Phonon-Assisted Resonant Tunneling of Electrons in Graphene-Boron Nitride Transistors.

We observe a series of sharp resonant features in the differential conductance of graphene-hexagonal boron nitride-graphene tunnel transistors over a wide range of bias voltages between 10 and 200 mV. We attribute them to electron tunneling assisted by the emission of phonons of well-defined energy. The bias voltages at which they occur are insensitive to the applied gate voltage and hence independent of the carrier densities in the graphene electrodes, so plasmonic effects can be ruled out. The phonon energies corresponding to the resonances are compared with the lattice dispersion curves of graphene-boron nitride heterostructures and are close to peaks in the single phonon density of states.

Effect of Structural Relaxation on the Electronic Structure of Graphene on Hexagonal Boron Nitride.

We performed calculations of electronic, optical, and transport properties of graphene on hexagonal boron nitride with realistic moiré patterns. The latter are produced by structural relaxation using a fully atomistic model. This relaxation turns out to be crucially important for electronic properties. We describe experimentally observed features such as additional Dirac points and the "Hofstadter butterfly" structure of energy levels in a magnetic field. We find that the electronic structure is sensitive to many-body renormalization of the local energy gap.

Quantitative analysis of organ tissue damage after septic shock.

The objective of this study was to quantify end-organ damage caused by bacteremic sepsis. Twelve adult swine were divided into two groups. The anesthesia control group (n = 6) received general anesthesia for 4 hours. The septic shock group (n = 6) received an infusion of Aeromonas hydrophila under general anesthesia for 4 hours. Swine were sacrificed at the end of the 4-hour procedure. Tissues from lungs, kidneys, livers, and hearts were stained with hematoxylin and eosin. Images of tissues were studied with digital image analysis. In lungs, cytoplasmic area (CA), nuclear area (NA), intra-alveolar hemorrhage (IAH), total airspace (TAS), and alveolar septum thickness (ST) were measured. Nuclear and cytoplasmic intensities (NI and CI) were measured in integrated optical density units (IOD). In kidneys, livers, and hearts, CA, CI, NA, and NI were measured similarly. Sinusoidal blood in the liver and vacuolization (VAC) in the kidney were also measured. In septic lungs, CI, NA, NI, ST, IAH, TAS, and ratios of NA/CA, NI/CI, and IAH/TAS were significantly increased compared with the control (P < 0.02). In septic kidneys, CI, NA, VAC, NA/CA, and NI/CI were significantly increased (P < 0.0005). In livers, CA, CI, and NI/CI were significantly increased (P < 0.005). In hearts, the ratios of NA/CA and NI/CI were statistically significant. End organs from septic swine, with exception of the heart, showed significantly higher levels of cellular damage. Digital image analysis provides an objective, precise, and accurate method of quantifying image characteristics. Automating these tasks is a high priority in the research and clinical community in providing a reproducible method for longitudinal analysis of various biological studies.

A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with gram-negative urosepsis. Urosepsis Study Group.

Evidence from in vitro experiments and animal and human studies indicate that antibiotic therapy may induce the release of endotoxin from the outer membrane of Gram-negative bacteria. Antibiotics that bind preferentially to penicillin-binding protein-2 (PBP-2)--such as imipenem--are associated with little release of endotoxin, while antibiotics that preferentially bind to PBP-3--such as ceftazidime--are associated with far greater release of endotoxin. We conducted a randomized, multicenter, double-blind study comparing imipenem to ceftazidime in patients with urinary tract infections caused by Gram-negative bacilli associated with signs and symptoms of systemic inflammation. A total of 33 patients were randomized to receive either imipenem (n = 14) or ceftazidime (n = 19) for initial treatment for urosepsis. No differences in plasma endotoxin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) or urine endotoxin, IL-6 or IL-8 levels were found between the two treatment groups within the first 8 h after antibiotic administration. We conclude that, if differences exist with respect to endotoxin release by these two antimicrobial agents, these differences are not readily demonstrable in this clinical study with carefully defined patients with Gram-negative urinary tract infections.

Concurrent platinum-based chemotherapy and hyperfractionated radiotherapy with late intensification in advanced head and neck cancer.

