David E. Schwartz

death and Other Complications of Emergency Airway Management in Critically Ill Adults : a Prospective Investigation of 297 Tracheal Intubations

Background Hospitalized patients outside of the operating room frequently require emergency airway management. This study investigates complications of emergency airway management in critically ill adults, including: (1) the incidence of difficult and failed intubation; (2) the frequency of esophageal intubation; (3) the incidence of pneumothorax and pulmonary aspiration; (4) the hemodynamic consequences of emergent intubation, including death, during and immediately following intubation; and (5) the relationship, if any, between the occurrence of complications and supervision of the intubation by an attending physician. Methods Data were collected on consecutive tracheal intubations carried out by the intensive care unit team over a 10‐month period. Non‐anesthesia residents were supervised by anesthesia residents, critical care attending physicians, or anesthesia attending physicians. Results Two hundred ninety‐seven consecutive intubations were carried out in 238 adult patients. Translaryngeal tracheal intubation was accomplished in all patients. Intubation was difficult in 8% of cases (requiring more than two attempts at laryngoscopy by a physician skilled in airway management). Esophageal intubation occurred in 25 (8%) of the attempts but all were recognized before any adverse sequelae resulted. New infiltrates suggestive of pulmonary aspiration were present on chest radiograph after 4% of intubations. Seven patients (3%) died during or within 30 min of the procedure. Five of the seven patients had systemic hypotension (systolic blood pressure less or equal to 90 mmHg), and four of the five were receiving vasopressors to support systolic blood pressure. Patients with systolic hypotension were more likely to die after intubation than were normotensive patients (P < 0.001). There was no relationship between supervision by an attending physician and the occurrence of complications. Conclusions In critically ill patients, emergency tracheal intubation is associated with a significant frequency of major complications. In this study, complications were not increased when intubations were accomplished without the supervision of an attending physician as long as the intubation was carried out or supervised by an individual skilled in airway management. Mortality associated with emergent tracheal intubation is highest in patients who are hemodynamically unstable and receiving vasopressor therapy before intubation.

Resuscitation with Lipid versus Epinephrine in a Rat Model of Bupivacaine Overdose

Background:Lipid emulsion infusion reverses cardiovascular compromise due to local anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac toxicity to determine whether lipid provides a benefit over epinephrine. Methods:Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml · kg−1 · min−1) or epinephrine (30 &mgr;g/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate–pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min. Results:Lipid infusion resulted in higher rate–pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min. Conclusions:Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic local anesthetic toxicity.

Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability.

We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1, the caveolae scaffold protein. The permeability increase induced by PMN activation was blocked in caveolin-1 knockout mice and by suppressing caveolin-1 expression in rats. The response was also dependent on Src phosphorylation of caveolin-1 known to activate caveolae-mediated endocytosis in endothelial cells. To address the role of PMN interaction with endothelial cells, we used an intercellular adhesion molecule (ICAM)-1 blocking monoclonal antibody. Preventing the ICAM-1–mediated PMN binding to endothelial cells abrogated Src phosphorylation of caveolin-1, as well as the increase in endothelial permeability. Direct ICAM-1 activation by crosslinking recapitulated these responses, suggesting that ICAM-1 activates caveolin-1 signaling responsible for caveolae-mediated endothelial hyperpermeability. Our results provide support for the novel concept that a large component of pulmonary vascular hyperpermeability induced by activation of PMNs adherent to the vessel wall is dependent on signaling via caveolin-1 and increased caveolae-mediated transcytosis. Thus, it is important to consider the role of the transendothelial vesicular permeability pathway that contributes to edema formation in developing therapeutic interventions against PMN-mediated inflammatory diseases such as acute lung injury.

Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest

Objectives:Lipid emulsion infusion is an emerging antidotal therapy for toxin-induced cardiac arrest. To compare the efficacy of resuscitation from bupivacaine-induced asystole using lipid emulsion infusion vs. vasopressin, alone and with epinephrine. Design:Prospective, randomized, animal study. Setting:University research laboratory. Subjects:Adult, male Sprague-Dawley rats. Interventions:Instrumented rats were given an intravenous bolus of 20 mg/kg bupivacaine to induce asystole (zero time). Rats (n = 6 for all groups) were ventilated with 100% oxygen, given chest compressions, and randomized to receive 30% lipid emulsion (L, 5 mL/kg bolus then 1.0 mL/kg/min infusion) and vasopressin 0.4 U/kg bolus alone (V) or combined with epinephrine, 30 &mgr;g/kg (V + E); boluses (L, V, or V + E) were repeated at 2.5 and 5 minutes for a rate–pressure product (RPP) less than 20% baseline. Measurements and Main Results:The arterial blood pressure and electrocardiogram were measured continuously for 10 minutes when blood was drawn for arterial blood gas analysis, lactate content, and central venous oxygen saturation (ScvpO2). Hemodynamic parameters of the L group at 10 minutes (30,615 ± 4782 mm Hg/min; 151 ± 19.1 mm Hg; 197 ± 8.6 min−1; RPP, systolic blood pressure and heart rate, respectively) exceeded those of the V group (5395 ± 1310 mm Hg/min; 85.8 ± 12 mm Hg; 61 ± 10.8 min−1) and the V + E group (11,183 ± 1857 mm Hg/min−1; 75.5 ± 12.9 min−1, RPP and heart rate, respectively; systolic blood pressure was not different). Metrics indicated better tissue perfusion in the L group (7.24 ± 0.02; 83% ± 3.5%; 2.2 ± 0.36 mmol/L; pH, ScvpO2, lactate, respectively) than V (7.13 ± 0.02; 29.9% ± 4.4%; 7.5 ± 0.6 mmol/L) and V + E groups (7.07 ± 0.03; 26.2% ± 8.9%; 7.7 ± 1 mmol/L). Wet-to-dry lung ratios in V (8.3 ± 0.6) and V + E (8.7 ± 0.2) were greater than that in the L group (6.2 ± 05) (mean ± sem; p < 0.05 for all shown results). Conclusions:Lipid emulsion in this rat model provides superior hemodynamic and metabolic recovery from bupivacaine-induced cardiac arrest than do vasopressors. Systolic pressure was not a useful metric in the vasopressor groups. Vasopressin was associated with adverse outcomes.

Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade.

Background: Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells. Methods: NCI-H838 lung cancer cells were incubated with tumor necrosis factor-&agr; in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM–100 &mgr;M). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated. Results: Ropivacaine treatment (100 &mgr;M) of H838 cells for 20 min decreased basal Src activity by 62% (P = 0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-&agr; statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P = 0.005) in presence of 1 &mgr;M ropivacaine and 21% by 1 &mgr;M lidocaine (P = 0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition. Conclusions: This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-&agr;-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.

Scalable printed electronics: an organic decoder addressing ferroelectric non-volatile memory

Scalable circuits of organic logic and memory are realized using all-additive printing processes. A 3-bit organic complementary decoder is fabricated and used to read and write non-volatile, rewritable ferroelectric memory. The decoder-memory array is patterned by inkjet and gravure printing on flexible plastics. Simulation models for the organic transistors are developed, enabling circuit designs tolerant of the variations in printed devices. We explain the key design rules in fabrication of complex printed circuits and elucidate the performance requirements of materials and devices for reliable organic digital logic.

A flexible high potential printed battery for powering printed electronics

Mechanically flexible arrays of alkaline electrochemical cells fabricated using stencil printing onto fibrous substrates are shown to provide the necessary performance characteristics for driving ink-jet printed circuits. Due to the dimensions and material set currently required for reliable low-temperature print processing of electronic devices, a battery potential greater than that sourced by single cells is typically needed. The developed battery is a series interconnected array of 10 low resistance Zn-MnO2 alkaline cells, giving an open circuit potential of 14u2009V. This flexible battery is used to power an ink-jet printed 5-stage complementary ring oscillator based on organic semiconductors.

Activation of NLRP3 Inflammasome in Alveolar Macrophages Contributes to Mechanical Stretch-Induced Lung Inflammation and Injury

Mechanical ventilation of lungs is capable of activating the innate immune system and inducing sterile inflammatory response. The proinflammatory cytokine IL-1β is among the definitive markers for accurately identifying ventilator-induced lung inflammation. However, mechanisms of IL-1β release during mechanical ventilation are unknown. In this study, we show that cyclic stretch activates the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes and induces the release of IL-1β in mouse alveolar macrophages via caspase-1– and TLR4-dependent mechanisms. We also observed that NADPH oxidase subunit gp91phox was dispensable for stretch-induced cytokine production, whereas mitochondrial generation of reactive oxygen species was required for stretch-induced NLRP3 inflammasome activation and IL-1β release. Further, mechanical ventilation activated the NLRP3 inflammasomes in mouse alveolar macrophages and increased the production of IL-1β in vivo. IL-1β neutralization significantly reduced mechanical ventilation-induced inflammatory lung injury. These findings suggest that the alveolar macrophage NLRP3 inflammasome may sense lung alveolar stretch to induce the release of IL-1β and hence may contribute to the mechanism of lung inflammatory injury during mechanical ventilation.

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Comparison of Static and Dynamic Printed Organic Shift Registers

Dynamic and static shift-register circuits are fabricated with an inkjet process for printing complementary organic semiconductors. The static design is based on edge-triggered master-slave flip-flops, and the dynamic design is based on a true-single-phase-clock architecture. The merits and drawbacks of the two approaches are considered and compared.