Critical Care Medicine

B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The fact that humans express a very large repertoire of antibodies is due to the complex mechanism of V(D)J recombination of immunoglobulin (Ig) genes as well as other processes including somatic hypermutation, gene conversion and class switching. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two Ig heavy chains, two Ig light chains and two heterodimers of Igα and Igβ. To eliminate foreign antigens, B cells cooperate with other cells of the immune system including macrophages, dendritic cells and T cells. B cell development is a tightly controlled process in which over 75% of the developing cells become apoptotic because of inappropriate immunoglobulin gene rearrangements or recognition of self antigens by Igs. Hence, the majority of B cell-associated disorders are caused by the incorrect function of genes/proteins involved in B cell development.

Airway occlusion pressure at 0.1 sec (P0.1) is an index of respiratory center output. During pressure-support ventilation, P0.1 correlates with the mechanical output of the inspiratory muscles and has an inverse relationship with the amount of pressure-support ventilation. Based on these observations, we designed a closed-loop control which, by automatically adjusting pressure-support ventilation, stabilizes P0.1, and hence patient inspiratory activity, at a desired target. The purpose of the study was to demonstrate the feasibility of the method, rather than its efficacy or even its influence on patient outcome. Prospective, randomized trial. A general intensive care unit of a university hospital in Italy. Eight stable patients intubated and ventilated with pressure-support ventilation for acute respiratory failure. Patients were transiently connected to a computer-controlled ventilator on which the algorithm for closed-loop control was implemented. The closed-loop control was based on breath by breath measurement of P0.1, and on comparison with a target set by the user. When actual P0.1 proved to be higher than the target value, the P0.1 controller automatically increased pressure-support ventilation, and decreased it when P0.1 proved to be lower than the target value. For safety, a volume controller was also implemented. Four P0.1 targets (1.5, 2.5, 3.5, and 4.5 cm H2O) were applied at random for 15 mins each. The closed-loop algorithm was able to control P0.1, with a difference from the set targets of 0.59 +/- 0.27 (SD) cm H2O. The study shows that P0.1 can be automatically controlled by pressure-support ventilation adjustments with a computer. Inspiratory activity can thus be stabilized at a level prescribed by the physician.

To compare 4% albumin with 6% hydroxyethyl starch (HES) 130/0.4 in terms of perioperative blood loss and intraoperative fluid requirements in children undergoing cardiac surgery. Prospective randomized study. Single University Hospital. Pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. One hundred nineteen children were randomized to receive up to 50 mL.kg of either 4% albumin (Alb: n = 59) or 6% HES 130/0.4 (HES: n = 60) for intraoperative fluid volume replacement including the cardiopulmonary bypass priming fluid. Ringer's lactate was used for further intraoperative volume needs. Monitoring, anesthetic, and surgical techniques were standardized. Packed red blood cells were administered according to a strict transfusion protocol. Intra- and postoperative blood loss were measured and also calculated from children's estimated blood volume, pre- and postoperative hematocrit, and volume of transfused packed red blood cells. Volume of colloid used intraoperatively was similar in both groups (median [interquartiles]) (Alb: 50 [45-50] mL x kg; HES: 50 [37-50] mL x kg). Measured and calculated blood loss were not different between groups, but a higher number of children in the albumin group required allogeneic blood transfusion (78% vs. 57%; difference between proportions: 0.213; 95% confidence interval: 0.05-0.38; p = 0.0188). Intraoperative fluid balance was lower in the HES group (Alb 23 [11-39] mL x kg; HES: 12 [-5-30] mL x kg; p = 0.005). Postoperative outcome was not different between groups. In children undergoing cardiac surgery, 6% HES 130/0.4 may represent an interesting alternative to 4% albumin for intraoperative fluid volume replacement because of its lower cost.

Objectives: To compare the plasma volume (PV) expanding effect of a fast infusion rate with that of a slow infusion rate of a fixed volume of 5% albumin, of the synthetic colloids, 6% hydroxyethyl starch 130/0.4 and 4% gelatin, and of 0.9% NaCl in a rat sepsis model and to compare the plasma-expanding effect among these fluids. Design: Prospective, randomized animal study. Setting: University hospital laboratory. Subjects: One hundred and twelve adult male rats. Interventions: Sepsis was induced by cecal ligation and incision followed by closure of the abdomen. After 3 hrs, an infusion of the PV expander under study was started at a volume of 12mL/kg for the colloids and of 48mL/kg for 0.9% NaCl, either for 15 mins or for 3 hrs. A control group underwent the same experimental procedure but no fluid was given. Measurements and main results: Three hours after start of the infusion (end of experiment), the plasma-expanding effect was better with a slow than a fast infusion rate for the colloids, especially albumin, but the NaCl groups did not differ significantly from the control group. The PV for the control group was 28.7±3mL/kg. In the slow and the fast infusion groups, it was 38.9±4.3 and 32.6±4.2mL/kg for albumin (p < 0.001), 32.9±4.3 and 29.5±4.4mL/kg for hydroxyethyl starch 130/0.4 (p < 0.05), 31.8±3.9 and 28.2±4.1mL/kg for gelatin (p < 0.05), and 31.8±5.3 and 30.7±6.6mL/kg for NaCl (n.s), respectively. Conclusions: The study showed that the PV expansion by a colloid was greater when given at a slow than at a fast infusion rate, an effect more pronounced for albumin. This difference was not seen for NaCl. The PV-expanding effect was poor for NaCl and better for albumin than for the other colloids.

Capillary leakage, a frequent complication in septic shock, is characterized by loss of intravasal fluid resulting in generalized edema and hemodynamic instability despite massive fluid therapy. We have shown that administration of an established colloid 200/0.5 hydroxyethyl starch (HES) stabilized plasma volume in a porcine septic shock model. Recently, a new HES with a low molecular weight (130 kD) and lower molar substitution (0.42) has been developed. In this study, we compared effects of HES 130/0.42 and HES 200/0.5 on capillary leakage in porcine septic shock. Prospective randomized, controlled animal study. University department of anesthesiology. Fourteen pigs (22.9 +/- 2.8 kg). Anesthetized and mechanically ventilated pigs were observed over 6 hrs. Septic shock was induced with fecal peritonitis (0.75 g.kg of body weight autologous feces). Animals were allocated to volume-replacement therapy with either HES 130/0.42 (n = 5) or HES 200/0.5 (n = 5) and compared with nonseptic controls receiving HES 130/0.42 (n = 4). Infusion rate was titrated to maintain a central venous pressure of 12 mm Hg. Albumin escape rate was calculated using iodine 125-labeled albumin. Plasma volume was determined using chromium-51-tagged erythrocytes. Albumin escape rate increased significantly in both groups in comparison to controls (HES 200/0.5, 45% +/- 3; HES 130/0.42, 38% +/- 5), but this increase was significantly smaller with HES 130/0.42. Both HES 200/0.5 (-14%, not significant) and HES 130/0.42 (-1%, not significant) stabilized plasma volume compared with controls. Systemic oxygenation was not significantly altered in either group. In this porcine septic shock model, HES 130/0.42 attenuated capillary leakage significantly more effectively than HES 200/0.5.

