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.

Structure, stability and defects of single layer hexagonal BN in comparison to graphene.

We study by molecular dynamics the structural properties of single layer hexagonal boron nitride (h-BN) in comparison to graphene. We show that the Tersoff bond order potential developed for BN by Albe et al (1997 Radiat. Eff. Defects Solids 141 85-97) gives a thermally stable hexagonal single layer with a bending constant κ = 0.54 eV at T = 0. We find that the non-monotonic behaviour of the lattice parameter, the expansion of the interatomic distance and the growth of the bending rigidity with temperature are qualitatively similar to those of graphene. Conversely, the energetics of point defects is extremely different: instead of Stone-Wales defects, the two lowest energy defects in h-BN involve either a broken bond or an out-of-plane displacement of a N atom to form a tetrahedron with three B atoms in the plane. We provide the formation energies and an estimate of the energy barriers.

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.

Prostacyclin is neither sufficient alone nor necessary to cause pulmonary dysfunction: results from infusions of prostacyclin and antiprostacyclin antibody in porcine septic shock.

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.

Prospectively validated predictions of shock and organ failure in individual septic surgical patients: the Systemic Mediator Associated Response Test.

INTRODUCTION: Clinically useful predictions of end-organ function and failure in severe sepsis may be possible through analyzing the interactions among demographics, physiologic parameters, standard laboratory tests, and circulating markers of inflammation. The present study evaluated the ability of such a methodology, the Systemic Mediator Associated Response Test (SMART), to predict the clinical course of septic surgery patients from a database of medical and surgical patients with severe sepsis and/or septic shock. PATIENTS AND METHODS: Three hundred and three patients entered into the placebo arm of a multi-institutional sepsis study were randomly assigned to a model-building cohort (n = 200; 119 surgical) or to a predictive cohort (n = 103; 55 surgical). Using baseline and baseline plus serial measurements of physiologic data, standard laboratory tests, and plasma levels of IL-6, IL-8, and granulocyte colony-stimulating factor (GCSF), multivariate models were developed that predicted the presence or absence of pulmonary edema on chest radiography, and respiratory, renal, coagulation, hepatobiliary, or central nervous system dysfunction and shock in individual patients. Twenty-eight-day survival was predicted also in baseline plus serial data models. These models were validated prospectively by inserting baseline raw data from the 55 surgical patients in the predictive cohort into the models built on the comprehensive training cohort, and calculating the area under the curve (AUC) of predicted versus observed receiver operator characteristic (ROC) plots. RESULTS: SMART predictions of physiologic, respiratory, metabolic, hepatic, renal, and hematologic function indicators were validated prospectively, frequently at clinically useful levels of accuracy. ROC AUC values above 0.700 were achieved in 30 out of 49 (61%) of SMART baseline models in predicting shock and organ failure up to 7 days in advance, and in 30 out of 54 (56%) of baseline plus serial data models. CONCLUSION: SMART multivariate models accurately predict pathophysiology, shock, and organ failure in individual septic surgical patients. These prognostications may facilitate early treatment of end-organ dysfunction in surgical sepsis.

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.

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.

Preoperative chemotherapy-sensitized radiation therapy for cervical metastases in head and neck cancer.

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.

Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock.

OBJECTIVE: 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. DESIGN: Prospective, nonrandomized, controlled trial. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty-four female Yorkshire swine. INTERVENTIONS: Animals were divided into six experimental groups: five septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr, gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6; prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no mediator inhibitor and served as a septic control, and one anesthesia control group (n = 6) received no intervention. MEASUREMENTS AND MAIN RESULTS: PAF receptor blockade significantly increased systemic hypotension and mixed venous oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene inhibition increased mean arterial pressure, pulmonary and systemic vascular resistance indices, and arterial and mixed venous oxygen saturation and reduced pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption, and all measured mediators. Thromboxane receptor blockade lowered TNF and leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and significantly increased arterial and tissue oxygenation compared with septic controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations, arterial hypoxemia, and oxygen consumption during sepsis and increased circulating leukotriene B4. CONCLUSIONS: Elevations in plasma TNF predictably precede peak levels of eicosanoids in this model. PAF, leukotrienes, and thromboxane A2 are necessary for pulmonary hypertension during bacteremia. Systemic hypotension and increased vascular permeability are mediated by both leukotrienes and PAF. There are complex interactions among mediators during sepsis and further studies are required to define these relationships.

Efficacy of jejunogram after jejunostomy insertion.

The era of managed care has spawned a national debate over the allocation of health care resources. We hypothesized that routine postjejunostomy jejunogram rarely provides additional clinical information or changes patient management and, therefore, is unwarranted. We retrospectively reviewed the charts of 128 consecutive patients undergoing feeding jejunostomy tube insertion between January 1995 and December 1996. All patients had postinsertion jejunograms. Eighty-five (66%) of the jejunograms were performed after operative insertion of the jejunostomy, and 43 (33%) were performed after percutaneous reinsertion of a previously placed jejunostomy. Data extracted from the charts include age, sex, indication for jejunogram, length of time prior jejunostomy was in place at time of reinsertion, and results of jejunogram. There were no patients (0%) with misplaced jejunostomy or extravasation of dye, as noted on jejunogram. There were no management changes implemented as a result of jejunogram readings (P < <0.05). The use of routine jejunogram after operative insertion or reinsertion of a prior jejunostomy that has become dislodged or occluded does not alter patient management, incurs unnecessary costs, and, therefore, is unwarranted.

