Browse Health
Surgical Specialist
35 years of experience
Accepting new patients

Education ?

Medical School Score
Wayne State University (1975)
  • Currently 1 of 4 apples

Awards & Distinctions ?

Appointments
Umdnj Robert Wood Johnson Medical School
Professor
Associations
American Board of Surgery
American College of Surgeons
American Head and Neck Society

Affiliations ?

Dr. Slotman is affiliated with 9 hospitals.

Hospital Affilations

Score

Rankings

  • Our Lady Of Lourdes Medical Center
    1600 Haddon Ave, Camden, NJ 08103
    • Currently 2 of 4 crosses
  • South Jersey Healthcare - Regional Medical Center
    1505 W Sherman Ave, Vineland, NJ 08360
    • Currently 2 of 4 crosses
  • Cooper University Hospital
    1 Cooper Plz, Camden, NJ 08103
    • Currently 2 of 4 crosses
  • Lourdes Medical Center of Burlington County
    218A Sunset Rd, Willingboro, NJ 08046
    • Currently 1 of 4 crosses
  • Cooper Medical Center
  • Kennedy Health Systems
    18 E Laurel Rd, Stratford, NJ 08084
  • South Jersey Healthcare - Elmer Hospital
    501 Front St, Elmer, NJ 08318
  • Cooper Hospital Umc
  • South Jersey Hospital - Bridgeton
    333 Irving Ave, Bridgeton, NJ 08302
  • Publications & Research

    Dr. Slotman has contributed to 59 publications.
    Title Prostacyclin is Neither Sufficient Alone nor Necessary to Cause Pulmonary Dysfunction: Results from Infusions of Prostacyclin and Antiprostacyclin Antibody in Porcine Septic Shock.
    Date August 2001
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVE: This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock. DESIGN: Experimental. SETTING: Laboratory. SUBJECTS: Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion. MEASUREMENTS AND MAIN RESULTS: Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups. CONCLUSIONS: Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

    Title The Cardiovascular Hemodynamics and Leukotriene Kinetics During Prostacyclin and Anti-prostacyclin Antibody Infusions in Septic Shock.
    Date November 2000
    Journal Shock (augusta, Ga.)
    Excerpt

    This study evaluated whether or not prostacyclin (PGI2) was necessary or sufficient by itself in a pathophysiologic concentration to mediate the cardiovascular dysfunction of septic shock. Anesthetized adult swine received anesthesia only (ANESTHESIA CONTROL, n = 6); graded Aeromonas hydrophila, 10(10)/mL, infusion at 0.2 mL/kg/h that increased to 4.0 mL/kg/h over 3 h (SEPTIC SHOCK CONTROL, n = 6); pathophysiologic prostacyclin infusion to match septic shock control plasma levels without bacteremia (PGI2 INFUSION, n = 6), or graded Aeromonas hydrophila plus anti-prostacyclin antibody infusion (ANTI-PGI2-Ab INFUSION, n = 5). This graded porcine bacteremia model was 100% lethal after 4 h. Cardiovascular hemodynamics, arterial blood gases, and plasma levels of arachidonate metabolites were measured at baseline and hourly over a 4-h period. The results showed that PGI2 was not a necessary mediator of impaired cardiovascular hemodynamics in graded bacteremia, as anti-PGI2 antibody infusion did not improve the cardiac index, systemic vascular resistance, or peripheral oxygen balance in septic animals. Also, PGI2 was not sufficient alone to cause the cardiovascular dysfunction of sepsis, as pathophysiologic infusion of PGI2 did not reproduce such changes in normal animals. PGI2 blockade during bacteremia significantly increased LTC4D4E4, and LTB4 whereas PGI2 infusion suppressed LTC4D4E4 concentration, suggesting that endogenous PGI2 may blunt leukotriene release during septic shock. These results indicate a complex dynamic equilibrium among prostacyclin and leukotrienes in septic shock.

    Title Preoperative Chemotherapy-sensitized Radiation Therapy for Cervical Metastases in Head and Neck Cancer.
    Date March 2000
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To determine the efficacy of concurrent preoperative cisplatin chemotherapy and radiotherapy (CT/RT) for patients with advanced head and neck cancer and cervical metastatic disease. DESIGN: Retrospective analysis. SETTING: University hospitals. PATIENTS: Eighty-eight patients with operable stage III and IV squamous cell carcinoma of the head and neck and palpable cervical lymphogenous metastases received preoperative concurrent CT/RT followed by planned neck dissection. INTERVENTIONS: All patients undergoing CT/RT received concomitant continuous infusions of cisplatin (20 mg/m2) on days 1 to 4 and 22 to 25 of CT/RT. Thirty-nine patients underwent single-fraction (1.8-Gy) radiotherapy to 45.0 Gy, and 49 patients received 10 single-fraction (1.8-Gy) treatments, which were hyperfractionated (1.2-Gy twice a day) to 46.8 Gy. MAIN OUTCOME MEASURES: The 71 patients for whom complete post-CT/RT data were available were evaluated for clinical response in addition to survival. Histologic complete response (HCR) was confirmed from planned neck dissection specimens (n = 48) after clinical complete response (CCR) from initial CT/RT. Kaplan-Meier statistical analysis for disease-specific survival and overall survival was performed on all 88 patients who received CT/RT. RESULTS: A CCR and an HCR were noted in 78% (18/23) and 59% (10/17) of patients with N1 lesions, respectively, and in 60% (29/48) and 45% (14/31) of patients with N2-3 lesions, respectively. The percentage of patients with CCR who also had HCR was 67% (10/15) for patients with N1 lesions and 54% (14/26) for patients with N2-3 lesions. With a median follow-up of 18.5 months, the Kaplan-Meier disease-specific survival rate at 54 months (n = 88) was 70% (21/30) for patients with N1 lesions, 60% (24/40) for patients with N2 lesions, and 39% (7/18) for patients with N3 lesions. The overall survival and disease-specific survival rates at 5 years for all nodal groups combined were 36% (32/88) and 59% (52/88), respectively. CONCLUSIONS: A CCR to CT/RT was achieved in nearly two thirds of patients with head and neck cervical lymphogenous metastases, independent of nodal tumor load. Most patients (59% [24/41]) with CCR were pathologically tumor free before neck dissection.

    Title Platelet-activating Factor and Arachidonic Acid Metabolites Mediate Tumor Necrosis Factor and Eicosanoid Kinetics and Cardiopulmonary Dysfunction During Bacteremic Shock.
    Date December 1999
    Journal Critical Care Medicine
    Excerpt

    Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF). The purpose of this investigation was to a) examine temporal patterns of TNF and arachidonic acid metabolite release in a porcine model of bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and leukotrienes to determine the relationships among these inflammatory response mediators and the alterations in cardiorespiratory dysfunction for which they are required.

    Title Interleukin-1 Mediates Hemodynamic Dysfunction and Release of Eicosanoids and Tumor Necrosis Factor During Graded Bacteremia.
    Date August 1999
    Journal Shock (augusta, Ga.)
    Excerpt

    The pathophysiologic events of sepsis mediated by interleukin-1 (IL-1) remain ill-defined. The purpose of this study was to identify the circulatory derangements of which IL-1 was a necessary mediator and evaluate its interactions with tumor necrosis factor (TNF) and the eicosanoids during graded bacteremia. Eleven adult female swine were anesthetized, mechanically ventilated, and monitored with pulmonary artery catheters and arterial lines; they received intravenously either saline vehicle (septic control, n = 6) or human recombinant IL-1 receptor antagonist (IL-1ra, n = 5). The animals were then infused with Aeromonas hydrophila (10(9)/mL) for 4 h at rates gradually increased from .2 mL/kg/h to 4 mL/kg/h over 3 h, then sacrificed after 4 h. Mean arterial pressure (MAP), left ventricular stroke work index (LVSWI), and systemic vascular resistance index (SVRI) were recorded at baseline and hourly thereafter, and plasma 6-keto-PGF1alpha (6-KETO), tumor necrosis factor-alpha (TNF) and leukotrienes B4(LTB4) and C4D4E4 (LTCDE), pg/mL, were measured by ELISA. MAP, LVSWI, arterial P(O2) all decreased in the septic control group to levels significantly below those of the IL-1 antagonist animals. Circulating 6-KETO, LTCDE, and TNF increased significantly in all septic animals. Plasma LTB, and TNF were reduced by IL-1 blockade, compared with septic controls. TxB2 was not affected by IL-1 inhibition. There were no intergroup differences in platelet aggregation, but the in vitro aggregation response decreased from baseline in septic controls to 54+/-27% (p < .05). IL-1 is necessary to the development of systemic hypotension impaired LVSWI, and increased intravascular platelet aggregation during graded bacteremia. Conversely, IL-1 helps to maintain stroke volume and low SVRI in graded bacteremia, possibly through increased prostacyclin release. It may contribute to impaired pulmonary gas exchange and increased tissue oxygen demands. TNF release is stimulated in the presence of unopposed IL-1 and may be synergistic with it in the adverse hemodynamic effects of endogenous IL-1. IL-1 is required for increased leukotriene and prostacyclin levels in this model, but it is not involved in thromboxane release. Whether the lack of survival benefit from IL-1ra in human sepsis is due to these mixed cardiopulmonary and mediator effects, to species differences, or to timing of IL-1ra administration is not clear from the data.