OBJECTIVE, DESIGN AND PATIENTS: The risk of acute kidney injury (AKI) associated with hydroxyethyl starch may be limited to higher molecular weight agents. We retrospectively evaluated the risk of AKI using pentastarch 10% (250 kDa, 0.45) in a random cohort of 563 patients operated for a cardiac surgery at a university hospital. We assessed previously identified preoperative, perioperative, and postoperative risk factors, and the volume of pentastarch given until the end of the first postoperative day. We defined AKI by a 50% rise in serum creatinine within 4 days after surgery. Different propensity adjustment methods were used to further assess the selection bias. Fifty-four (10%) patients developed AKI. Risk factors of AKI were age, female gender, preoperative creatinine clearance, hypertension, diuretic use, left ventricular ejection fraction, valvular surgery, duration of extracorporeal circulation, duration and dose of postoperative vasopressor support, and the number of red blood cells and fresh frozen plasma transfusions. Patients with AKI received 16 +/- 9 mL/kg of pentastarch as opposed to 10 +/- 7 mL/kg in controls (p < 0.001). Pentastarch remained independently predictive of AKI, with an adjusted odds ratio per mL/kg of 1.08 (95% confidence interval 1.04-1.12, p = 0.001). This risk was dose-dependent, and the optimal cutoff volume predicting AKI was 14 mL/kg. Different propensity adjustment methods were tested, and pentastarch as a risk factor of AKI was identified. This study identified a dose-dependent risk of AKI with pentastarch following cardiac surgery, given until the end of the first postoperative day.

Catheters coated with minocycline and rifampin are proven to decrease the rates of central line-associated bloodstream infection; however, it is unclear whether success occurs independent of other infection control precautions. We evaluated the effect of catheters coated with minocycline and rifampin with and without other infection control precautions on our rates of central line-associated bloodstream infection in critically ill patients and on antibiotic resistance throughout the hospital and in the intensive care unit. Retrospective clinical cohort study conducted during 1999-2006 with an observational laboratory component. A tertiary university-based cancer center. All 8009 patients admitted to the medical intensive care unit were subjects for the surveillance of central line-associated bloodstream infection. All Staphylococcus aureus and coagulase-negative staphylococci clinical isolates cultured at our institution during the same period were subjects for laboratory testing. Using catheters coated with minocycline and rifampin and implementing infection control precautions. Incidence of central line-associated bloodstream infection in the medical intensive care unit. Change in resistance to tetracycline and rifampin in clinically relevant staphylococcal isolates in the intensive care unit and hospitalwide. During the study period, 9200 catheters coated with minocycline and rifampin were used hospitalwide over a total of 511,520 catheter days. The incidence of central line-associated bloodstream infection per 1000 patient days in the medical intensive care unit significantly and gradually decreased from 8.3 in 1998 to 1.2 in 2006 (p ≤ .001). The resistance of S. aureus and coagulase negative staphylococci clinical isolates to tetracycline or rifampin in the intensive care unit and on a hospitalwide level remained stable or decreased significantly during the same period. Catheters coated with minocycline and rifampin significantly decreased the incidence of central line-associated bloodstream infection in the medical intensive care unit in a manner that was independent and complementary to the infection control precautions. Although this study strongly suggests an association between catheters coated with minocycline and rifampin use and a decrease in central line-associated bloodstream infection, because of multiple other concurrent interventions, the results should be interpreted cautiously until a prospective study is conducted. Furthermore, long-term use of these devices is not associated with increased resistance of staphylococcal isolates to tetracycline and rifampin in the intensive care unit or throughout the hospital.

To assess the acute (4-hr), subacute (7-day), and chronic (21-day) effects of simulated aspiration of a 0.7% sucralfate suspension in rats. Prospective, multigroup trial in which rats were randomized to various simulated aspiration groups. Experimental animal laboratory. Forty-five Sprague-Dawley rats. Simulated aspiration was induced by single, direct, tracheal instillation of 2 mL/kg of either room air, sucralfate, or normal saline. Lung histologic changes were assessed using a quantitative numerical scoring scale. There was an increase in bronchiolar inflammation in rats undergoing acute, simulated sucralfate aspiration compared with controls. There were no significant differences (p > .05) in any other features at any time interval studied (two-way analysis of variance). Even though significant inflammatory airway lesions were produced in this acute model, these abnormalities resolved without evidence of subacute or chronic histologic progression. It remains to be determined if this pattern is unique to this specific experimental model or if it can be extrapolated to critically ill patients.

To compare heparin (3 mL, 10 units/mL) and 0.9% sodium chloride (NaCl, 10 mL) flush solutions with respect to central venous catheter lumen patency. Single-center, randomized, open label trial. Medical intensive care unit and Surgical/Burn/Trauma intensive care unit at Barnes-Jewish Hospital, St. Louis, MO. Three hundred forty-one patients with multilumen central venous catheters. Patients with at least one lumen with a minimum of two flushes were included in the analysis. Patients were randomly assigned within 12 hrs of central venous catheter insertion to receive either heparin or 0.9% sodium chloride flush. The primary outcome was lumen nonpatency. Secondary outcomes included the rates of loss of blood return, inability to infuse or flush through the lumen (flush failure), heparin-induced thrombocytopenia, and catheter-related blood stream infection. Assessment for patency was performed every 8 hrs in lumens without continuous infusions for the duration of catheter placement or discharge from intensive care unit. Three hundred twenty-six central venous catheters were studied yielding 709 lumens for analysis. The nonpatency rate was 3.8% in the heparin group (n = 314) and 6.3% in the 0.9% sodium chloride group (n = 395) (relative risk 1.66, 95% confidence interval 0.86-3.22, p = .136). The Kaplan-Meier analysis for time to first patency loss was not significantly different (log rank = 0.093) between groups. The rates of loss of blood return and flush failure were similar between the heparin and 0.9% sodium chloride groups. Pressure-injectable central venous catheters had significantly greater rates of nonpatency (10.6% vs. 4.3%, p = .001) and loss of blood return (37.0% vs. 18.8%, p <.001) compared to nonpressure-injectable catheters. The frequencies of heparin-induced thrombocytopenia and catheter-related blood stream infection were similar between groups. 0.9% sodium chloride and heparin flushing solutions have similar rates of lumen nonpatency. Given potential safety concerns with the use of heparin, 0.9% sodium chloride may be the preferred flushing solution for short-term use central venous catheter maintenance.