PURPOSE: To determine whether a course of hyperfractionated radiation therapy concomitant with escalated radiosensitizing platinum compounds can be administered with acceptable morbidity and achieve a high rate of loco-regional control for Stage III and IV head and neck cancer and whether the patients can be tumor free at the primary site after initial therapy and cured by the additional chemoradiation without radical resection of the primary tumor. METHODS AND MATERIALS: Patients with Stage III/IV head and neck cancer were treated in this multicenter Phase II Study with 1.8 Gy fraction radiotherapy for 2 weeks, with escalation to 1.2 Gy b.i.d. hyperfractionation to 46.8 Gy. Concomitant continuous infusion cisplantinum (CDDP) 20 mg per meter square on day 1 to 4 and 22 to 25 was given. Reassessment by biopsy of primary and nodes was done. Patients with a complete response continued with hyperfractionated radiotherapy to 75.6 Gy with simultaneous carboplatinum (Carbo), 25 mg per meter square b.i.d. for 12 consecutive treatment days. Patients with residual disease at 46.8 Gy required curative surgery. Seventy-four patients were treated at the three institutions; 20 were Stage III and 54 were Stage IV. All patients had daily mouth care, nutritional, and psychosocial support. RESULTS: This regime was well tolerated. Eighty-five percent of toxicities were Grade 1 or 2 and there was only one Grade 4 hematologic toxicity. Late toxicities included xerostomia in 25 patients, dysphasia in 18, and mild speech impediment in 11. Biopsies of primary site were done after the first course of treatment in 59 patients. Neck dissections were performed in 35 patients. Forty-four of 59 (75%) primary sites and 16 of 35 (46%) lymph nodes had pathologically complete response (CR). Of the 74 patients, only 12 required surgical resection of the primary site. Thirty-five of the 50 node positive patients had neck dissections, 16 of these were CRs at surgery. At 4 years (median follow-up of 26 months), disease-specific survival is 63%. The actuarial survival for all patients is 51%. Patients with pathological CR after initial treatment have disease specific survival of 73% at 4 years vs. 48% of patients with partial response (PR) only. CONCLUSION: This study, developed on the basis of radiobiological and cell kinetic precepts, produced results that compare favorably with other reports of management of patients with advanced head and neck cancer. In comparison with our previous study, these results are comparable, not impressively better. The associated morbidity was somewhat worse.

Concurrent cis-platinum and radiation with or without surgery for advanced head and neck cancer.

PURPOSE: This study was undertaken to assess the efficacy of concurrent cis-platinum and radiation in patients with advanced head and neck cancer and to determine if patients responding to the preoperative regimens may be cured without radical surgery. METHODS AND MATERIALS: One hundred and one patients with potentially operable Stage III and IV squamous cell carcinoma of the head and neck received 45 Gy at 1.8 Gy fractions and continuous infusion cis-platinum 20 mg/m2 over 24 h on days 1 through 4 and 22 through 25 of the radiation schedule. Three to 4 weeks later, radical surgery of the primary site and neck dissections for patients presenting with cervical adenopathy was undertaken or if a complete response had been achieved, continued with radiation to 72 Gy with another course of concurrent continuous infusion cis-platinum. RESULT: Complete and partial responses were achieved in 92% of the primary sites and 95% of the nodes. Over 80% of the patients were rendered tumor free at surgery after only the initial course of chemotherapy and radiation. There were no grade 3 or 4 toxicities from chemotherapy and radiation. Ninety-five percent of the patients who initiated treatment completed it. With a median follow-up of 41 months for all patients, 49% of the patients have survived disease free up to 9 years, independent of whether or not their primary tumors were resected or were treated definitively by further chemotherapy sensitized radiation. The disease-specific survival is 78% after 3 years with no local failures thereafter. CONCLUSION: These findings suggest that continuous infusion cis-platinum administered concurrently with radiotherapy can improve survival in advanced head and neck cancer. Patients responding to the preoperative regimen may be cured without radical surgery, which can be reserved for salvage.

Prospectively validated prediction of organ failure and hypotension in patients with septic shock: the Systemic Mediator Associated Response Test (SMART).

Conventional outcomes research provides only percentage risk categories that are not applicable to individual patients, and it predicts only mortality, utilization of resources and/or broad groupings of multiple organ system dysfunction. The purpose of the present study was to determine whether or not the Systemic Mediator Associated Response Test (SMART) methodology could identify interactions among demographics, physiologic parameters, standard hospital laboratory tests, and circulating cytokine concentrations to predict continuous and dichotomous dependent clinical variables, in advance, in individual patients with septic shock and to integrate these into prospectively validated models. Two hundred forty (240) patients with septic shock who were entered into the placebo arm of a multi-institutional clinical trial were randomly separated into a model building training cohort (n = 154) and a predictive cohort (n = 86), which was used to prospectively validate the prognostic models built upon the training cohort database. From baseline patient demographics; hospital laboratory tests; and plasma levels of interleukin-6, interleukin-8, and granulocyte colony stimulating factor, multiple regression models were developed that predicted clinically important continuous dependent variables quantitatively in individual patients. Multivariate stepwise logistic regression was utilized to develop models that prognosticated dichotomous dependent end points. At the completion of the modeling process, baseline data from individual patients in the predictive cohort was inserted into each multivariate model for each day. Prospective validation was accomplished by simple linear regression of individual predicted versus observed values for continuous dependent variables, and by establishing the Receiver Operator Characteristics Area Under the Curve (ROC AUC) for logistic regression models that predicted dichotomous end points. Through seven days, SMART quantitative predictions of selected physiologic and metabolic parameters were validated at r > 0.500 in 51%. Up to seven days after baseline, 31/49 (63%) SMART models for renal and liver function indicators were validated prospectively at the r > 0.700 level. For hematologic/coagulation models, 37/56 (66%) up to seven days had r > 0.900. Among dichotomous models, ROC AUC > 0.700 was achieved in 30/49 (61%) during the first week. SMART integration of demographics, bedside physiology, hospital laboratory tests, and circulating cytokines predicts organ failure and physiologic function indicators in individual patients with septic shock.