    Title Effect of Advance Directives on the Management of Elderly Critically Ill Patients.
    Date May 1998
    Journal Critical Care Medicine
    Excerpt

    To evaluate the effects of advance directives on the management of elderly, critically ill patients.

    Title Interactions Between Outcomes and Tumor Response to Preoperative Cisplatin-sensitized Radiotherapy in Advanced Head and Neck Cancer. Southern New Jersey Head and Neck Cancer Treatment Group.
    Date December 1997
    Journal American Journal of Surgery
    Excerpt

    Whether or not tumor response to chemotherapy-sensitized radiation therapy (CTRT) for head and neck cancer leads to an improved outcome is unknown.

    Title Differences in Eicosanoid and Cytokine Production Between Injury/hemorrhage and Bacteremic Shock in the Pig.
    Date November 1997
    Journal Shock (augusta, Ga.)
    Excerpt

    Plasma concentrations of the eicosanoids leukotriene (LT)B4, LTC4D4E4, thromboxane (TX)A2 and prostaglandin (PG)I2, and tumor necrosis factor (TNF) were measured during acute bacteremic shock and injury/hemorrhage in two porcine models. As TXA2 and PGI2 are rapidly metabolized, we measured their stable metabolites TXB2 and 6-keto-PGF1 alpha. Bacteremic shock was induced by a graded infusion of Aeromonas hydrophila over 4 h. Injury/hemorrhage was produced by a 30 min, 30% total blood volume hemorrhage followed by a 30 min shock period and then reinfusion of shed blood. Nociceptive afferent nerve stimulation was applied to the brachial plexi to mimic the cardiovascular responses to tissue injury. There was no increase in eicosanoid or TNF levels in the injury/hemorrhage model. In sepsis there was an early peak in TNF (at 60 min) followed by peaks in LTB4 and LTC4D4E4 at 180 min. Both TXB2 and 6-keto-PGF1 alpha showed large increases at the end of the study but there was no evidence that they had reached a peak. These results suggest that the very early inflammatory response in bacteremic shock and injury/hemorrhagic shock may be quite different. This may have implications for any therapies aimed at reducing the incidence of multiple organ failure after either of these physiological insults.

    Title Multivariate Regression Modeling for the Prediction of Inflammation, Systemic Pressure, and End-organ Function in Severe Sepsis.
    Date November 1997
    Journal Shock (augusta, Ga.)
    Excerpt

    The purpose of this study was to evaluate the feasibility of developing multivariate equations that predicted blood pressure and measured levels of end-organ function indicators quantitatively up to 72 h in advance in critically ill patients with severe sepsis. Data collected prospectively from 59 patients entered into two sequential placebo-controlled clinical trials of recombinant interleukin-1 receptor antagonist in severe sepsis and septic shock was analyzed retrospectively. A series of multivariate equations were developed to predict systemic pressure, coagulation, and vital organ function indicators quantitatively at 24, 48, and 72 h after the onset of severe sepsis. These equations used physiologic and clinical laboratory measurements, plus circulating levels of eicosanoids and cytokines obtained when severe sepsis criteria first were met, and end-organ function indicators measured 24, 48, and 72 h later. Multivariate predictive equations were developed for temperature, white blood cell count, mean arterial pressure (MAP), Pao2/FiO2 ratio, the Murray acute lung injury score, alanine and aspartate aminotransferases, prothrombin time, partial thromboplastin time, platelet count, serum creatinine, and Glasgow Coma Scale. The percentage of data variation explained by the equations ranged from 11.4% (MAP at 48 h) to 85.1% (platelet count at 24 h). Linear regression analysis of predicted values, obtained by entering baseline data from individual patients into the multivariate equations, versus observed results at 24, 48, and 72 h yielded regression coefficients ranging from .371 (MAP at 48 h) to .924 (platelet count at 24 h). Among patients without end-organ dysfunction at baseline, sensitivities for predicting values consistent with the onset of organ failure were > or = 88% in 21/27 (78%) of the predictive equations. Resolution of organ failure indicators present at baseline was predicted successfully in individual patients, with 20/27 (74%) specificities > or = 76%. In critically ill patients with severe sepsis, multivariate analysis of interactions among clinical observations, standard laboratory tests, and inflammatory response mediators produced equations that predicted systemic blood pressure and inflammatory and end-organ function indicators quantitatively up to 72 h in advance. Whether or not this methodology might be developed further to predict subclinically the onset and resolution of acute organ failure and shock in critically ill patients, and if it can be validated in a prospective trial will require further studies.

    Title Pilot Study of Cytokines in Emergency Department Patients with Systemic Inflammatory Response Syndrome.
    Date September 1997
    Journal Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine
    Excerpt

    OBJECTIVE: To determine the potential utility of cytokine and arachidonic acid metabolite levels in ED patients with systemic inflammatory response syndrome (SIRS) as a predictor of progression to severe sepsis. METHODS: A prospective, observational study of test performance was performed using convenience samples of adult control subjects and admitted patients. The latter patients were identified in the ED as having signs of SIRS. Level of cytokines and arachidonic acid metabolites measured from specimens obtained in the ED were compared between groups and associated with the progression of sepsis within 24 hours in the SIRS patients. RESULTS: There were 30 control patients and 29 SIRS patients. There were 8 SIRS subjects who progressed to severe sepsis within 24 hours using the following criteria (hypotension, n = 1; and organ dysfunction, n = 2). Of the 21 SIRS subjects who did not progress to severe sepsis, 11 had resolution of SIRS criteria at 24 hours. There were no significant differences in mean mediator levels between the SIRS patients who progressed to severe sepsis and those who did not. Of the 11 patients with resolution of SIRS criteria at 24 hours, the mean interleukin-6 (IL-6) level was significantly lower than that for the patients who did not recover or who progressed at 24 hours (n = 18); 65.4 +/- 49.1 vs 230 +/- 112 pg/mL, p = 0.001). Six of 15 subjects with IL-6 > 150 pg/mL progressed to severe sepsis (p = NS). Using threshold values based on the range of levels for normals, the sensitivity of an abnormal marker for the development of severe sepsis within 24 hours varied from 50% to 87%, while the specificity varied from 11% to 84%. CONCLUSION: While mean levels were significantly elevated when compared with those of normal control subjects, they had limited ability to predict the subset of patients likely to progress to severe sepsis. However, initial low levels of cytokines may have exclusionary prognostic value. Prospective validation of the latter finding is warranted.

    Title Unopposed Interleukin-1 is Necessary for Increased Plasma Cytokine and Eicosanoid Levels to Develop in Severe Sepsis.
    Date August 1997
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: The purpose of the study was to identify the changes in plasma prostaglandin, leukotriene, and cytokine levels during clinical severe sepsis for which interleukin-1 was necessary. SUMMARY BACKGROUND DATA: Circulating prostaglandins, leukotrienes, and cytokines have been implicated as causative agents of systemic inflammation due to sepsis. However, interactions between interleukin-1 and the other cytokine and eicosanoid mediators of severe sepsis are not well-defined. METHODS: As part of two sequential multisite, prospective, randomized, double-blind, placebo-controlled clinical trials, 37 patients with severe sepsis received interleukin-1 receptor antagonist (IL-1ra) 100-mg bolus followed by 2 mg/kg per hour intravenously for 72 hours (n = 20) or placebo (n = 17). Plasma thromboxane B2 (TxB2), prostaglandin 6-keto-F1alpha (PGI), leukotriene B4 (LTB4), leukotriene C4D4E4 (LTC4D4E4), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay before study drug infusion (baseline) and at 24, 48, and 72 hours after the beginning of the study drug infusion. RESULTS: Differences between placebo and IL-1ra for plasma LTB4 were not significant, but only IL-1ra LTB4 increased from baseline. Plasma TxB2, PGI, LTC4D4E4, TNF, and IL-6, expressed as % baseline, decreased significantly in patients receiving IL-1ra compared with the placebo group (p < 0.05), whereas plasma IL-1 increased significantly. CONCLUSIONS: Interleukin-1 may be a necessary mediator of increased circulating PGI, TxB2, LTC4D4E4, TNF, and IL-6 levels in patients with severe sepsis. Plasma IL-1 and LTB4 are increased with infusion of IL-1 receptor antagonist. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

    Title Confirmatory Interleukin-1 Receptor Antagonist Trial in Severe Sepsis: a Phase Iii, Randomized, Double-blind, Placebo-controlled, Multicenter Trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.
    Date August 1997
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

    Title Pathophysiologic Plasma Levels of Leukotriene C4 in Relation to the Hemodynamic Dysfunction and Mediator Release of Graded Bacteremia.
    Date June 1997
    Journal Shock (augusta, Ga.)
    Excerpt

    This study was undertaken to identify those events of bacteremic shock that pathophysiologic levels of leukotriene C4 (LTC4) alone were sufficient to cause. Sixteen adult swine were studied for 4 h in three groups: ANES (n = 6) received anesthesia only; Septic (n = 6) received Aeromonas hydrophila, 10(9)/mL, intravenously, increased incrementally from .2 to 4.0 mL/kg/h; LTC4 (n = 4) received LTC4 infused intravenously, at rates that approximated LTC4 levels of Septic animals. Measurements included mean arterial pressure and arterial PO2, mmHg, pulmonary and systemic (SVRI) vascular resistance indexes, cardiac index (CI), oxygen extraction ratio, hematocrit; thromboxane B2 (TxB2), prostaglandin 6 keto F1 alpha (6 keto), leukotrienes B4 and C4D4E4, and tumor necrosis factor were measured in pg/mL by ELISA. Statistical analysis was performed by ANOVA and general linear model). Mean arterial pressure increased from 100 +/- 5 to 141 +/- 9 in the LTC4 group, but decreased in the Septic group from 90 +/- 7 at baseline to 62 +/- 6 at 3 h. In the LTC4 group, SVRI did not differ from ANES, and pulmonary vascular resistance, PO2, and CI did not change from baseline. In the LTC4 group, TxB2 and 6 keto levels decreased from 149 +/- 26 to 87 +/- 18 and 58 +/- 10 to 44 +/- 12, respectively; in the Septic group, TxB2 increased 140-fold and 6 keto increased 60-fold. Pathophysiologic LTC4 is not sufficient alone to cause the derangements in CI and SVRI, and tissue metabolism induced by graded bacteremia. Significantly increased systemic blood pressure suggests that endogenous pathophysiologic LTC4 may be involved. LTC4 does not increase plasma eicosanoids and tumor necrosis factor, but may down-regulate prostaglandin and leukotriene release.