To compare the acute effects of 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Controlled laboratory experiment. University laboratory. Sixty adult, male Sprague-Dawley rats. We induced sepsis by cecal ligation and puncture and randomized animals to receive fluid resuscitation with either 0.9% saline or Plasma-Lyte solution for 4 hours after 18 hours of cecal ligation and puncture (10 mL/kg in the first hour and 5 mL/kg in the next 3 hr). Blood and urine specimens were obtained from baseline, 18 hours after cecal ligation and puncture, immediately after 4 hours fluid resuscitation, and 24 hours later. We measured blood gas, plasma electrolytes, creatinine, interleukin-6, cystatin C, and neutrophil gelatinase-associated lipocalin concentrations. We also analyzed urine for cystatin C and neutrophil gelatinase-associated lipocalin. We used Risk, Injury, Failure, Loss and End-stage criteria for creatinine to assess severity of acute kidney injury. We observed all animals for survival up to 1 day after resuscitation. Surviving animals were killed for kidney histology. Finally, we carried out an identical study in 12 healthy animals. Compared with Plasma-Lyte, 0.9% saline resuscitation resulted in significantly greater blood chloride concentrations (p < 0.05) and significantly decreased pH and base excess. Acute kidney injury severity measured by RIFLE criteria was increased with 0.9% saline compared with Plasma-Lyte resuscitation (p < 0.05), and these results were consistent with kidney histology and biomarkers of acute kidney injury. Twenty-four-hour survival favored Plasma-Lyte resuscitation (76.6% vs 53.3%; p = 0.03). Finally, in healthy animals, we found no differences between fluids and no evidence of acute kidney injury. Volume resuscitation with Plasma-Lyte resulted in less acidosis and less kidney injury and improved short-term survival when compared with 0.9% saline in this experimental animal model of sepsis.

To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. Multicentered, randomized, placebo-controlled, safety and efficacy study. Forty-eight intensive care units in Europe, North America, and Australia. A total of 312 patients with septic shock diagnosed within 24 hr before randomization. Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

To assess the hemodynamic effects of the nitric oxide synthase inhibitor 546C88 in patients with septic shock, although this was not a stated aim of the protocol. The predefined primary efficacy objective of the protocol was resolution of shock determined at the end of a 72-hr treatment period. Multicentered, randomized, placebo-controlled, safety and efficacy study. Forty-eight intensive care units in Europe, North America, and Australia. A total of 312 patients with septic shock diagnosed within 24 hr before randomization. Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Requirement for vasopressors, systemic and pulmonary hemodynamics, indices of oxygen transport, and plasma concentrations of arginine and nitrate were assessed over time. The median mean arterial pressure for both groups was maintained > or =70 mm Hg. There was an early increase in systemic and pulmonary vascular tone and oxygen extraction, whereas both cardiac index and oxygen delivery decreased for patients in the 546C88 cohort. Although these parameters subsequently returned toward baseline values, the observed differences between the treatment groups, except for pulmonary vascular resistance and oxygen extraction, persisted throughout the treatment period, despite a reduced requirement for vasopressors in the 546C88 cohort. These changes were associated with a reduction in plasma nitrate concentrations, which were elevated in both groups before the start of therapy. The nitric oxide synthase inhibitor 546C88 can reduce the elevated plasma nitrate concentrations observed in patients with septic shock. In this study, treatment with 546C88 for up to 72 hrs was associated with an increase in vascular tone and a reduction in both cardiac index and oxygen delivery. The successful maintenance of a target mean arterial blood pressure > or =70 mm Hg was achieved with a reduction in the requirement for, or withdrawal of, conventional inotropic vasoconstrictor agents (i.e., dopamine and norepinephrine). There were no substantive untoward consequences accompanying these hemodynamic effects. An international, randomized, double-blind, placebo-controlled phase III study has since been conducted in patients with septic shock. Recruitment into the study was discontinued due to the emergence of increased mortality in the 546C88-treated group.

Objectives: Patients with severe, persistent hypoxemic respiratory failure have a higher mortality. Early identification is critical for informing clinical decisions, using rescue strategies, and enrollment in clinical trials. The objective of this investigation was to develop and validate a prediction model to accurately and timely identify patients with severe hypoxemic respiratory failure at high risk of death, in whom novel rescue strategies can be efficiently evaluated. Design: Electronic medical record analysis. Setting: Medical, surgical, and mixed ICU setting at a tertiary care institution. Patients: Mechanically-ventilated ICU patients. Measurements and main results: Mechanically ventilated ICU patients were screened for severe hypoxemic respiratory failure (Murray lung injury score of ≥ 3). Survival to hospital discharge was the dependent variable. Clinical predictors within 24 hours of onset of severe hypoxemia were considered as the independent variables. An area under the curve and a Hosmer-Lemeshow goodness-of-fit test were used to assess discrimination and calibration. A logistic regression model was developed in the derivation cohort (2005-2007). The model was validated in an independent cohort (2008-2010). Among 79,341 screened patients, 1,032 met inclusion criteria. Mortality was 41% in the derivation cohort (n = 464) and 35% in the validation cohort (n = 568). The final model included hematologic malignancy, cirrhosis, aspiration, estimated dead space, oxygenation index, pH, and vasopressor use. The area under the curve of the model was 0.85 (0.82-0.89) and 0.79 (0.75-0.82) in the derivation and validation cohorts, respectively, and showed good calibration. A modified model, including only physiologic variables, performed similarly. It had comparable performance in patients with acute respiratory distress syndrome and outperformed previous prognostic models. Conclusions: A model using comorbid conditions and physiologic variables on the day of developing severe hypoxemic respiratory failure can predict hospital mortality.

