Novel role of PKR in inflammasome activation and HMGB1 release.

The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1ß, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1ß, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.

Neurological management of fulminant hepatic failure.

Acute liver failure (ALF) is uncommon in the United States, but presents acutely and catastrophically, often with deadly consequences. Hepatic encephalopathy, cerebral edema, elevated intracranial pressure, and intracranial hemorrhage due to coagulopathy are common occurrences in patients with ALF. Appropriate management of multi-system organ failure and neurological complications are essential in bridging patients to transplant and ensuring satisfactory outcomes.

Clinical setting and extent of premortem evaluation do not predict autopsy discrepancy rates.

Autopsy rates have been affected by a number of factors, including technological advances and clinician beliefs of the diminished value of the autopsy. Such factors have resulted in a cultural shift in medicine away from the autopsy. Despite this shift, a number of studies have shown significant differences between antemortem clinical diagnoses and postmortem findings. Surveys of clinician beliefs about the autopsy have pointed toward antemortem diagnostic advancements as an important factor in declining rates. No study to date has addressed the hypothesis that such perceptions in diagnostic certainty have been matched by an actual decay in the yield of valuable or new information obtained by the autopsy. To address this hypothesis, we retrospectively compared the class I and class II discrepancies identified in 284 patients who died in three clinical settings with differing intensities of antemortem diagnostic workup. Despite a significantly different intensity of antemortem workup for patients in each clinical setting, including patients on a medical intensive care unit, patients on a surgical service and patients in an affiliated nursing home, discrepancy rates were found to be similar. Overall discrepancy rates for the medical intensive care unit, surgery service and nursing home patients were 27.8, 32.7 and 31.3%, respectively (P=0.84). In addition, we found no statistical difference in the complexity of workup in discrepant and nondiscrepant cases in each clinical setting. Our study data refute the hypothesis that the intensity of antemortem diagnostic evaluation correlates with an actual decrease in the rate of major diagnostic discrepancies identified at autopsy.

How I manage the adult potential organ donor: donation after neurological death (part 1).

The need for organ donation has become a growing concern over that last decade as the gap between organ donors and those awaiting transplant widens. According to UNOS, as of 8/2009, there were 102,962 patients on the transplant waiting list and only 6,004 donors in 2009 (UNOS.org. Accessed 4/8/2009). In 2008, an estimated 17 patients died each day awaiting transplant (OPTN.org). Though currently most organ donations come after brain death (DND or donation after neurological death), tissue donation (cornea, skin, bone, and musculoskeletal tissue), and donation after cardiac death (DCD) and are also possible. The term "extended criteria donor" refers to potential donors over 60 years of age or age 50-59 years plus 2 of the 3 following criteria: stroke as the cause of death, creatnine > 1.5 meq/dl, or a history of hypertension. Historically, extended criteria donors have had a lower organ yield per donor. In order to preserve the choice of organ donation for the family, intensive management of the potential organ donor is necessary. Since each potential donor could save seven lives or more, nihilism in the care of such patients can have far reaching ramifications. This article describes intensive care management practices that can optimize organ donation.

Increasing quality through telemedicine in the intensive care unit.

This article explores the hypothesis that a telemedicine intensive care unit (Tele-ICU) platform is uniquely suited to facilitate quality performance improvement (PI). This article addresses some substantial hurdles to overcome that may limit the effectiveness of a Tele-ICU platform to achieve PI objectives. Lastly, this article describes the author's experience with a PI project to improve ventilator management conducted via a Tele-ICU hub interacting with 11 geographically dispersed ICUs. Using this example to illustrate the concepts, the author hopes to shed some light on the successes and lessons learned so as to generate best-practice guidelines for Tele-ICU-directed PI initiatives.

Infection in the chronically critically ill: unique risk profile in a newly defined population.