    Title Evaluation of Enzyme-linked Immunosorbent Assays for Quantitation of Eicosanoid Mediators of Sepsis Syndrome.
    Date January 1997
    Journal Shock (augusta, Ga.)
    Excerpt

    Thromboxane, prostacyclin, and the leukotrienes are eicosanoids that have been implicated as mediators of the host inflammatory response to infection and injury. Commercial enzyme-linked immunosorbent assays (ELISA) are being increasingly utilized to quantitate plasma eicosanoid concentrations in both clinical and experimental systemic inflammatory conditions. The objectives of this study were to 1) critically examine the performance characteristics of commercial ELISA kits for thromboxane B2, 6 keto-prostaglandin F1 alpha, leukotriene B4, and leukotrienes C4, D4, and E4; 2) apply the four ELISA kits in obtaining actual eicosanoid plasma values under both baseline and septic conditions; and 3) recommend quality control measures for general use. Although averages of multiple standard curves from individual assays were variable, there was a strong linear regression relationship between the backfit dose and nominal dose for each level of standard. Precision profiles constructed for each assay type defined a working range where the intra-assay coefficient of variation is less than 10%. Backfit doses deviated most from nominal doses at both extremes of the standard curves and this variation is reflected in the higher percentage errors in these regions. Recovery of each eicosanoid analyte was 96-103%. Calculated sensitivities were somewhat higher than the manufacturer's specifications. When applied to actual measurements in human and porcine plasma, the assays yielded values that fell within the working ranges of the standard curves with the exception of leukotriene B4. Thus, the ELISAs examined were reproducible, precise, and accurate within a specific working range for each assay type. However, internal controls were lacking in the commercial kits examined, which made assessment of intra- and inter-assay variation difficult.

    Title Platelet Activating Factor Mediates Cardiopulmonary Dysfunction During Graded Bacteremic Shock.
    Date September 1996
    Journal The Journal of Trauma
    Excerpt

    OBJECTIVE: To determine whether or not platelet activating factor (PAF) is a necessary mediator of cardiovascular dysfunction during graded bacteremia, and to identify PAF interactions with eicosanoids and tumor necrosis factor-alpha (TNF-alpha). METHODS: Seventeen anesthetized, hemodynamically monitored adult swine were studied for 4 hours in three groups. Group 1 (ANES, n = 5) were anesthesia controls; group 2 (septic control, SC, n = 6) received intravenous Aeromonas hydrophila (109/mL) at rates incrementally increased from 0.2 to 4.0 mL/ kg/h; group 3 (WEB, n = 6) received the PAF receptor antagonist WEB 2086, 3.0 mg/kg intravenously, then A. hydrophila. Cardiopulmonary parameters and plasma thromboxane B2 (TXB2), prostaglandin 6-keto F1 alpha (PGI2), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), and TNF-alpha were measured hourly. Statistical analysis was carried out using two-way analysis of variance (ANOVA) for repeated measurements, Dunnett's t test, and Student's t test, where appropriate. Statistical significance was determined at the 95% confidence interval. Values are presented as the mean +/- SEM. RESULTS: Pulmonary arterial pressure, pulmonary capillary wedge pressure, central venous pressure heart rate, VO2 and O2ER decreased significantly after WEB 2086 infusion, compared with SC, and mean arterial pressure, systemic vascular resistance index, stroke volume index, and left ventricular stroke work index increased. Arterial pH decreased significantly in SC animals, but was maintained at normal levels during bacteremia in the WEB group. Differences between WEB and SC for cardiac index, pulmonary vascular resistance index, right ventricular stroke work index, PaO2, SaO2, and PcO2, were not significant. The addition of WEB 2086 significantly decreased plasma levels of TXB2, PGI2, LTB4, and TNF-alpha compared with the SC group. LTC4D4E4 was decreased in WEB compared with SC animals, in which LTC4D4E4 increased during graded bacteremia. CONCLUSIONS: PAF is necessary to the development of systemic vasodilation and hypotension, pulmonary hypertension, decreased stroke volume, metabolic acidosis, and increased oxygen uptake during graded bacteremia. PAF-induced eicosanoid and cytokine release may be involved.

    Title Interleukin-1 Mediates Increased Plasma Levels of Eicosanoids and Cytokines in Patients with Sepsis Syndrome.
    Date April 1996
    Journal Shock (augusta, Ga.)
    Excerpt

    The purpose of this was to study evaluate the effects of interleukin-1 (IL-1) inhibition by human recombinant IL-1 receptor antagonist (IL-1ra) on plasma prostaglandin, leukotriene, and cytokine levels in sepsis syndrome. As part of a multisite, prospective, randomized, double-blind, placebo-controlled clinical trial, 19 septic patients received IL-1ra in a 100 mg bolus followed by 2.0 mg/kg/h i.v. for 72 h (n = 10) or placebo (n = 9). Plasma thromboxane B2 (TXB2), prostaglandin 6-keto-F1 alpha (PGI), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF) were measured by ELISA before study drug infusion (baseline) and at 24, 48, 72, and 96 h after the beginning of the study drug infusion. Differences between placebo and IL-1-ra for plasma LTB4 and TNF were not significant. Plasma TXB2, PGI, LTC4D4E4, and IL-6, expressed as % baseline, were significantly lower in patients receiving IL-1ra than in the placebo group (p < .05), while plasma IL-1 was increased significantly. IL-1 may be a necessary mediator of increased circulating PGI, TXB2, LTC4D4E4, and IL-6 levels in patients with sepsis syndrome. Plasma IL-1 is increased with infusion of IL-1ra. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

    Title Comparison of the Hemodynamic Effects of Gasless Abdominal Distention and Co2 Pneumoperitoneum During Incremental Positive End-expiratory Pressure.
    Date February 1995
    Journal The Journal of Surgical Research
    Excerpt

    Laparoscopy is used increasingly in managing critically ill patients. Carbon dioxide (CO2) pneumoperitoneum is used during these procedures. The increased intra-abdominal pressure of CO2 pneumoperitoneum, however, can affect cardiopulmonary performance adversely. Recently, gasless abdominal wall distention has been introduced as an alternative to CO2 pneumoperitoneum. The purpose of this study was to compare the hemodynamic effects of gasless abdominal distention (GAD) with those of CO2 pneumoperitoneum during mechanical ventilation with positive end-expiratory pressure (PEEP). Six anesthetized, paralyzed, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at incremental values of PEEP (0-20 cm H2O, by 5, Control) and then allowed to return to baseline hemodynamic status at 0 cm H2O PEEP. The animals were then randomly assigned to receive either CO2 pneumoperitoneum at 15 mm Hg intra-abdominal pressure (PNEUMO) or GAD (equal to anterior abdominal wall displacement of CO2) and PEEP was reapplied. The animals were allowed to return to hemodynamic baseline and PEEP was reapplied with the alternate method of abdominal wall distention. A complete hemodynamic profile and arterial/mixed venous blood gas measurements were monitored at each value of PEEP. With GAD, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and PaCO2 were significantly reduced, compared to PNEUMO, and PaO2 was increased. Cardiac index was higher in GAD versus PNEUMO at baseline, but was lower for GAD at PEEP levels above 10 cm H2O. These results indicate that in its net effect, GAD does not exacerbate the adverse hemodynamic effects of PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients with Sepsis Syndrome. Results from a Randomized, Double-blind, Placebo-controlled Trial. Phase Iii Rhil-1ra Sepsis Syndrome Study Group.
    Date June 1994
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    OBJECTIVE--To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN--Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION--A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE--Twenty-eight-day all-cause mortality. RESULTS--There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS--There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

    Title Initial Evaluation of Human Recombinant Interleukin-1 Receptor Antagonist in the Treatment of Sepsis Syndrome: a Randomized, Open-label, Placebo-controlled Multicenter Trial.
    Date April 1994
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVES: To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome. DESIGN: Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra. SETTING: Twelve academic medical center intensive care units in the United States. PATIENTS: Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo. INTERVENTIONS: Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. MEASUREMENTS AND MAIN RESULTS: A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated. CONCLUSIONS: This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.