To investigate the interrelationship between cardiac surgery, age, circulating concentrations of the vitamin D hormone 1,25-dihydroxyvitamin D, and clinical outcome. Prospective, monocentric, two-arm parallel study. Tertiary Heart and Diabetes Center in the Federal State of North Rhine-Westphalia, Germany. Twenty-nine cardiac surgical patients aged ≤ 65 yrs and 30 patients ≥ 75 yrs. We assessed 1,25-dihydroxyvitamin D and other biochemical parameters of mineral metabolism (calcium, phosphate, 25-hydroxyvitamin D, and parathyroid hormone), various inflammatory markers (C-reactive protein, interleukin-6 and 8), and different immunological parameters (CD4 and CD8 cells, monocyte HLA-DR expression). We collected blood samples preoperatively, immediately after surgery, and on postoperative days 1, 5, and 30. In addition, we assessed adverse outcome until discharge as a composite of myocardial infarction, low cardiac output syndrome, infection, stroke, or in-hospital death. There were significant transient cardiac surgery-related fluctuations in 1,25-dihydroxyvitamin D and the aforementioned parameters of mineral metabolism, inflammation, and immune status. Compared to younger patients, older patients had consistently lower 1,25-dihydroxyvitamin D and phosphate levels (p = .013 and p = .036, respectively) and significantly higher interleukin 6 and 8 levels (p = .008 and p < .001, respectively). Circulating 1,25-dihydroxyvitamin D was directly related to glomerular filtration rate (R(2) = .227; p < .001) and inversely related to interleukin 6 (R(2) = .105; p = .012). The rate of adverse outcome tended to be higher in older than in younger patients (20.0% vs. 3.5%; p = .081). In risk score-adjusted logistic regression analysis, adverse outcome risk decreased by 7.7% (SE: 3.7%) for each pmol/L increment in 1,25-dihydroxyvitamin D (p = .037). Circulating 1,25-dihydroxyvitamin D levels fluctuate in relation to cardiac surgery. Low 1,25-dihydroxyvitamin D levels are associated with inflammatory processes and age-related differences in clinical outcome. Future studies should determine whether therapies aimed at treating low 1,25-dihydroxyvitamin D levels can improve the outcome in older cardiac surgery patients.

Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. Multicenter, double-blind, phase III, placebo-controlled, randomized study. A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. Lenercept had no significant effect on mortality in the study population.

Fructose-1,6-bisphosphate has been shown to improve the outcome of hypoxic ischemic brain injury in adult rabbits. We wished to see if these results could be extended to a newborn animal. Twenty-four 0- to 3-day-old piglets were randomized to receive 300 mg/kg of fructose-1,6-bisphosphate 5 mins before injury, followed by a continuous infusion of 15 mg/kg/min of fructose-1,6-bisphosphate for the next 90 mins, or the equivalent volume of normal saline. Hypoxic ischemic central nervous system damage was induced by ligating both carotid arteries and reducing their BP to two thirds of the normal value for 30 mins. In the last 15 mins of this 30 mins, the FIO2 was reduced to 0.6. At 30 mins, the piglets were resuscitated with an FIO2 of 1.0, the carotid ligatures were released, and the removed blood was reinfused. The neurologic examination scores at 1, 2, and 3 days after injury and pathologic examination scores at 3 days after injury were not different in the fructose-1,6-bisphosphate-treated and the control animals. Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic brain injury in the newborn pig.

Fructose 1,6-bisphosphate (F1,6BP) protects organs against a wide range of challenges involving inflammation. We hypothesized that the primary action of F1,6BP is to prevent macrophage activation and cytokine release. Our aim was to determine the tissue and cellular targets for this bisphosphorylated sugar and to provide new insights into its mechanisms of action. Prospective, controlled laboratory study. Animal resource facilities and research laboratory. Male Sprague-Dawley rats (200-250 g body weight). The protective action of F1,6BP was analyzed in galactosamine (GalN)-induced hepatitis in rats. The in vivo effects of F1,6BP were evaluated by changes in transaminase activities, blood endotoxins, and tumor necrosis factor (TNF)-alpha production in GalN-challenged rats. The targets of F1,6BP to reduce macrophage response to lipopolysaccharide (LPS) were determined by correlation between changes in TNF-alpha production and K+ fluxes through cell membrane in primary cultures of Kupffer cells. The in vivo results indicate that F1,6BP treatment prevented GalN-induced injury in liver parenchymal cells. This protection was mainly associated with a reduction of the inflammatory response. F1,6BP prevention of GalN-induced endotoxemia correlated with preclusion of mast cell degranulation and histamine release that preceded the increased plasma endotoxins and liver production of TNF-alpha. In addition, F1,6BP treatment decreased sensitivity to LPS, which reduced the GalN-induced increase in TNF-alpha. The in vitro results show that F1,6BP inhibited Kupffer cell response and reduced TNF-alpha production by preventing LPS-induced K+ channel activation. The role of exogenous F1,6BP as a K+ channel modulator underlies its antihistaminic and anti-inflammatory action and increases its interest as a protective compound.

To determine whether fructose-1,6-diphosphate (FDP) pretreatment can attenuate acute lung injury induced by ischemia-reperfusion in our isolated lung model in rats. Randomized, controlled study. Animal care facility procedure room. Twenty-four adult male Sprague-Dawley rats each weighing 250-350 g. Typical acute lung injury in rats was induced successfully by 10 mins of hypoxia followed by 75 mins of ischemia and 50 mins of reperfusion. Ischemia-reperfusion significantly increased microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight to body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lav-age fluid. Pretreatment with FDP significantly attenuated the acute lung injury induced by ischemia-reperfusion as shown by a significant decrease in all of the assessed variables (p <.05 p <.001). The protective effect of FDP was nearly undetectable when promazine (an ecto-adenosine 5-triphosphatase inhibitor) was added before FDP pretreatment. Pretreatment with FDP significantly ameliorates acute lung injury induced by ischemia-reperfusion in rats.

This study evaluated the effect of fructose-1,6-diphosphate (FDP), theophylline, or the addition of both together to the preservation solution (University of Wisconsin [UW]) on apoptosis during preservation and the effect of apoptosis minimization on the early reperfusion period after transplantation. Prospective, randomized, and controlled animal study. Laboratory of a research institute. Male Wistar rats. The jejunum was isolated and preserved for 6 hrs in UW solution. FDP and theophylline were added to the UW solution to evaluate their effects on apoptosis both alone and together. The role of adenosine with respect to FDP was examined by increasing endogenous adenosine. In addition, rats were subjected to intestinal transplantation for the evaluation of the effect of apoptosis on bacterial translocation, histology, and neutrophil infiltration after reperfusion. Caspase-3 activity, assayed both in vitro or by cleaved caspase-3 levels in Western blots or immunohistochemically, and the number of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL)-positive cells decreased with FDP and with theophylline addition to UW solution. Increase of endogenous adenosine reversed the antiapoptotic effect of FDP. FDP and theophylline together demonstrated a more pronounced antiapoptotic effect and prevented bacterial translocation after transplantation. Supplementary FDP to UW solution decreased apoptosis through an adenosine-independent mechanism. Addition of theophylline to UW solution decreased both apoptosis and bacterial translocation. Concomitant theophylline and FDP addition to preservation solution is recommended to maintain low levels of apoptosis during intestinal hypothermic preservation and to decrease bacterial translocation.