Although CCI is defined as prolonged ventilatory failure with tracheotomy stemming from preceding critical illness, the contention that multisystem debilities impact on most CCI patients' care and recovery is a central thesis of this volume. Perhaps reflecting the combined debilities inherent in CCI, infectious complications take their toll in morbidity, mortality, and persistent ventilatory insufficiency. Enhanced susceptibility to infection results from a potent admixture of barrier breakdown, exposure to virulent and resistant nosocomial pathogens, and postulated "immune exhaustion" that stems from the combined impact of comorbidities and the sequellae of critical illness. Strategies to improve outcome in CCI-related infection include standard measures of support especially nutrition, reducing environmental inoculum through pulmonary hygiene measures, skin care, and limiting barrier breaches, and appropriate antimicrobials directed at likely pathogens. Future stratification of patient risk on the basis of immune phenotype or genotype and potential immunomodulatory prophylaxis may be around the corner, as new prospects in the pharmaceutical armamentarium are presently undergoing testing.

A multicenter population-based effectiveness study of teleintensive care unit-directed ventilator rounds demonstrating improved adherence to a protective lung strategy, decreased ventilator duration, and decreased intensive care unit mortality.

PURPOSE OF THE STUDY: The purpose of the study is to determine if teleintensive care unit (ICU)-directed daily ventilator rounds improved adherence to lung protective ventilation (LPV), reduced ventilator duration ratio (VDR), and ICU mortality ratios. METHOD USED: A retrospective observational longitudinal quarterly analysis of adherence to low tidal volume LPV (<7.5 mL/kg predicted body weight; Pao2/fraction of inspired oxygen<300), ventilator duration, and ICU mortality ratios (Acute Physiology and Chronic Health Evaluation IV-adjusted). The teleICU practice used Philips (Andover, MA) VISICU eCareManagerTM (Andover, MA) platform, providing ICU care and process improvement. RESULTS: Before ventilator rounds implementation, there was wide variation in hospital adherence to low tidal volume (29.5±18.2; range 10%-69%). Longitudinal improvement was seen across hospitals in the 3 Qs after implementation, reaching statistical significance by Q3 postimplementation (44.9±15.7; P<.002 by 2-tailed Fisher exact test), maintained at 2 subsequent Qs (48% and 52%; P<.001). Ventilator duration ratio also showed preimplementation variability (1.08±.34; range 0.71-1.90). After implementation, absolute and significant mean VDR reduction was observed (0.92±.28; -15.8%, P<.05). Intensive care unit mortality ratio demonstrated longitudinal improvement, reaching significance after the Q3 postimplementation (0.94 vs 0.67; P<.04), and this was sustained in the most recent Q analyzed (0.65; P<.03). CONCLUSIONS: Implementation of teleICU-directed ventilator rounds was associated with improved and durable adherence to LPV and significant reductions in both VDR and ICU mortality.

Accessory cell function of airway epithelial cells.

Accessory cell function of airway epithelial cells. We previously demonstrated that airway epithelial cells (AECs) have many features of accessory cells, including expression of class II molecules CD80 and CD86 and functional Fcgamma receptors. We have extended these studies to show that freshly isolated AECs have mRNA for cathepsins S, V, and H [proteases important in antigen (Ag) presentation], invariant chain, human leukocyte antigen (HLA)-DM-alpha and HLA-DM-beta, and CLIP, an invariant chain breakdown product. A physiologically relevant Ag, ragweed, was colocalized with HLA-DR in AECs, and its uptake was increased by granulocyte-macrophage colony-stimulating factor and IFN-gamma treatments, which had no effect on CD80 and CD86 expression. We demonstrate the presence of other costimulatory molecules, including B7h and B7-H1, on AECs and the increased expression of B7-H1 on AECs after treatment with granulocyte-macrophage colony-stimulating factor and IFN-gamma. Finally, we compared T cell proliferation after allostimulation with AECs and dendritic cells (DCs). The precursor frequency of peripheral blood T cells responding to AECs was 0.264% compared with 0.55% for DCs. DCs stimulated CD45RO(+), CD45RA(+), CCR7(+) and CCR7(-)CD4(+), and CD8(+) T cells, whereas AECs stimulated only CD45RO(+), CD45RA(-), CCR7(-), CD4(+), and CD8(+) T cells. There was no difference in cytokine production, type of memory T cells stimulated (effector vs. long-term memory), or apoptosis by T cells cocultured with AECs and DCs. The localization of AECs exposed to the external environment may make them important in the regulation of local immune responses.