    Title Hemodynamic Effects of Carbon Dioxide Pneumoperitoneum During Mechanical Ventilation and Positive End-expiratory Pressure.
    Date November 1993
    Journal The Journal of Trauma
    Excerpt

    Laparoscopy is frequently used for diagnosis and treatment of critically ill trauma patients. Its effects on cardiopulmonary performance in the intensive care unit patient population, however, are not well-defined. This study evaluated the effects of positive end-expiratory pressure (PEEP) and carbon dioxide (CO2) pneumoperitoneum on hemodynamic function during mechanical ventilation. Five anesthetized, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at 0, 5, 10, 15, and 20 cm H2O PEEP without, and then with 15 mm Hg CO2 pneumoperitoneum. A hemodynamic profile, analyses of arterial and mixed venous blood gases and mixed venous hemoglobin oxygen saturation values were obtained at each data point. Compared with the non-insufflated group, CO2 pneumoperitoneum significantly increased central venous pressure, mean arterial pressure, mean pulmonary artery pressure, pulmonary vascular resistance index, and stroke index for the range of PEEP levels. With PEEP of 10 cm H2O, hemodynamic changes in non-insufflated animals were not statistically significant, but with CO2 pneumoperitoneum, stroke index and left ventricular stroke work index were decreased at 5 cm H2O PEEP, as was cardiac index at 10 cm PEEP. Pulmonary gas exchange was not affected by CO2 pneumoperitoneum. The results indicate that, in this paradigm, CO2 pneumoperitoneum for laparoscopy increases ventricular afterload and exacerbates the adverse effects of PEEP. These findings could be clinically significant in critically ill patients.

    Title Detrimental Effects of High-dose Methylprednisolone Sodium Succinate on Serum Concentrations of Hepatic and Renal Function Indicators in Severe Sepsis and Septic Shock. The Methylprednisolone Severe Sepsis Study Group.
    Date March 1993
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVE: To evaluate the effects of high-dose methylprednisolone sodium succinate on biochemical markers of hepatic and renal function in patients with severe sepsis and septic shock. DESIGN: Retrospective analysis of serial serum chemistries in 382 patients who were entered prospectively into a randomized, placebo-controlled, double-blind clinical trial of high-dose methylprednisolone or placebo in the sepsis syndrome. SETTING: The original study was conducted at 19 academic centers. PATIENTS: Adult patients in severe sepsis or septic shock who met the study entry criteria, which included a clinically defined source of infection and signs of systemic sepsis, were enrolled into the study. Three hundred eighty-two patients were evaluated. INTERVENTIONS: Patients received either methylprednisolone (30 mg/kg) or placebo by iv infusion every 6 hrs for four doses. Hemodynamic variables and serum concentrations of creatinine, urea nitrogen, bilirubin, and aspartate aminotransferase (AST) were recorded on entering the study, at 12 and 24 hrs, and at 3, 7, and 14 days after the first infusion of methylprednisolone or placebo. These data were analyzed retrospectively. MAIN OUTCOME MEASUREMENTS: Hemodynamic and biochemical data were analyzed to determine whether or not hepatic and renal function in the sepsis syndrome had been influenced by methylprednisolone treatment. RESULTS: Differences between methylprednisolone and placebo in hemodynamic variables, the occurrence rate of shock and recovery from shock, mortality rates and serum concentrations of creatinine and AST were not statistically significant. At 12 and 24 hrs, and at 3 and 7 days after the first drug infusion (of methylprednisolone or placebo), blood urea nitrogen was increased from baseline values in a significantly (p < .01) greater proportion of the methylprednisolone-treated patients compared with placebo-treated patients. The frequency of increased serum bilirubin concentrations was significantly (p < .01) greater among methylprednisolone patients vs. the placebo group at 12 and 24 hrs. CONCLUSIONS: The frequency of acutely increased blood urea nitrogen and bilirubin concentrations in severe sepsis was increased significantly with high-dose methylprednisolone therapy. Similar frequencies of circulatory shock in the study groups excluded differences in global perfusion as a cause of this phenomenon. Possible adverse effects of pharmacologic concentrations of methylprednisolone in critically ill patients should be considered in planning treatment.

    Title Hypothermia in the Sepsis Syndrome and Clinical Outcome. The Methylprednisolone Severe Sepsis Study Group.
    Date November 1992
    Journal Critical Care Medicine
    Excerpt

    OBJECTIVE: To evaluate the consequences of clinical hypothermia associated with sepsis syndrome and septic shock. DESIGN: Analysis of data from a multi-institutional, randomized, placebo-controlled, prospective study with predetermined end-point analysis of development of shock, recovery from shock, hospital length of stay, and death. SETTING: Multi-institutional medical and surgical ICUs. PATIENTS: Patients meeting predetermined criteria for severe sepsis syndrome. INTERVENTIONS: Appropriate sepsis and shock care with 50% of patients receiving methylprednisolone and 50% receiving placebo. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of hypothermia (< 35.5 degrees C) is 9% in this population. When compared with febrile patients, hypothermic patients had a higher frequency of central nervous system dysfunction (88% vs. 60%), increased serum bilirubin concentration (35% vs. 15%), prolonged prothrombin times (50% vs. 23%), shock (94% vs. 61%), failure to recover from shock (66% vs. 26%), and death (62% vs. 26%). The hypothermic patients were also more likely to be classified as having a rapidly or ultimately fatal disease upon study admission. CONCLUSIONS: This prospective study confirms that hypothermia associated with sepsis syndrome has a significant relationship to outcome manifest by increased frequency of shock and death from shock. This finding is in sharp contrast to the protective effects of induced hypothermia in septic animals and perhaps man.

    Title Preoperative Combined Chemotherapy and Radiation Therapy Plus Radical Surgery in Advanced Head and Neck Cancer. Five-year Results with Impressive Complete Response Rates and High Survival.
    Date June 1992
    Journal Cancer
    Excerpt

    Radiation therapy combined with cisplatin as a chemoradiation sensitizer (CT/RT) has been reported to enhance tumor response in squamous cell carcinoma of the head and neck. In the present study, CT/RT was used preoperatively in advanced Stage III and IV head and neck cancer. Fifty-three patients were entered prospectively into a Phase II study. Treatment consisted of 4500 cGy of radiation therapy in 5 weeks combined with cisplatin 20 mg/m2 for 4 days during weeks 1 and 4 of radiation therapy. This was followed 4 to 8 weeks later by curative surgery. Pretherapy dental care; long-term nutritional support; individualized skin, mouth, and wound care; and continuous interdisciplinary communication were integral parts of this regimen. In four patients, CT/RT toxicity was seen (8%); three episodes of skin reaction or stomatitis and three episodes of leukopenia (less than 2500/microliters), causing a delay in CT/RT treatment in one patient. Three patients died of other causes during the preoperative interval, without clinical evidence of toxicity. Fifty patients (94%) had a complete (CR) or partial response (PR) to CT/RT. Clinical CR was seen in 38 of 51 (75%) primary tumors and 21 of 27 (78%) cervical nodes. Forty-one patients (77%) underwent curative surgery. In 27 of 32 (84%) resected CR primary tumors and 16 of 18 (89%) CR metastatic nodes, the surgical specimen was microscopically free of tumor. Postoperative morbidity was 32%. Five patients (12%) required additional surgery for their complications. Perioperative mortality was 5%. Five patients had tumor recurrence: three postoperatively after clinical PR to CT/RT and two in clinical CR patients who refused further treatment after CT/RT, then had a recurrence and were salvaged surgically. No patient with a CR in both the tumor and nodes who underwent surgery had a tumor recurrence. With a follow-up of 8 years (median, 40 months), the median survival for all patients was 45 months. The 5-year actuarial survival rate was 43% for all patients and 55% for patients who had CT/RT and surgery. This multimodality treatment of advanced head and neck cancer has low toxicity and impressive survival. It renders a significant number of patients tumor-free before surgery. These patients may be candidates for additional study triaging additional CT/RT for complete CR only and surgery for PR and biopsy-proved residual disease.

    Title The Effects of Prostaglandin E1 on Non-pulmonary Organ Function During Clinical Acute Respiratory Failure. The Prostaglandin E1 Study Group.
    Date May 1992
    Journal The Journal of Trauma
    Excerpt

    The effects of prostaglandin E1 (PGE1) on non-pulmonary vital organs in critically ill patients are not well defined. This study evaluated the role of exogenous PGE1 in systemic homeostasis during the adult respiratory distress syndrome (ARDS). Indicators of end-organ function were analyzed retrospectively in 146 septic or post-trauma patients with ARDS who received PGE1 (30/ng/kg/min) or placebo IV for up to 7 days in a randomized, double-blind clinical trial. Hemodynamic variables and serum levels of creatinine, bilirubin, and SGOT, platelet count, and changes in the white blood cell count were measured daily. Our results indicate that mean arterial pressure, pulmonary artery pressure, and systemic and pulmonary vascular resistance indices were significantly lower in the PGE1 group versus the placebo-treated group. Cardiac index, stroke index, and oxygen delivery index were significantly increased in the PGE1 group. Serum bilirubin and SGOT were decreased significantly among PGE1-treated patients compared with placebo-treated patients, while the white blood cell count increased more significantly from baseline values with PGE1 treatment. Intergroup differences in platelet count and serum creatinine levels were not statistically significant. The results indicate that PGE1 improves cardiovascular performance, hepatic function, and leukocyte availability during clinical ARDS. Prostaglandin E1 did not affect platelet counts and renal function in this study.