The aim of this research project was to test the ability of fructose 1,6-bisphosphate (FBP), which has anti-inflammatory effects and maintains cellular energy levels, to inhibit the septic process in an experimental model in rats. Prospective, controlled animal trial. Research laboratory. Fed male Wistar rats. Three experimental groups were formed for the test: control group, untreated septic group, and septic group treated with FBP (500 mg/kg). In the control group, there were no deaths; in the untreated septic group, the mortality rate was 100% within 15 hrs; in the septic group treated with FBP, the mortality rate reached 20% within 15 hrs. The blood cell tests revealed that concentrations of hematocrit, leukocytes, monocytes, and immature cells increased significantly in the untreated septic group compared with both the FBP-treated septic group and the control group. The histologic lesions verified in the heart, lungs, liver, and kidneys of septic animals were smaller and even absent in those treated with FBP. FBP reduced the mortality rate provoked by experimental sepsis and ameliorated hematologic and histologic alterations.

We demonstrated earlier in our laboratories that fructose-1,6-bisphosphate (FDP) would improve the outcome of hypoxic ischemic injury to the brain in the adult rabbit. Since many human newborns suffer hypoxic injury to the brain, with a secondary ischemic component due to hypoxic cardiac failure, we set out to reproduce similar experiments in newborn piglets. Hypoxic ischemic CNS damage was induced by ligating both carotid arteries and reducing BP to 66% of normal for 30 min; in the last 15 min, FIO2 was reduced to 0.6. Twelve piglets were randomized to receive either 175 mg/kg of FDP in the last 5 min before reoxygenation or the equivalent volume of saline. The other 20 piglets received 75 mg/kg of FDP in the 5 min immediately before carotid ligation, followed by 1.8 mg/kg.min continuous infusion for the 30 min of hypoxia and ischemia or an equivalent volume of saline. There were no significant differences in the neurologic exam scores or pathologic exam scores between the FDP and control animals at either dose level. In this animal model, FDP at the doses given was not effective in ameliorating hypoxic ischemic injury to the CNS.

In order to assess the immediate and long-term outcome of very low birth weight infants, a retrospective analysis of clinical and biochemical parameters of 100 consecutive newborns with birth weights less than 1000 g was carried out. Overall neonatal mortality for this group was 69%. For infants between 751 to 1000 g, the mortality rate was 52%. Of the 23 infants who were discharged, neurodevelopmental assessment was performed in 16. Twelve of the 16 were neurologically normal. The data indicate a favorable prognosis for infants with birth weight less than 1000 g.

To describe normal serum levels of S-100beta in healthy children and determine whether serum S-100beta levels after traumatic brain injury are associated with outcome. Prospective cohort study. Urban, tertiary care, children's teaching hospital. A total of 136 healthy children and 27 children with traumatic brain injury. Serum S-100beta levels were measured in 136 healthy children. A total of 27 children with traumatic brain injury had S-100beta levels collected within 12 hrs of injury. Other indices of severity of injury measured were admission Glasgow Coma Scale score, and Pediatric Risk of Mortality score at 24 hrs (PRISM 24). Outcome was measured by the Pediatric Cerebral Performance Category (PCPC) score at hospital discharge and 6 months postinjury or at death. S-100beta levels in healthy children had a mean of 0.3 microg/L (90% confidence interval, 0.03-1.47) and inversely correlated with age, (r = -.32, p <.001). In children with traumatic brain injury, 6-month postinjury outcome inversely correlated with Glasgow Coma Scale score (r = -.47, p =.01) and correlated with PRISM 24 score (r =.83, p <.001) and S-100beta levels (r =.75, p <.001). Six months postinjury, comparing good outcome (PCPC < or = 3, n = 20) vs. poor outcome (PCPC > or = 4, n = 7), median admission Glasgow Coma Scale scores were 8 (range, 3-15) and 3 (range, 3-7, p =.01), median PRISM 24 scores were 7 (range, 0-19) and 30 (range, 18-35, p <.001), and median S-100beta levels were 0.85 microg/L (range, 0.08-4.8 microg/L) and 3.6 microg/L (range, 1.4-20 microg/L, p <.001), respectively. A serum S-100beta level of > or =2.0 microg/L is associated with poor outcome, with a sensitivity of 86% and a specificity of 95%. The area under the receiver operating curve for S-100beta was 0.94 (+/-0.05). Serum S-100beta levels in healthy children have a moderate inverse correlation with age. After traumatic brain injury in children, the acute assessment of serum S-100beta levels seems to be associated with outcome.

We investigated the role of right-to-left shunt with standardized transcranial Doppler ultrasonography in a large population of divers referred for symptoms of decompression illness. Case series compared with a control group. Military teaching hospital, hyperbaric unit. Patients were 101 consecutive divers with clinical evidence of decompression illness and a control group of 101 healthy divers. Specification of the type of decompression illness involved and detection/evaluation of right-to-left shunt by standardized transcranial Doppler. The degree of right-to-left shunt was defined as major if the number of high-intensity transient signals in the middle cerebral artery was >20. We evaluated the odds ratios by logistic regression analysis with vs. without right-to-left shunt for subjects with cochleovestibular symptoms, cerebral decompression illness, spinal decompression illness, and Caisson sickness. Of the 101 divers presenting with decompression illness, transcranial Doppler detected a right-to-left shunt in 59 (58.4%), whereas control subjects demonstrated a right-to-left shunt in 25 cases (24.8%; odds ratio, 4.3; 95% confidence interval, 2.3-7.8; p=.09). When a right-to-left shunt was detected, the right-to-left shunt was major in 12 of 25 patients in the control group and in 49 of 59 patients in the decompression illness group (odds ratio, 8.7; 95% confidence interval, 4.2-18.0; p<.001). Within the decompression illness group, the proportion of major right-to-left shunt was 24 of 34 (odds ratio, 29.7; 95% confidence interval, 10.0-87.2; p<.0001) in the cochleovestibular subgroup, 13 of 21 (odds ratio, 24.1, 95% confidence interval, 6.8-86.0, p< 0.0001) in the cerebral decompression illness subgroup, ten of 31 (odds ratio, 3.9; 95% confidence interval, 1.5-10.3; p<.01) in the spinal decompression illness subgroup, and two of two (odds ratio, 1.1; 95% confidence interval, 0.2-5.7; p=.9) in the subgroup of divers with Caisson sickness. Based on our results, we conclude that major right-to-left shunt was associated with an increased incidence of cochleovestibular and cerebral decompression illness, suggesting paradoxical embolism as a potential mechanism.

