F2 alpha, and 6-keto-PGF1 alpha. Radioimmunoassay (RIA) following HPLC resolution confirmed that PAF induced a significantly increased release of peptido-leukotrienes, PGD2, PGE2, PGF2 alpha, LTB4, and 5-HETE, as well as thromboxane (TX) B2. The most remarkable increase was LTC4/D4/E4 (15 x control) and PGD2 (4 x control). The PAF antagonist Ro 19-3704 had an inhibitory effect on the PAF-stimulated release of peptido-leukotrienes. We conclude that PAF stimulates the production of a variety of lipoxygenase and cyclooxygenase pathway metabolites in feline airways.

Endotoxin-neutralizing properties of the 25 kD N-terminal fragment and a newly isolated 30 kD C-terminal fragment of the 55-60 kD bactericidal/permeability-increasing protein of human neutrophils.

The bactericidal/permeability-increasing protein (BPI) of polymorphonuclear leukocytes (PMN) is a potent cytotoxin, specific for Gram-negative bacteria, that also inhibits endotoxin activity by neutralizing isolated bacterial lipopolysaccharides (LPS). We have previously shown that an isolated 25 kD N-terminal fragment of human BPI carries all the antibacterial activities of the parent 55-60 kD molecule. In this study we have compared the LPS-neutralizing activities of human holo-BPI, the N-terminal fragment and a 30 kD C-terminal fragment that we have now isolated. We show that the N-terminal fragment also has LPS-neutralizing activity as detected by inhibition (up to 95%) of (a) activation by LPS of procoagulant proteases in Limulus amebocyte lysates, (b) LPS "priming" of PMN, and (c) LPS-mediated production of tumor necrosis factor in whole human blood. Holo-BPI and the 25 kD fragment have similar neutralizing potency (in nanomolar range) in all assays toward "smooth" LPS from Escherichia coli O111:B4 and O55:B5 (possessing long chain polysaccharide or O-antigen), and "deep rough" LPS from Salmonella minnesota Re595 mutant (possessing no O-antigen). The C-terminal fragment of BPI is devoid of antibacterial activity when tested against BPI-sensitive E. coli J5, but does have endotoxin-neutralizing activity. This activity is weak relative to holo-BPI and the 25 kD N-terminal fragment in the Limulus and PMN-priming assay, but is comparable for inhibition of TNF production in whole blood. We conclude that the principal determinants for LPS recognition and neutralization, like those for antibacterial action, reside in the N-terminal half of the BPI molecule, but that sites within the C-terminal half can also contribute to BPI-LPS interaction once LPS is detached from the bacterial envelope.

Antibiotics versus cardiovascular support in a canine model of human septic shock.

This study compares the efficacy of antibiotics (cefoxitin and gentamicin), cardiovascular support (fluids and dopamine titrated by intravascular monitoring to hemodynamic end points), and a combination of these two therapies in dogs with septic shock induced by an intraperitoneal clot containing Escherichia coli. Survival rates were 0, 13, 13, and 43% in groups receiving no therapy (controls), antibiotics alone, cardiovascular support alone, or combined therapy (P less than 0.01), respectively. The improved survival observed in the group receiving combined therapy considerably exceeded that in the groups receiving either therapy alone (i.e., a synergistic increase P less than 0.05). Compared with antibiotics alone, cardiovascular support alone prolonged survival time (P less than 0.006). All groups developed similar and significant (P less than 0.01) increases in endotoxin levels; however, in the combined therapy group, nonsurvivors (compared with survivors) had higher levels of endotoxemia (P less than 0.05). Although survivors and nonsurvivors in the combined therapy group required similar (P = 0.10) quantities of fluid therapy, nonsurvivors gained more weight (P less than 0.05), suggesting abnormal vascular permeability with extravascular retention of fluids in the nonsurvivors. This study demonstrates that antibiotics alone and cardiovascular support alone are relatively ineffective in the treatment of septic shock. When combined, however, these two therapies provide moderately successful treatment for this highly lethal disorder.