    Title Decompression After Gastric Surgery. Gastrostomy Versus Nasogastric Tube.
    Date August 1989
    Journal The American Surgeon
    Excerpt

    The efficacy and associated morbidity and mortality of gastrostomy (G) versus nasogastric (NG) tube decompression after gastric surgery were analyzed in a review of 100 patients. Age, sex, and risk factors were homogeneously distributed between the two groups, while perforated ulcers and emergency operations were more common in the G group. A gastrostomy did not completely eliminate the need for NG tube decompression in the G group. Postoperative morbidity was similar in the two groups, with the exception of an increased incidence of atelectasis in the elective NG group and increased mortality in the emergency G group. There was also a significant increase in length and cost of hospitalization in the emergency G group compared with emergency NG patients. Gastrostomy does not appear to offer any significant advantage over nasogastric decompression after gastric surgery and should be limited to special cases.

    Title Sepsis Syndrome: a Valid Clinical Entity. Methylprednisolone Severe Sepsis Study Group.
    Date June 1989
    Journal Critical Care Medicine
    Excerpt

    The sepsis syndrome represents a systemic response to infection and is defined as hypothermia (temperature less than 96 degrees F) or hyperthermia (greater than 101 degrees F), tachycardia (greater than 90 beat/min), tachypnea (greater than 20 breath/min), clinical evidence of an infection site and with at least one end-organ demonstrating inadequate perfusion or dysfunction expressed as poor or altered cerebral function, hypoxemia (PaO2 less than 75 torr), elevated plasma lactate, or oliguria (urine output less than 30 ml/h or 0.5 ml/kg body weight.h without corrective therapy). One hundred ninety-one patients with the sepsis syndrome were evaluated prospectively and comprised the placebo group of a multicenter trial of methylprednisolone in sepsis syndrome and septic shock. Forty-five percent of the patients were found to be bacteremic. Thirty-six percent of the patients were in septic shock (sepsis syndrome plus a systolic BP less than 90 mm Hg or a decrease from baseline in systolic BP greater than 40 mm Hg) on study entry. An additional 23% of the patients developed shock after admission with 70% doing so within 24 h of study entry. Shock reversal occurred with a 73% frequency. Twenty-five percent of the patients developed the adult respiratory distress syndrome (ARDS). Mortality for the patients with sepsis syndrome who did not develop shock was 13%. Mortality for the groups of patients with shock on admission and shock postadmission was 27.5% and 43.2%, respectively. Forty-seven percent of the bacteremic patients developed shock after study admission compared to 29.6% of the nonbacteremic patients (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Ketoconazole Prevents Acute Respiratory Failure in Critically Ill Surgical Patients.
    Date June 1988
    Journal The Journal of Trauma
    Excerpt

    Effective prophylaxis against acute respiratory failure (ARDS) has not been established. This study investigated whether or not ketoconazole could prevent ARDS in critically ill surgical patients. Seventy-one Surgical Intensive Care Unit (SICU) patients without liver dysfunction received either ketoconazole (n = 35), 200 mg daily via the gastrointestinal tract, or placebo (n = 36), for 21 days or until discharge from the SICU, in a prospective, randomized, double-blind study. Patients were monitored clinically for signs of ARDS, defined as all the following: intrapulmonary shunt greater than 15%, a PaO2/FIO2 ratio less than 150, normal central venous, pulmonary capillary wedge, or left atrial pressure, no other cause of hypoxemia, and a consistent chest X-ray. Thirteen patients (18%) developed ARDS with significantly increased mortality versus non-ARDS patients (69% vs. 29%). The incidence of ARDS was decreased among ketoconazole patients compared to placebo (6% vs. 31%; p less than 0.01), as was median SICU stay (7.0 days vs. 15.5 days; p less than 0.05), and median SICU cost (+5,600. vs. +12,400.; p less than 0.05). Mortality is increased with ARDS after trauma and surgery. We conclude that ketoconazole prevents ARDS, shortens SICU stay, and lowers hospital costs.

    Title Ketoconazole: a Thromboxane Synthetase and 5-lipoxygenase Inhibitor with Antimetastatic Activity in B16-f10 Melanoma.
    Date June 1988
    Journal The Journal of Surgical Research
    Excerpt

    Arachidonic acid metabolites have been implicated in the development of hematogenous tumor metastases. The purpose of this study was to determine the antimetastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor. One hundred seventy-four C57 black male mice were randomized to receive either placebo or 0.0057 mg/g of ketoconazole. Drug and placebo were delivered once daily by intraperitoneal injection beginning 24 hr prior to tumor injection and continuing until sacrifice. All animals were injected subcutaneously in the flank with 5 x 10(6) B16-F10 melanoma cells. Animals were sacrificed at 3 weeks (n = 60), 4 weeks (n = 84), and 5 weeks (n = 30). Metastases were assessed by circumferential inspection of the lungs of all animals at autopsy. Differences in survival and primary tumor mass between study groups were not statistically significant. Pulmonary metastases were present in 37/174 animals. Twenty-nine of the mice with metastases were in the placebo groups, and 8 were in the ketoconazole groups. The incidence of metastases was significantly reduced in the ketoconazole-treated mice compared to placebo both within each group and overall, P was less than 0.05 and 0.001, respectively. This effect was not mediated through changes in local tumor growth.

    Title Effect of Ischemic Skin Flap Elevation on Tissue and Plasma Thromboxane A2 and Prostacyclin Production: Modification by Thromboxane Synthetase Inhibition.
    Date May 1988
    Journal Annals of Plastic Surgery
    Excerpt

    The circulating prostaglandins have been implicated as mediators of microcirculatory derangements in skin and skin-muscle flaps. The study described here investigated the roles of thromboxane A2 and prostacyclin, measured as thromboxane B2 (TxB2) and prostaglandin 6-keto-F1a (PGF1a), in ischemic skin flaps, and the effects of thromboxane synthetase inhibition on flap blood flow and survival. A canine ventral island flap model was used to measure the appearance of TxB2 and PGF1a in the central arterial and venous plasma, and in the tissue and venous effluent of acutely raised flaps; with and without pretreatment with the specific thromboxane A2 synthetase inhibitor UK38485. Prostaglandin levels change significantly during flap elevation, and can be modified beneficially by thromboxane A2 synthetase inhibition, causing dramatic increases in flap blood flow and survival, as predicted by intravital dye penetration. The results presented in this article suggest that the manipulation of these compounds may provide a method of producing a pharmacological delay phenomenon and perhaps even allow effective intervention in the failing flap.

    Title Early Methylprednisolone Treatment for Septic Syndrome and the Adult Respiratory Distress Syndrome.
    Date January 1988
    Journal Chest
    Excerpt

    From November 1, 1982 through December 31, 1985, there were 19 centers and 382 patients that evaluated the effect of methylprednisolone sodium succinate (MPSS) on the septic syndrome. Seventeen of these centers enrolled 304 patients in a prospective, randomized, double-blind, placebo-controlled study to determine if early treatment with MPSS would decrease the incidence of severity of the adult respiratory distress syndrome (ARDS) in patients at risk of ARDS from sepsis. To ensure early institution of the MPSS or placebo therapy (PLA), patients with the presumptive diagnosis of sepsis were identified. That diagnosis was based on the presence of fever or hypothermia (temperature greater than 38.3 degrees C or less than 35.5 degrees C, rectal), tachypnea (greater than 20 bpm), tachycardia (greater than 90 bpm) and the presence of one of the following indices of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels or oliguria. The treatment, either MPSS 30 mg/kg or PLA, was given in four 20-minute infusions six hours apart and was initiated within two hours of the presumptive diagnosis of sepsis. The development and reversal of the adult respiratory distress syndrome (ARDS) was followed and resulted in data on 304 of the 382 randomized patients. A trend toward increased incidence of ARDS was seen in the MPSS group 50/152 (32 percent) compared to the placebo group 38/152(25 percent) p = 0.10. Significantly fewer MPSS patients reversed their ARDS 15/50 (31 percent) compared to placebo 23/38 (61 percent) p = 0.005. The 14-day mortality in patients with ARDS treated with MPSS was 26/50 (52 percent) compared to placebo 8/22 (22 percent) p = 0.004. We conclude that early treatment of septic syndrome with MPSS does not prevent the development of ARDS. Additionally, MPSS treatment impedes the reversal of ARDS and increases the mortality rate in patients with ARDS.

    Title A Controlled Clinical Trial of High-dose Methylprednisolone in the Treatment of Severe Sepsis and Septic Shock.
    Date October 1987
    Journal The New England Journal of Medicine
    Excerpt

    The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock.