We tested the hypothesis that the administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742) or cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS 19755) or the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), at the appropriate doses, would all have efficacy in decreasing early postischemic brain injury in a feline model of transient focal ischemia. Prospective, randomized, controlled animal trial. University research laboratory. Forty mixed-breed cats. Halothane-anesthetized cats underwent 90 mins of left middle cerebral artery occlusion plus 4 hrs of reperfusion. At 75 mins of ischemia, control cats received intravenous saline (n = 10). Experimental cats (n = 10 in each group) were treated with NPC 17742 (5 mg/kg bolus and 2.5 mg/kg/hr throughout reperfusion), MK-801 (5 mg/kg intravenous bolus), or CGS 19755 (40 mg/kg intravenous bolus) in a randomized fashion. Microsphere-determined blood flow to the ipsilateral inferior temporal cortex and caudate nucleus decreased to the same extent during ischemia, and recovered to the same extent during early reperfusion, in the four groups. Triphenyltetrazolium-determined injury volume of the ipsilateral caudate nucleus in cats treated with NPC 17742 (105 +/- 25 [SEM] mm3), MK-801 (97 +/- 22 mm3), and CGS 19755 (97 +/- 13 mm3) was less than in control cats (198 +/- 21 mm3). Hemisphere injury volumes with NPC 17742 (1209 +/- 405 mm3) and MK-801 (1338 +/- 395 mm3) were less than that value in controls (2193 +/- 372 mm3), whereas injury volume with CGS 19755 (1553 +/- 519 mm3) treatment did not attain significance (p < .09). NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions after 90 mins of transient focal ischemia in the cat. At the doses chosen, there appear to be no major differences in therapeutic efficacy for competitive and noncompetitive NMDA receptor antagonists.

We reviewed all patients treated for intoxication in the pediatric ICU (PICU) of the Sainte-Justine Hospital over a 3-yr period. Poisoning (105 patients) constituted 3.1% of PICU admissions. Most involved children less than 3 (42%) yr or greater than 12 (33%) yr. Products most commonly ingested included tricyclic antidepressants (22%), benzodiazepines (15%), theophylline (10%), ethanol (10%), hallucinogens (8%), salicylates (8%), narcotics (8%), antihistamines (7%), and carbamazepine (5%). Three children became comatose after ingesting about 1 g of hashish. Multiple drug ingestions were frequent (22%), particularly in suicide attempts (11/23). Treatment was, in general, interventionist and nonspecific; aggressive measures for poisoning were required in only two patients who were hemodialyzed. Two patients stayed in the PICU greater than 2 days. All patients survived with no sequelae, except for one patient who required an intestinal resection. Poisoning in children is a common occurrence leading to PICU admission; however, the medical prognosis is usually excellent.

To analyze the time course and changes of cerebral microdialysis parameters after aneurysmal subarachnoid hemorrhage (SAH) in respect to the clinical course (asymptomatic, delayed, and acute ischemic neurologic deficits) to evaluate the method of bedside microdialysis in these patients. Prospective, controlled study during a 3-yr period. Neurosurgical intensive care unit at a primary level university hospital, supervised and staffed by members of both the department of neurosurgery and the department of anesthesiology and intensive care medicine. Ninety-seven patients (51 females/21 males; 52 +/- 13 yrs; World Federation of Neurological Surgeons Scale grades 0-5) after aneurysmatic SAH. A microdialysis catheter (CMA 100) was inserted into the region most likely to be affected by vasospasm directly after aneurysm clipping, connected to a pump, and perfused with Ringer solution (0.3 microL/min). The dialysates were collected hourly and analyzed at the bedside for glucose, lactate, lactate-pyruvate ratio, glutamate, and glycerol (CMA 600). Patients were classified according to clinical presentation as being asymptomatic or having acute (AIND) or delayed (DIND) ischemic neurologic deficits. DIND patients (n = 18) had significantly higher lactate and glutamate concentrations on days 1-8 post-SAH and a higher lactate-pyruvate ratio on days 3-8 post-SAH compared with asymptomatic patients (n = 57; p <.025). Glucose and glycerol levels did not differ in asymptomatic and DIND patients. AIND patients (n = 22) had the worst metabolic pattern: the extracellular glucose concentration was low, whereas the lactate, lactate-pyruvate ratio, glutamate, and glycerol levels were significantly elevated compared with asymptomatic and DIND patients. In 83% of the DIND patients, the changes in metabolites indicative of cerebral ischemia preceded the onset of symptomatic vasospasm. All DIND patients clinically improved in their Glasgow Coma Scale scores with induced hypertension, intentional hypervolemia, and/or hemodilution therapy (p =.01). Cerebral bedside microdialysis is a safe and promising technique for monitoring (impending) regional cerebral ischemia. The dialysate changes can indicate early the onset of delayed neurologic deterioration and are in good accordance with the clinical course of SAH patients. In the future, this technique may be used to monitor the efficacy of the intensive care therapy of these patients.

To determine the value and safety of fiberoptic bronchoscopy in an intensive care unit (ICU). Prospective survey. ICUs at a tertiary care hospital (except for seven procedures that were performed at a peripheral hospital ICU). A total of 107 patients with a mean age of 43.9 yrs (range 15 to 84). One hundred forty-seven fiberoptic bronchoscopy procedures (116 performed on patients who were undergoing mechanical ventilation) were performed on 107 patients. Ninety-four procedures were for diagnostic reasons (upper and lower airway inspection, focal and diffuse pulmonary infiltrates), 37 for therapeutic reasons (bronchial toilet, pulmonary hemorrhage, endotracheal intubation), and 16 for both reasons. Topical anaesthesia was used for fiberoptic bronchoscopy; sedation was rarely needed. Appropriate diagnostic and therapeutic procedures were performed. Oxygen saturation, electrocardiogram, and blood pressure were monitored. Transbronchial biopsies (all on mechanical ventilation) for diffuse pulmonary infiltrates were diagnostic in five of seven cases, and were suggestive of the diagnosis in a further case. Endobronchial biopsies were not diagnostic in any of three cases. Bronchial brushings for microbiology were positive in nine of 50 procedures and for cytology in one of nine procedures. Protected specimen brushes for pulmonary infiltrates gave positive microbiology findings in five of 23 procedures. In pulmonary hemorrhage, focal bleeding was found in five cases, diffuse bleeding in four, and no bleeding source in three. In lobar atelectasis, bronchial toilet led to full reexpansion (n = 20 procedures), partial reexpansion (n = 5), and no change (n = 3). Intubation with fiberoptic bronchoscopy was successful in four of five patients. Hypoxemia (oxygen saturation < 90%) occurred in 29 procedures; it caused no problems. Complications included hemorrhage (n = 2), supraventricular tachycardia (n = 1), pneumothorax (n = 1), pneumatocele (n = 1), and bronchospasm (n = 1). No deaths were attributable to fiberoptic bronchoscopy. Fiberoptic bronchoscopy in the ICU is safe, contributes valuable diagnostic information, and is useful for therapeutic purposes.