Multivariate regression modeling for the prediction of inflammation, systemic pressure, and end-organ function in severe sepsis.

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.

Pathophysiologic plasma levels of leukotriene C4 in relation to the hemodynamic dysfunction and mediator release of graded bacteremia.

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.

Evaluation of enzyme-linked immunosorbent assays for quantitation of eicosanoid mediators of sepsis syndrome.

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.

The cardiopulmonary, eicosanoid, and tissue microanatomic effects of fluconazole during graded bacteremia.

Imidazole compounds have been shown to be beneficial in systemic sepsis and inflammation. The purpose of this study was to delineate the effects of fluconazole on systemic hemodynamics and on microanatomy of the heart, lung, liver, and kidney parenchyma of swine during graded bacteremia. Eighteen adult swine were studied in three groups: 1), anesthesia control; 2), septic control (Aeromonas hydrophila, 10(9)/mL, infused i.v. for 4 h); 3) fluconazole (fluconazole, 30 mg/kg i.v., followed by A. hydrophila infusion). After 4 h of graded bacteremia, autopsy was performed. Compared with the septic control group, cardiac index, oxygen delivery, and oxygen consumption were reduced significantly after fluconazole pretreatment, and mixed venous hemoglobin oxygen saturation (SVO2) and oxygen extraction were increased. Plasma thromboxane A2 and leukotriene levels were not affected by fluconazole. Computerized digital image analysis of the liver, heart, and kidney specimens revealed no statistically significant differences between the septic control group and fluconazole-pretreated animals. In the lung specimens, preinfusion of fluconazole decreased alveolar wall thickness in septic swine (anesthesia control group: 8.15 x 10(-3) +/- 1.3 x 10(-3)mm versus septic control group: 9.9 x 10(-3) +/- 1.3 x 10(-4) versus fluconazole group: 6.8 x 10(-3) +/- 1.6 x 10(-3); p < or = .05). Fluconazole pretreatment before graded bacteremia has no beneficial effect on cardiopulmonary performance or septic tissue edema of the heart, kidney, or liver. Tissue oxygen metabolism might be down-regulated by fluconazole. However, preinfusion of fluconazole appears to normalize the sepsis-induced increase in pulmonary alveolar wall thickness. The net significance of these changes on clinical outcome is not clear from these data.

Interleukin-1 mediates increased plasma levels of eicosanoids and cytokines in patients with sepsis syndrome.

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.

Differences in eicosanoid and cytokine production between injury/hemorrhage and bacteremic shock in the pig.

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.

Interleukin-1 mediates hemodynamic dysfunction and release of eicosanoids and tumor necrosis factor during graded bacteremia.

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.

The cardiovascular hemodynamics and leukotriene kinetics during prostacyclin and anti-prostacyclin antibody infusions in septic shock.

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.

Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome.

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.

Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group.