    Title Interaction of Thromboxane A2 and Tissue Pathology During Graded Bacteremia.
    Date April 1987
    Journal The Journal of Trauma
    Excerpt

    The purpose of this study was to determine whether or not thromboxane A2 (TXA2) was necessary or sufficient for the development of end-organ pathology during graded bacteremia. Pulmonary artery catheters were placed in 21 adult male pigs under pentobarbital anesthesia and breathing room air. After a control period, animals were studied in four groups: Group 1, anesthesia only; Group 2, infusion of 1 X 10(9) ml Aeromonas hydrophila which was gradually increased from 0.2 ml/kg/hr to 4.0 ml/kg/hr over 4 hours; Group 3, pretreatment with SQ 29,548 (TXA2 antagonist) then Aeromonas h. infusion; Group 4, infusion of U46619 (TXA2 agonist) to pulmonary artery pressures measured in Group 2. Animals were sacrificed after 4 hours and the lungs, liver, spleen, kidneys, and heart were examined under light microscopy by a pathologist unaware of study groups. The results indicated that physiologic thromboxane A2 agonist (Group 4) was sufficient alone to cause pulmonary inflammation. Thromboxane A2 was neither necessary nor sufficient for significant renal, hepatic, pulmonary, or splenic pathology to occur in graded bacteremia, manifested in similar microanatomic abnormalities in these organs in Groups 2 and 3 and in Groups 1 and 4. Pulmonary leukocyte infiltration was significantly increased in Group 3 compared to all other groups, suggesting that TXA2 impairs inflammatory responses.

    Title Ketoconazole Prevents Candida Sepsis in Critically Ill Surgical Patients.
    Date February 1987
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    We conducted a prospective, randomized, double-blind, placebo-controlled study to determine whether or not ketoconazole could prevent yeast colonization or invasion in critically ill adult surgical patients. Fifty-seven patients in a surgical intensive care unit (SICU) with three or more clinical risk factors for Candida infection were randomized to receive ketoconazole, 200 mg via the gastrointestinal tract daily (27 patients), or placebo (30 patients). Patients with hepatic dysfunction were excluded. The study was continued for 21 days or until one week after discharge from the SICU, whichever was longer. Stool cultures were obtained every three days and other cultures as indicated clinically. Patients were observed for yeast colonization (sputum, urine, stool, or wound) and invasion (fungemia or deep tissue focus). The incidence of Candida colonization was significantly lower in the ketoconazole group than the placebo group. Invasive yeast sepsis developed in five (17%) of the placebo-treated patients and in no patient in the ketoconazole group, a significant difference. Length of stay in the SICU was significantly lower in the ketoconazole group, as were the basic SICU patient charges. Sixty percent of the patients with invasive fungal sepsis died.

    Title Prostacyclin and Thromboxane A2 in Septic Shock: Species Differences.
    Date February 1987
    Journal Circulatory Shock
    Excerpt

    Prostacyclin and thromboxane A2 have been implicated as mediators of septic shock. Correlations between the human prostanoid response to sepsis and experimental paradigms are poorly understood. The purpose of this study was to compare changes in plasma levels of prostaglandin 6-keto-F1 alpha (PGI) and thromboxane B2 (TxB) during septic shock in Sprague-Dawley rats, domestic pigs, mongrel dogs, and man. Severe sepsis followed by septic shock (systolic BP less than 90 mmHg) was induced in rats by inoculation of 1.0 X 10(9) Aeromonas hydrophila, in pigs by graded IV infusion of 1.0 X 10(9)/ml A. hydrophila; and in dogs by an IV bolus injection of 5.0 X 10(9)/ml Escherichia coli. Plasma PGI and TxB (pg/ml) were measured by radioimmunoassay in control, septic, and septic shock experimental blood samples, and in normal controls, severly septic, and septic shock (systolic BP less than 90 mmHg) S.I.C.U. patients. Control, septic, and septic shock TxB levels in the dog and the pig were significantly greater than in the rat and man. PGI levels in the dog were significantly greater than in other species. TxB increased significantly in murine sepsis and PGI increased significantly in sepsis and septic shock. TxB increased during porcine sepsis and septic shock. In man, both PGI and TxB were significantly increased in severe sepsis, compared to normal controls, but only PGI was significantly higher in septic shock versus normotensive sepsis. Patterns of change in TxB/PGI ratios were similar for all species studied. Changes in PGI in the porcine septic experiments most closely paralleled those observed clinically.

    Title Enterobacter Bacteremia in Surgical Patients.
    Date December 1986
    Journal Surgery
    Excerpt

    The records of 63 surgical patients with one or more positive blood cultures for Enterobacter organisms were reviewed to determine clinical, epidemiologic, and mortality risk factors. Enterobacter bacteremia occurred, on the average, on the twenty-third day of hospitalization, most frequently in male patients (47), after antibiotic therapy (48 patients), placement of central venous catheters (38 patients), gastrointestinal tract operations (36 patients), and respiratory failure (31 patients). Portals of entry were most commonly sputum (25 patients), open skin wounds (16 patients), and central venous lines (12 patients). Mortality risk (22 patients, 35%) was increased with Enterobacter bacteremia occurring after the fifteenth day of hospitalization (18 of 45 patients versus 4 of 28 patients, p less than 0.01), a preceding Enterobacter focus (13 of 22 patients versus 9 of 41 patients, p less than 0.05), preceding non-Enterobacter bacteremia (10 of 15 patients versus 12 of 48 patients, p less than 0.02), preceding total parenteral nutrition (11 of 21 patients versus 11 of 42 patients p less than 0.01), respiratory failure (19 of 36 patients versus 3 of 27 patients p less than 0.01), and renal failure (11 of 12 patients versus 11 of 51 patients p less than 0.01). The mortality risk was not diminished by specific antibiotic therapy. Enterobacter is emerging as an important pathogen in surgical patients. Prolonged antibiotic administration, particularly that of cephalosporins, may promote Enterobacter colonization of the tracheobronchial tree and skin with subsequent invasion enhanced by respiratory failure, open skin wounds, or central venous catheters traversing the skin. Mortality risk is determined primarily by factors associated with critical illness rather than effects of Enterobacter organisms and their specific treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Microbial Filtrates Activate Granulocytes Without Complement or Prostaglandins.
    Date September 1986
    Journal Circulatory Shock
    Excerpt

    Cardiorespiratory dysfunction in sepsis may be mediated by circulating complement, activated leukocytes, prostaglandins, or by a direct effect of endotoxin. The purposes of this study were to determine if pathogenic microbes produce these substances and to evaluate the direct effects of substances released by micro-organisms on granulocyte aggregation (GA). Escherichia coli, (E. coli), Aeromonas hydrophila (Aeromonas h.), Staphylococcus aureus (S. aureus), and Candida albicans, (Candida a.) were incubated in broth to a concentration of 10(9)/ml. Broth was filtered and analyzed by radioimmunoassay for complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and by the limulus amebocyte lysate test (LAL) for endotoxin. GA, % of maximum zymosan activated aggregation (% max. T), was performed with broth, microbial filtrates, and endotoxin or normal purified human leukocytes in HBSS. Organisms were incubated in broth (B), broth + 0.0135 mg/ml arachidonic acid (BA), and broth + arachidonic acid + indomethacin (BAI). Broth alone was the control (C). Results: C3a, C5a, TxB, and PGI were not detectable in C broth or in any microbian filtrate. LAL was positive in all filtrates, but negative in C broth. GA responses were significantly greater in E. coli (56 +/- 5% max T) and Aeromonas h. (57% +/- 8% max T) compared to S. aureus (10 +/- 5% max T), Candida a. (14 +/- 8% max T) and C broth (1 +/- 1% max T). GA with purified E. coli endotoxin at concentrations measured in the filtrates was not related to the GA responses the original filtrates.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Thromboxane A2 Mediates Hemodynamic and Respiratory Dysfunction in Graded Bacteremia.
    Date September 1986
    Journal Surgery
    Excerpt

    Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.

    Title Thromboxane, Prostacyclin, and the Hemodynamic Effects of Graded Bacteremic Shock.
    Date July 1986
    Journal Circulatory Shock
    Excerpt

    This study investigates the interaction of thromboxane, prostacyclin, and the hemodynamic dysfunction of graded bacteremia. Arterial, venous, and pulmonary artery catheters were inserted into eight adult female pigs under barbiturate anesthesia. After a 60-min control period Aeromonas hydrophila (1.0 X 10(9)/ml) was infused intravenously at 0.2 ml/kg/hr, increasing gradually to 4.0 ml/kg/hr at 4 hr. Hemodynamic measurements, blood gases, and radioimmunoassay of thromboxane B2 (TxB) and prostaglandin 6-keto-F1 (PGI) were performed during the control period, at 10, 20, 30, 45, 60, 75, and 90 min of bacteremia and at 30-min intervals thereafter. During the bacterial infusion, cardiac index (CI), mean arterial pressure (MAP), paO2, pvO2, stroke volume (SV), and left ventricular stroke work (LVSW) decreased significantly, and pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and intrapulmonary shunt (Qs/Qt) increased significantly. TxB was significantly increased at 30 min and remained elevated thereafter. PGI did not rise above control levels until after 240 min of bacterial infusion. TxB cross-correlated most frequently with CI, PVR, SV, paO2, and Qs/Qt, changes in TxB preceding the other variables by 0-60 min. PGI cross-correlated significantly with MAP, LVSW, CI, paO2, and Qs/Qt, changes in PGI preceding MAP, LVSW, and CI by 0-60 min, but following paO2 and Qs/Qt by 30-60 min. TxB is increased early in graded bacteremia and appears related to cardiorespiratory dysfunction. PGI increases late in graded bacteremia, following the onset of respiratory failure, and may mediate the arterial hypotension of septic shock.