The survival benefit of prone positioning during mechanical ventilation for acute respiratory distress syndrome has been a matter of debate. Recent multicenter randomized controlled trials have shown a significant reduction of 28-day and 90-day mortality associated with prone positioning during mechanical ventilation for severe acute respiratory distress syndrome. We performed an up-to-date meta-analysis on this topic and elucidated the effect of prone positioning on overall mortality and associated complications. PubMed, EMBASE, BioMed Central, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and conference proceedings through May 2013. Randomized controlled trial comparing overall mortality of prone-versus-supine positioning in patients with acute respiratory distress syndrome. Data were extracted for populations, interventions, outcomes, and risk of bias. The prespecified primary endpoint was overall mortality, using the longest available follow-up in each study. The odds ratio with 95% CI was the effect measure. This analysis included 11 randomized controlled trial, 2,246 total adult patients, and 1,142 patients ventilated in the prone position. Prone positioning during ventilation significantly reduced overall mortality in the random-effect model (odds ratio, 0.77; 95% CI, 0.59-0.99; p = 0.039; I = 33.7%), and the effects were marked in the subgroup in which the duration of prone positioning was more than 10 hr/session, compared with the subgroup with a short-term duration of prone positioning (odds ratio, 0.62; 9% CI, 0.48-0.79; p = 0.039; pinteraction = 0.015). Prone positioning was significantly associated with pressure ulcers (odds ratio, 1.49; 95% CI, 1.18-1.89; p = 0.001; I = 0.0%) and major airway problems (odds ratio, 1.55; 95% CI, 1.10-2.17; p = 0.012; I = 32.7%). Ventilation in the prone position significantly reduced overall mortality in patients with severe acute respiratory distress syndrome. Sufficient duration of prone positioning was significantly associated with a reduction in overall mortality. Prone ventilation was also significantly associated with pressure ulcers and major airway problems.

Amino acids and thiobarbituric acid reactive substances (TBARs) in the cerebrospinal fluid (CSF) and plasma were identified and assayed in 5 patients with septic encephalopathy. Levels of all the high molecular weight neutral amino acids (LNAAs) appeared to increase in the CSF. CSF levels of phenylalanine (PHE) and methionine (MET) increased significantly by factors of 20.9 and 9.5, respectively, and the plasma PHE level increased 7.5-fold. No significant changes in branched-chain amino acids were observed in either the CSF or plasma. The CSF/plasma ratios of valine (VAL), tyrosine (TYR), PHE, and MET significantly increased to 0.21, 0.46, 0.52, and 0.52, respectively. TBAR levels increased 4-fold in the CSF and also were slightly increased in the plasma, suggesting that lipid peroxidation in the central nervous tissues is markedly increased. We conclude that increases in LNAA levels and in lipid peroxidation in the central nervous tissues may play important roles in the development of septic encephalopathy.

To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion. Randomized, controlled trial. Animal laboratory. Twenty seven domestic pigs, weighing 24 to 31 kg. All pigs were anesthetized and mechanically ventilated during the experiment. Eighteen pigs were subjected to an intracaval infusion of 10% allogeneic bone marrow suspension at a dose of 100 mg/kg over 5 mins. Nine pigs received only bone marrow suspension (fat embolism group). Nine pigs were given an intravenous bolus of aspirin (300 mg) 1 hr before the bone marrow suspension infusion. After the induction of fat embolism, intravenous aspirin was administered at a dose of 150 mg/hr for 2 hrs (aspirin-treated group). Nine pigs were infused with saline (control group). In the fat embolism group, cardiac index decreased within 30 mins, while mean arterial pressure remained unchanged. Central venous pressure and pulmonary artery occlusion pressure remained relatively stable over time in the animals with fat embolism. Mean pulmonary arterial pressure and pulmonary vascular resistance increased immediately after the bone marrow suspension infusion from 23 +/- 0.8 (SEM) to 34 +/- 1.3 mm Hg and from 305 +/- 28 to 585 +/- 45 dyne x sec/cm5, respectively; these variables remained increased throughout the study period. Simultaneously, pulmonary shunt in the fat embolism group increased persistently from the baseline of 12.3 +/- 2.8%, and reached its maximum of 26.1 +/- 4.8% at the end of the experiment. Instant and gradual decreases in PaO2 (from 95 +/- 4 to 67 +/- 5 torr [12.6 +/- 0.5 to 8.9 +/- 0.7 kPa]), hemoglobin oxygen saturation (from 97.2 +/- 0.4 to 91.8 +/- 1.8%), and oxygen delivery (from 16.3 +/- 1.0 to 12.6 +/- 0.4 mL/min/kg) were observed in the fat embolism group. In the bone marrow suspension-infused animals, urine 2,3-dinor-6-ketoprostaglandin F1alpha excretion increased transiently from 451 +/- 63 up to 1466 +/- 499 pg/micromol creatinine, while urine 11-dehydrothromboxane B2 excretion increased transiently from 385 +/- 36 up to 2307 +/- 685 pg/micromol creatinine. In the aspirin-treated animals, urinary excretion of these prostanoid metabolites was reduced by 81% and 88%, respectively. The changes in mean pulmonary arterial pressure and PaO2 were ameliorated, and the alterations in pulmonary shunt and SaO2 were abolished in the animals with aspirin treatment. Pulmonary hypertension, increased pulmonary vascular tone, and increased pulmonary shunt are hallmarks of the present fat embolism model. These hemodynamic responses may, at least partly, be related to the changed balance between prostacyclin and thromboxane A2 production.

The objective of this study was to review and discuss the medical response to the Pentagon attack on September 11, 2001. The authors conducted a retrospective review of hospital records and emergency agency report. This study was conducted at an adult tertiary hospital with regional burn and trauma centers. Observational. One hundred eighty-nine persons lost their lives. Area health facilities received 106 patients; 49 were admitted for treatments and 57 were treated and released. Nine patients were admitted to the burn center. The average total body burn surface was 34%. The average age was 45 yrs. A total of 108 operations were performed. The average burn critical care and hospital length of stays were 31 and 61.7 days, respectively. One patient died of an inhalation injury on day 7. The Pentagon attack produced few severely injured patients. The regional hospitals were back to normal function the day after. The severely burned patients increased the workload of the burn service but did not affect admissions of subsequent non-Pentagon patients after the second day. In case of a much larger number of critically injured patients, regional to national cooperation and transfer of patients should be considered.