STUDY OBJECTIVE: To determine the epidemiology of multiple organ failure (MOF) in patients with the adult respiratory distress syndrome. PATIENTS: We followed up 50 patients with serial determinations of respiratory and nonrespiratory organ function for seven days after diagnosis. DESIGN: Data were stratified between patients who died and those who survived (defined as hospital discharge). MEASUREMENTS AND RESULTS: Values that did not differ at any time between the two groups of patients included oxygen availability, oxygen consumption, oxygen extraction, PaCO2, respiratory rate, heart rate, systolic blood pressure, cardiac output, stroke index, systemic vascular resistance, and temperature. Patients who died had greater defects in oxygenation (from day 1 through day 7). They also exhibited decreased arterial oxygen content (from day 1 to day 4), decreased mixed venous oxygen content (day 1), increased peak inspiratory pressure (present on day 2, persisted to day 5, reappeared on day 7), decreased diastolic blood pressure (seen on days 1 through 3, reappeared on day 7), and increased mean pulmonary artery pressure (seen on days 2 and 3). Nonsurvivors also exhibited greater degrees of thrombocytopenia (from day 1 to day 4). Decreases in pH (seen on day 1, reappeared from days 4 to 7), abnormalities in liver function (seen only on day 1), and increases in serum creatinine levels (appeared on day 7) were also observed. CONCLUSIONS: Multiorgan dysfunction (MOD) was frequently observed in both groups of patients. Alterations in organ function and the pattern of abnormalities were often subtle and would not be characterized as significant organ dysfunction by most available organ scoring systems. Adult respiratory distress syndrome is a manifestation of systemic disease produced by widespread increases in endothelial permeability; lung dysfunction dominates the early clinical course. When respiratory function is supported, it becomes evident that alterations occur in other organs. Multiorgan failure is really a misnomer; the term emphasizes end-stage changes. Multiorgan dysfunction is common and often resolves without progressing to MOF. Alternatively, MOD can progress to MOF.

An early test of survival in patients with the adult respiratory distress syndrome. The PaO2/FIo2 ratio and its differential response to conventional therapy. Prostaglandin E1 Study Group.

Patients with established adult respiratory distress syndrome (ARDS) have a mortality rate that exceeds 50 percent. We analyzed the magnitude of hypoxemia as manifest by the PaO2/FIO2 ratio and its early response to conventional therapy including positive end-expiratory pressure (PEEP) in the placebo group of a large multicenter study. The PaO2/FIO2 ratio was not different at the time of diagnosis of ARDS in those patients who lived compared to those who subsequently died. After one day of conventional therapy including PEEP, those patients who survived increased their PaO2/FIO2 ratio. The nonsurvivors did not improve over a seven-day course. The difference in the PaO2/FIO2 ratio was significant throughout the seven-day observation period. We conclude that the early response to conventional therapy picks a patient population with a good prognosis and can be used as a test of likely survival from ARDS.

Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Prostaglandin E1 Study Group.

Prostaglandin E1 (PGE1) was compared to placebo in a 100-patient (50 PGE1, 50 placebo) randomized, double-blind, clinical trial to determine whether PGE1 therapy enhances survival of patients with adult respiratory distress syndrome (ARDS) when infused through a central line at 30 ng/kg/min continuously for seven days. At 30 days postinfusion, 30 PGE1 and 24 placebo patients had died. Total deaths judged to be related to the syndrome were 32 and 28 in the PGE1 and placebo groups respectively at six months. We conclude that PGE1 did not enhance survival in patients with established ARDS. PGE1 augmented the hyperdynamic circulation of these patients by reducing systemic and pulmonary vascular resistance, which resulted in a reduction of blood pressures and increased stroke volume, cardiac output, and heart rate. An improvement in oxygen availability and oxygen consumption was observed with PGE1 therapy. PGE1 was associated with an increased incidence of diarrhea (six patients in the PGE1 group vs one in the placebo group, p less than 0.05). Other adverse effects included hypotension (ten patients in the PGE1 group vs seven in the placebo group), fever (six patients in the PGE1 group vs three in the placebo group), and non-fatal dysrhythmias (ten in the PGE1 group vs five in the placebo group).

Effects of prostaglandin E1 on oxygen delivery and consumption in patients with the adult respiratory distress syndrome. Results from the prostaglandin E1 multicenter trial. The Prostaglandin E1 Study Group.

We wanted to determine the long-term effects of a continuous infusion of PGE1 on DO2 and VO2 in patients with ARDS. Data were obtained from a randomized double-blind multicenter trial, which evaluated the effects of PGE1 on survival in patients with ARDS. Patients were stratified according to treatment and outcome: placebo-died (n = 8); PGE1-died (n = 12); placebo-survived (n = 9); and PGE1-survived (n = 8). In the placebo-died group, elevations occurred in VO2, which were associated with increases in O2ext and a constant DO2. In contrast, in the PGE1-died group, elevations in VO2 were associated with increases in DO2 and an unchanged O2ext. In the placebo-survived group, VO2 and DO2 decreased, whereas in the PGE1-survived group, VO2 and DO2 increased; however, O2ext decreased in both of these groups. Since impaired O2ext occurs in ARDS, PGE1-induced elevations in DO2, rather than compensatory increases in O2ext, may achieve better tissue oxygenation. We conclude that although the recently completed multicenter trial failed to show an enhancing effect of PGE1 on survival in patients with advanced ARDS, PGE1 may have important effects on oxygen transport and, therefore, may still have a role in the treatment of early manifestations of ARDS, either alone or in combination with other agents.