    Title Interaction of Prostaglandins, Activated Complement, and Granulocytes in Clinical Sepsis and Hypotension.
    Date June 1986
    Journal Surgery
    Excerpt

    Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.

    Title Leukocyte Aggregation Response to Quantitative Plasma Levels of C3a and C5a.
    Date March 1986
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    Granulocyte aggregation (GA) response has previously been described as a sensitive assay for complement activation in sepsis. Complement component C5a has been implicated as the plasma factor responsible for GA. The quantitative interaction of complement components C3a and C5a with GA, however, is not clearly defined. This study evaluates the relationship of GA responses to plasma levels of C5a and C3a in zymosan-activated plasma (ZAP). The C3a and C5a levels were measured by radioimmunoassay in serial dilutions of ZAP. Granulocyte aggregation responses of normal human leukocytes were determined for each ZAP dilution. The C5a levels in a 1:16 dilution of ZAP were higher than in normal plasma (22 +/- 7 vs 9 +/- 3 ng/mL), as were GA responses (24 +/- 1 vs 11 +/- 2 percentage of maximum light transmission). The C3a levels in a 1:8 dilution of ZAP are elevated above those of normal plasma (656 +/- 167 vs 411 +/- 29 ng/mL). Correlation coefficients were .9809 for C3a vs GA, .9788 for C5a vs G, and .9860 for C3a vs C5a. Complement components C3a and C5a are involved in GA in vitro. Granulocyte aggregometry can detect low levels of activated complement in ZAP but may not be specific for C5a. The relative contribution of C3a and C5a to observed GA is not clear from the data.

    Title Prostaglandin and Complement Interaction in Clinical Acute Respiratory Failure.
    Date March 1986
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

    Title Standard T-tube Cholangiogram: a Safe Method of Cholangiography. Bacteremia is an Unlikely Event After T-tube Cholangiography.
    Date November 1985
    Journal Rhode Island Medical Journal
    Title Thromboxane and Prostacyclin in Clinical Acute Respiratory Failure.
    Date August 1985
    Journal The Journal of Surgical Research
    Excerpt

    Plasma levels of thromboxane A2 and prostacyclin have been elevated during experimental acute respiratory failure (ARDS). The present study evaluates the relationship of plasma levels of thromboxane A2 and prostacyclin, measured by radioimmunoassay as the stable metabolites thromboxane B2 (TxB) and prostaglandin 6-K-F1 alpha (PGI) to the incidence of clinical ARDS. Sixty-seven consecutive patients at risk for ARDS were studied prospectively. TxB, PGI, platelet, and leukocyte counts were measured daily for up to 5 days. Of 55 patients without cerebral injury, 25 (45%) developed ARDS, and 30 did not. Of 12 patients with cerebral injury, none developed ARDS. This difference was highly significant (P less than 0.01). TxB was increased and age lower with head injury (P less than 0.05). PGI was significantly lower in ARDS (110 +/- 32 vs 227 +/- 211 pg/ml, P less than 0.05), and mean TxB was unchanged. TxB was increased in age greater than 60 and decreased with prostaglandin inhibitors. ARDS was significantly associated with TxB greater than 70 pg/ml, PGI below the detectable level of 103 pg/ml, TxB/PGI ratio greater than 0.7, and age greater than 60 years. Peak TxB occurred before or simultaneously with onset of ARDS in 68%. Leukocytes were decreased in ARDS (8.6 +/- 4 vs 11.1 +/- 4.4 X 10(3)/mm3) and platelets were unchanged. ARDS was decreased with steroid therapy. Elevated TxB is related to a high incidence of ARDS. Elevated PGI may protect against ARDS. Cerebral injury patients in this study were resistant to ARDS in spite of increased TxB.

    Title Adverse Effects of Hypothermia in Postoperative Patients.
    Date May 1985
    Journal American Journal of Surgery
    Excerpt

    The effect of intraoperative and postoperative temperature on morbidity, mortality, and other clinical risk factors was evaluated in 100 consecutive general surgical patients admitted postoperatively to a surgical intensive care unit. Hypothermia (temperature less than 97 degrees F) was present in 77 percent of the patients intraoperatively, in 53 percent at the end of surgery, and in 21 percent at 4 hours. Mortality was increased with patient age greater than 55 years, emergency surgery, operative blood pressure less than 100 mm Hg, operative fluid requirements greater than 1,500 ml/hour, temperature less than 97 degrees F at 2, 4, and 8 hours postoperatively, and presence of postoperative complications. Intraoperative fluid requirements were significantly greater for patients with mortality risk factors. Patients over 55 years of age were more often hypotensive and hypothermic than younger patients, but mortality was increased only for patients less than 55 years of age with a temperature of less than 97 degrees F at 8 hours or an operative blood pressure of less than 100 mm Hg. Mortality after general surgical procedures is increased with operative hypotensive and prolonged postoperative hypothermia. Hypothermic patients with mortality risk factors should be aggressively rewarmed postoperatively.

    Title Positive Pressure Respirations and Pneumatic Antishock Garment Application--hemodynamic Response.
    Date February 1985
    Journal The Journal of Trauma
    Excerpt

    Pneumatic antishock garment (PASG) application has been recommended for treatment of hypovolemic hypotension and intraperitoneal or retroperitoneal hemorrhage. Often these patients require positive pressure respiration (PPR). This study measured the hemodynamic response of low pressure PASG application, with and without PPR, in normovolemic man and the effects of PASG application on serum lactate. Ten patients after coronary artery bypass surgery were studied with PPR and PASG application (3 to 20 hours post-surgery), and PASG alone (24 to 30 hours post-surgery). PASG pressures of 0,5,10,20, and 0 mm Hg were applied for 10 minutes each after which LAP, PCWP, CVP, mean arterial pressure, heart rate, cardiac index, and serum lactate level were measured. PASG application produced significant elevations in right and left ventricular filling pressures. The left ventricular filling pressure response was significantly less with positive pressure respiration. The CVP and LAP increase did not result in a greater cardiac index. Serum lactate levels rose slightly during PASG application. Low-pressure PASG application results in an 'autotransfusion' effect which is greater without PPR.

    Title Enterococcal Bacteremia in Surgical Patients.
    Date February 1985
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    In 73 surgical patients enterococcal bacteremia was preceded by antibiotic administration (n = 58), central venous catheters (n = 52), other-organism bacteremia (n = 44), and gastrointestinal tract operations (n = 41). Surgical wounds and urinary tract infections were the most frequent portal of entry. The overall mortality was 42%. The mortality risk was significantly greater in patients with preceding or concomitant gram-positive bacteremia and four or more days of cephalosporin administration prior to enterococcemia. In 21 patients who had been given cephalosporins and who had gram-positive bacteremia, specific antienterococcal therapy resulted in survival in five of nine patients, compared with three of 12 who survived without therapy. Enterococcal bacteremia in surgical patients follows antibiotic administration, central venous catheter use, other-organism bacteremia, and intra-abdominal operations. Preceding or concomitant gram-positive bacteremia defines a subgroup of patients with high mortality who seem to respond to antienterococcal therapy.

    Title Crush Syndrome with Death Following Pneumatic Antishock Garment Application.
    Date January 1985
    Journal The Journal of Trauma
    Excerpt

    PASG is commonly employed for the prehospital therapy of traumatic hypovolemic hypotension. Although complications are reportly uncommon, several reports of compartment syndromes after PASG application and the present report of a crush syndrome following PASG application raise serious questions about the currently accepted guidelines for PASG therapy.

    Title The Incidence of Metastases After Multimodal Therapy for Cancer of the Head and Neck.
    Date November 1984
    Journal Cancer
    Excerpt

    Combined therapeutic regimens integrating chemotherapy, radiation therapy, and surgery are reported to be effective in treating advanced squamous cell carcinomas of the head and neck. The current study evaluates 58 consecutive patients with advanced (T4, N3) head and neck cancers. Forty patients (multimodal group) were treated with 2 courses of chemotherapy (cisplatin 2 mg/kg; methotrexate 280-560 mg/m2 with leucovorin rescue; bleomycin 30 mu X 3) followed by radiation therapy and surgery. Eighteen patients (combined group) were treated with preoperative radiation therapy followed by surgery. In the multimodal group there were 27 (67.5%) partial responses and nine (22.5%) complete responses, for an overall response rate of 90%. Response rates by site of primary lesion were: oral cavity, 11 of 11; oropharynx, 13 of 17; hypopharynx, 5 of 5; and larynx 7 of 7. Distant metastases (skin, lung, bone, central nervous system [CNS]) appeared in 16 patients (40%) (P less than 0.05 versus combined) at a median time of 8.5 months after diagnosis, 15 in patients having a partial (11) or complete (4) response. Thirteen patients (33%) developed distant metastases within 1 year of diagnosis (P less than 0.05 versus combined). In 11 of these patients, the primary lesion and neck disease were resectable. Two thoracotomies were performed for solitary pulmonary metastases; one was resected for cure. Fifteen patients (38%) underwent curative resection; 11 (73%) were alive at 1 year, and ten (67%) were free of disease. Overall survival was 20 of 40 (50%) at 1 year. In the combined group, there were 14 partial responses (78%) and no complete responses. Early distant metastases appeared in two patients (12.5%), at 2 and 6 months after diagnosis. Seven patients (38%) underwent curative resection; six of seven (86%) were alive at 1 year, four of seven (57%) were disease-free. Six of 16 patients at risk (37.5%) survived 1 year. After combined therapy, six of ten patients (60%) with responses to therapy survived 1 year versus 12 of 20 responders (57%) without distant metastases in the multimodal group. It is concluded that multimodal therapy for advanced head and neck cancer results in a higher response rate than with conventional combined therapy. The incidence of early and postoperative distant metastases was increased after the multimodal regimen. At 1 year there were no differences in survival between the combined and multimodal groups for responders without early metastases. Further observation is needed to determine the net long-term effects of this regimen. A prospective randomized comparison of combined and multimodal therapy for advanced lesions is indicated.