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.

Laminectomy compared with laparoscopic diskectomy and outpatient laparoscopic diskectomy for herniated L5-S1 intervertebral disks.

The objective of this study was to evaluate the clinical efficacy and cost effectiveness of inpatient and outpatient laparoscopic lumbar diskectomy (LLD) compared with laminectomy (LAM) in the surgical treatment of disabling L5-S1 disk herniation. Sixty-two adults underwent surgery for herniated L5-S1 intervertebral disks (31 LLD and 31 LAM). Operative blood loss (EBL) (milliliters), operative time (ORT) (minutes), hospital stay (LOS), and rehabilitation time to normal activity (REHAB) (days), recurrent symptoms, postoperative morbidity, percent pain free, and hospital patient charges were calculated. Thirty LLD patients (97%) had immediate relief of disk pain. Morbidity after LLD included transient urinary retention (one) and rectus hematoma (one). One LAM patient had a pseudomeningocele. Among patients observed for > or =6 months, with a median follow up time of 34 months, 22 of 25 LLD patients (88%) returned to normal activity, while 12 of the LAM group (52%) were disabled (p = 0.004). Functional outcome was improved by LLD for workers compensation patients followed > or =6 months, with 86% LAM disabled, vs. 10% LLD (p = 0.001). Sixteen LLD patients (52%) and 18 (58%) of the LAM group needed postoperative physical therapy. Four LLD patients recurred; three required reoperation. Four LAM patients had surgery for recurrent disk herniation. ORT was longer for LLD than LAM (210 vs. 158 minutes, median, p < 0.05). EBL and REHAB time were significantly reduced with LLD, vs. LAM. With a median follow-up of 34 months, 58% of LLD and 39% of LAM patients followed > or =6 months were pain free. Outpatient LLD (n = 9) reduced LOS (1 day vs. 2 days and 4 days, p < 0.01) and lowered patient charges ($4,405 vs. $5,723 and $7,192, p < 0.01) compared with inpatient LLD (n = 23) and LAM, respectively. LLD is a safe, cost-effective, minimally invasive alternative to LAM for treating herniated L5-S1 disks. Compared with LAM, LLD reduces EBL, LOS, REHAB time, and patient charges, improves function, and increases long-term pain relief. Cost effectiveness is optimized when LLD is performed as outpatient surgery.

Effect of advance directives on the management of elderly critically ill patients.

OBJECTIVE: To evaluate the effects of advance directives on the management of elderly, critically ill patients. DESIGN: Retrospective chart review. SETTING: Teaching hospital medical/surgical, noncardiac intensive care unit (ICU). PATIENTS: The medical records of 401 patients, > or =65 yrs of age, admitted to the ICU between 1992 and 1995 were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Advance directive statements included refusal of cardiopulmonary resuscitation (CPR), nutrition, intravenous medications, antibiotics, mechanical ventilation, and blood products. Nineteen (5%) patients had advance directives (study group). These patients were compared with 28 case-matched (age, Acute Physiology and Chronic Health Evaluation II score, and diagnosis) critically ill patients without advance directives (control group). We compared the following data: cost per day; number of surgical procedures; number of radiographic studies; number of central venous and pulmonary artery catheter insertions; number of complete blood counts, electrolytes, and cultures sent for laboratory testing; number of days in the ICU/hospital; and mortality rates. Statistical analysis was performed using the Student's t-test for independent means and the chi-square equation. For all observed parameters, quantitative and dichotomous differences between study and control groups were not statistically significant. Two patients received CPR, despite advance directive statements refusing this treatment. CONCLUSIONS: Few critically ill seniors have advance directives. As assessed by objectively documented information, the level of care delivered to elderly ICU patients is not affected by the presence or absence of advance directive statements. Medical personnel need to be aware of whether or not patients have advance directive statements, as unauthorized CPR was administered to 11% of the patients who died with advance directives.

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.

BACKGROUND: Whether or not tumor response to chemotherapy-sensitized radiation therapy (CTRT) for head and neck cancer leads to an improved outcome is unknown. METHODS: Forty patients who received preoperative cisplatin plus simultaneous radiotherapy for operable stage III and IV head and neck cancer were reviewed retrospectively regarding clinical demographics, staging, and survival status. RESULTS: Twenty-one (57%) patients had a histologic complete response (HCR) and 16 (43%) had a partial (PR) (9) or clinical complete (7) response (CCR). Tumor response of N1 versus N2-3 nodal disease showed 6 (75%) HCR and 4 (25%). Five-year disease-free survival overall was 82% for HCR versus 38% for PR/CCR (P <0.05). Disease-specific 5-year survival was 100% for HCR versus 27% for PR/CCR (P <0.002). CONCLUSIONS: Histologic complete response to CTRT for head and neck cancer is associated with increased survival and encouraging disease-free status. Response to CTRT is inversely proportional to lymphatic tumor load.

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.

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.

Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis.

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.

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.

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.