To compare estimates of pulmonary endothelial barrier integrity obtained using two different tracer proteins. Measure the pulmonary transcapillary escape rate with gallium (Ga)-68 labeled transferrin (PTCER(tf)) and positron emission tomography (PET) imaging and compare the results to similar measurements obtained with C-11 labeled methylalbumin (PTCER(alb)). Laboratory investigation. Mongrel dogs. No intervention in one group of dogs (n = 3); oleic-acid induced lung injury in another set (n = 4). Although PTCER(tf) was consistently higher than PTCER(alb) (mean difference: 50 x 10(-4)/min), the overall correlation between the two methods, after normalizing for differences in regression slope and intercept among the individual dogs, was excellent (r2 = .67). The data support the continued use of PET and Ga-68 transferrin as an appropriate means of evaluating and quantifying lung injury.

St. Vincent's Hospital in New York City was the primary recipient of patients after the 1993 bombing of the World Trade Center. This experience prompted the drafting of a formal disaster plan, which was implemented during the terrorist attack on the World Trade Center on September 11, 2001. Here, we outline the Emergency Management External Disaster Plan of St. Vincent's Hospital and discuss the time course of presentation and medical characteristics of the critically injured patients on that day. We describe how the critical care service adapted to the specific challenges presented and the lessons that we learned. We hope to provide other critical care systems with a framework for response to such large-scale disasters.

Propofol is a sedative, anesthetic, and antiepileptic agent that is frequently used in patients with refractory status epilepticus. Propofol infusion syndrome is a feared complication of propofol use, especially at high infusion rates for prolonged periods. The present study describes the use of propofol and its associated complications in patients with refractory status epilepticus. : Retrospective study with outcome assessment. Intensive care units at Mayo Clinic. Intensive care unit admissions with refractory status epilepticus. None. A computer-assisted search identified 41 consecutive patients from January 1997 to September 2008 admitted to our intensive care unit with refractory status epilepticus, defined by the need for continuous intravenous infusion of anesthetic agents to control seizures. Propofol infusion syndrome was defined per previously published criteria. The study population consisted of 24 males and 17 females with a median age of 51 yrs (range, 0.25- 80). Propofol was used in 31 (76%) of these patients (propofol group), and other agents like midazolam, lorazepam, and pentobarbital were used in the other ten (24%) patients (nonpropofol group). Median hospital (12 days; range, 2-112) and intensive care unit length of stay (9 days; range, 2-95) did not differ among the two groups. Propofol was used for a median of 63 hrs (range, 2-391) with a median cumulative dosage of 12,750 mg (range, 336-57,545). The median peak infusion rate was 67 microg/kg/min (range, 19-200). There were three sudden unexplained cardiorespiratory arrests in the propofol group (3 of 31, 10%), of which two were fatal. These three patients were aged 37, 46, and 55 yrs and had no prior cardiopulmonary disease. Eleven additional patients (11 of 31, 35%) had non-life-threatening features of propofol infusion syndrome. There were no such events noted in the nonpropofol group. The prolonged use of large doses of propofol to treat refractory status epilepticus was associated with significant mortality and morbidity.

At 07:39 am on March 11th, 2004, ten terrorist bomb explosions occurred almost simultaneously in four commuter trains in Madrid, Spain, killing instantly 177 people and injuring >2,000. There were 14 subsequent in-hospital deaths, bringing the definite death toll to 191 victims. This article describes the organization of the clinical management and patterns of injuries in casualties who were taken to the closest hospital, with emphasis on the critical patient population. There were 312 patients taken to that center, and 91 were hospitalized, 89 of them (28.5%) for >24 hrs. Sixty-two patients only had superficial bruises or emotional shock, but the remaining 250 patients had more severe lesions. The data on 243 of the latter form the basis of this report. Tympanic perforation occurred in 41% of 243 victims with moderate-to-severe trauma, chest injuries in 40%, shrapnel wounds in 36%, fractures in 18%, first- or second-degree burns in 18%, eye lesions in 18%, head trauma in 12%, and abdominal injuries in 5%. Between 8:00 am and 5:00 pm, 34 surgical interventions were performed on 32 victims. Twenty-nine casualties (12% of the total or 32.5% of those hospitalized) were deemed in critical condition, and two of them died within minutes of arrival. The other 27 survived to be admitted to intensive care units, and three of them died, bringing the critical mortality rate to 17.2% (5/29). The mean Injury Severity Score and Acute Physiology and Chronic Health Evaluation II scores of critical patients were 34 and 23, respectively. Among these critical patients, soft-tissue and musculoskeletal injuries predominated in 85% of cases, ear blast injury was identified in 67%, and blast lung injury was present in 63% (17 cases). Fifty-two percent suffered head trauma. There was probably an overtriage to the closest hospital, and the time of the blasts proved crucial for the adequacy of the medical and surgical response. The number of blast lung injuries seen is probably the largest reported by a single institution, and the critical mortality rate was reasonably low.

To determine the efficacy and safety of epidural bupivacaine and sufentanil for the management of sympathetic overactivity in tetanus. Retrospective case review. Sixteen-bed surgical intensive care unit in a tertiary care centre. All patients referred to the unit during a 63-month period with the diagnosis of tetanus were included in the study. All patients (n = 11) had severe tetanus and developed sympathetic overactivity, which was managed by epidural blockade. Three patients died, but there were no fatalities directly attributable to sympathetic overactivity. Before epidural blockade, the average difference between the mean maximum and mean minimum systolic blood pressures was 78 +/- 28 (so) mm Hg. After blockade, this difference was reduced to 38 +/- 15 (so) mm Hg (p < .0001). Similar significant reductions in diastolic blood pressure and heart rate were observed. The mean hourly infusion doses of bupivacaine and sufentanil were 17 mg and 21 microg, respectively. Midazolam was the principal adjunctive sedative agent and was used in all patients (mean dose, 9 mg/hr). Additional pharmacologic agents were necessary in two patients in whom epidural blockade alone was insufficient to control sympathetic overactivity. One patient developed renal failure and there were no instances of pneumothorax. One patient developed an epidural abscess of probable hematogenous origin, which was successfully treated without neurologic sequelae. Epidural blockade is effective in controlling sympathetic overactivity and the associated complications (renal failure, cardiac injury, and sudden death). Although a serious complication occurred in one patient, the efficacy of the technique deserves further validation.

To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. A two-phase study: a controlled, randomized, double-blind study followed by a prospective, open study. An 800-bed, teaching, university-affiliated hospital. Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. INTERVENTIONS; All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil administration; 40% relapsed into coma after 18 +/- 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant "waking" episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.