    Title Thromboxane Interaction with Cardiopulmonary Dysfunction in Graded Bacterial Sepsis.
    Date October 1984
    Journal The Journal of Trauma
    Excerpt

    The relationship between plasma levels of thromboxane A2, radioimmunoassayed as thromboxane B2 (TxB), and cardiopulmonary dysfunction in graded bacterial sepsis was investigated. Five adult female pigs under anesthesia were intubated and allowed to breathe room air spontaneously. Femoral arterial, venous, and pulmonary artery catheters were inserted. After a 60-minute control period Aeromonas hydrophila (1.0 X 10(9)/ml) was infused intravenously at 0.2 ml/kg/hr, gradually increasing to 4.0 ml/kg/hr over 4 hours. Arterial and mixed venous blood gases, hemodynamic measurements, and TxB plasma concentrations were obtained during the control period, at 10, 20, 30, 45, and 60 minutes and at 30-minute intervals thereafter. Cardiac index increased significantly from control at 20 minutes, remained above control levels for 1 hour, and then declined to significantly low values at 150 minutes. TxB was increased from control at 20 minutes, rising to four times control at 120 minutes. Mean arterial pressure, pulmonary capillary wedge pressure, left ventricular stroke work, paO2, and pvO2 decreased significantly during the experiment. Pulmonary artery pressure and pulmonary vascular resistance increased significantly. Changes in TxB were significantly cross-correlated with changes in cardiac index, pulmonary vascular resistance, stroke volume, left ventricular stroke work, and paO2. TxB elevations led the cross-correlated variables by 0 to 60 minutes. Pulmonary vascular resistance cross-correlated with mean arterial pressure and cardiac index. TxB is increased early in graded bacterial sepsis. Changes in TxB appear to precede impaired cardiopulmonary function. The data suggest that TxB is involved in the detrimental hemodynamic effects of early septicemia.

    Title The Hemodynamic Effect of Profound Hypercapnia on Acute Hypoxic Respiratory Failure.
    Date February 1984
    Journal Circulatory Shock
    Excerpt

    The effect of profound hypercapnia on acute hypoxic respiratory failure is evaluated. Eight dogs were subjected to oleic acid-induced acute respiratory failure. Four dogs were ventilated normally, and four dogs were made hypercapneic by rebreathing exhaled CO2. In the hypercapneic animals, heart rate and alveolar-arterial oxygen difference were significantly lower than in normocapneic animals, while mixed venous O2 cardiac index, oxygen delivery index, stroke volume index, and left ventricular stroke work were significantly higher. Mean arterial pressure was maintained at preinjury levels. Pulmonary and systemic vascular resistance increased in both experimental groups. There was no significant difference between groups for gravimetric determination of lung water. Cardiopulmonary performance in acute respiratory failure is improved with hypercapnia. This may be related to CO2-induced catecholamine release.

    Title Staphylococcus Epidermidis Sepsis in Surgical Patients.
    Date January 1984
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    We examined 58 surgical patients with two or more blood cultures positive for Staphylococcus epidermidis to determine factors associated with risk, mortality, and invasive sepsis. Bacterial sepsis was associated with gastrointestinal (GI) operations, total parenteral nutrition, and a regimen of two or more parenteral antibiotics. Mortality was 46% overall and significantly increased with age greater than 50 years, GI operations, other gram-positive sepsis, recurrent sepsis (positive blood culture 24 hours or more after the first blood culture), and the presence of organisms sensitive to three or less antibiotics. Antibiotic therapy appropriate for more than 50% of the S epidermidis organisms cultured from each patient resulted in significant reduction in mortality. Staphylococcus epidermidis should be considered a significant pathogen in critically ill surgical patients. Invasive S epidermidis sepsis can be recognized and requires specific antibiotic therapy.

    Title Fungal Sepsis in Surgical Patients.
    Date February 1983
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    Records of 65 surgical patients with positive fungal blood cultures were reviewed to address risk, overall mortality, and treatment. Negative urine cultures did not rule out sepsis. Staphylococcus epidermidis sepsis was present in 27 (42%) of the patients. In 70% of whom it occurred before or during fungemia. Increased mortality correlated with the use of multiple antibiotics, antibiotic use for prolonged periods, and with associated bacterial sepsis. Stopping antibiotic therapy did not reduce mortality. Amphotericin B reduced mortality in patients with dissemination, indicating that it is the treatment of choice for disseminated fungemia and that antibiotic therapy should not be discontinued when concomitant bacterial sepsis is present.

    Title Histologic and Hemodynamic Effects of Prostacyclin and Prostaglandin E1 Following Oleic Acid Infusion.
    Date August 1982
    Journal Surgery
    Excerpt

    The hemodynamic and histologic effects of exogenous prostacyclin (PGI2) and prostaglandin E1 (PGE1) on oleic acid-induced acute respiratory failure were investigated. Adult mongrel dogs infused with oleic acid were treated with saline solution, PGE1, and PGI2. Significantly lowered blood pressure, systemic and pulmonary vascular resistance, and arteriovenous oxygen difference and preservation of preoleic cardiac output were observed in the pGI2 group. Compared with the saline group, only the arteriovenous oxygen difference was improved with PGE1. Light microscopy revealed acute edema and inflammation in the saline- and PGE1-treated lungs. Histologic specimens in the PGI2 group were normal.

    Title The Hemodynamic Effects of Prostaglandin E1 (pge1) in Acute Hypoxic Respiratory Failure.
    Date January 1982
    Journal Advances in Shock Research
    Excerpt

    The hemodynamic effect of prostaglandin E1 (PGE1) on acute respiratory failure is investigated. Eight adult mongrel dogs were subjected to oleic acid-induced acute respiratory failure. Four dogs received PGE1 intravenously one hour after oleic acid injection, and four received an equal volume of saline. Cardiac output, arterial PO2 and alveolar-arterial oxygen difference decreased significantly in the saline-treated animals, and systemic vascular resistance increased. These parameters were maintained in the PGE1 group, and stroke volume and arterial-venous oxygen difference were improved. Pulmonary vascular resistance increased in both groups. This beneficial effect of PGE1 in acute respiratory failure may be related to maintenance of hemodynamics and pulmonary gas exchange and to improved tissue oxygenation.

    Title Effect of Prostaglandin E1 and Steroid Combination in the Treatment of Hemorrhagic Shock.
    Date August 1981
    Journal Advances in Shock Research
    Excerpt

    Prostaglandin E1 and methylprednisolone sodium succinate were administered simultaneously after shock in an intact canine hemorrhagic shock model and compared to treatment with each agent singly and with a 60 cc saline infusion. A detrimental effect of the prostaglandin E1/steroid combination was evidenced by decreased heart rate, mean arterial and central venous pressures, cardiac output, and arterial pH, and increased venous lactate. Survival was poor after the combined regimen. These changes may be related to vasodilation in the peripheral vascular system, causing pooling of blood. Lysosomal membranes were stabilized in spite of prolonged hypoperfusion.

    Title Alteration of Postischemic Renal Pathology by Prostaglandin Infusion.
    Date December 1980
    Journal The Journal of Surgical Research
    Title Hemodynamic Effect of Prostacyclin (pgi2) in Acute Hypoxic Respiratory Failure.
    Date May 1980
    Journal Surgical Forum
    Title The Effect of Hemorrhagic Shock on Plasma Amino Acids and Tissue Energy Substrates in the Primate.
    Date April 1980
    Journal The American Surgeon
    Excerpt

    Levels of plasma amino acids and muscle concentrations of energy substrates and metabolites after shock in the Macaca mulatta Rhesus monkey were investigated. The hemodynamic response to shock is similar to that of previously reported studies of primates in shock. Plasma glucose and ASAT increased significantly, while levels of ALAT and pyruvic acid did not change. Lactic acid was elevated. Muscle glycogen and concentrations of lactic acid were increased, and levels of pyruvic acid, creatine phosphate, and malate fell during shock. Levels of ATP in muscle were unchanged. Nine of the 23 arterial plasma amino acids analyzed decreased significantly. Aspartic acid was increased during shock. The increased levels of tissue carbohydrates and decreased concentrations of plasma amino acids observed in this study differ from results previously reported for other animal shock models. Changes in amino acid levels are similar to the results of some clinical studies.

    Title Increased Tissue Glucose: an Unusual Response to Shock in the Nutria.
    Date August 1979
    Journal Current Surgery

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