Impact of Neuraxial Versus General Anesthesia on Discharge Destination in Patients Undergoing Primary Total Hip and Total Knee Replacement.

BACKGROUND: Total knee replacement (TKR) and total hip replacement (THR) are 2 of the most common orthopedic surgical procedures in the United States. These procedures, with fairly low mortality rates, incur significant health care costs, with almost 40% of the costs associated with post acute care. We assessed the impact of general versus neuraxial anesthesia on discharge destination and 30-day readmissions in patients who underwent total knee and hip replacement in our health system. METHODS: This was a retrospective cohort study of 24,684 patients undergoing total knee or hip replacement in 13 hospitals of a large health care network. Following propensity score matching, we studied the impact of type of anesthetic technique on discharge destination (primary outcome) and postoperative complications including readmissions in 8613 patients who underwent THR and 13,004 patients for TKR. RESULTS: Our results showed that in patients undergoing THR and TKR, neuraxial anesthesia is associated with higher odds of being discharged from hospital to home versus other facilities compared to general anesthesia (odds ratio [OR] = 1.63, 95% confidence interval [CI], 1.52-1.76; P < .01) and (OR = 1.58, 95% CI, 1.49-1.67; P < .01), respectively. CONCLUSIONS: Our results suggest an association between use of neuraxial anesthesia for total joint arthroplasty and a higher probability of discharge to home and a reduction in readmissions.

Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.

INTRODUCTION: Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine whether the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues. METHODS: In total, 76 male adult Sprague-Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for 4 hours. Cytokines, chemokines, and leukocyte counts from blood, peritoneal cavity, and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the Mann-Whitney U test. RESULTS: Apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid-to-blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid-to-blood chemokine ratios, resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histologic injury in the lung, liver, and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis-treated animals. CONCLUSIONS: Our results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.

The effects of 2-chloroprocaine on coagulation and fibrinolysis in the parturient: an in vitro study.

PURPOSE: Amide local anesthetics are known to inhibit coagulation. 2-chloroprocaine is the only ester agent used in obstetric anesthesia. It is used during obstetric emergencies, and also to supplement inadequate epidural block produced by amide local anesthetics. There is no study to date that has evaluated the effect of ester local anesthetics on blood coagulation and fibrinolysis in the parturient. METHODS: In this study, we obtained blood samples from healthy, term-parturients and mixed them with varying amounts of 2-chloroprocaine for final concentrations ranging from 0.26 to 7.8 mM. Thromboelastograph(®) was used to study the coagulation profile of these samples. RESULTS: Chloroprocaine impaired coagulation in a dose dependent manner, with increased R and K, and decreased MA and α. The difference, when compared to saline controls, reached statistical significance at a dose of 7.8 mM. An additional significant finding was that 2-chloroprocaine also enhanced fibrinolysis. CONCLUSIONS: Amide local anesthetics are known to impair coagulation, but 2-chloroprocaine produced significant fibrinolysis in addition to decreasing coagulation. This is the first study to date to demonstrate fibrinolytic properties of an ester local anesthetic. Further study evaluations are required to determine the cause of the variation in fibrinolysis. There is also a need to address the mechanism of increased fibrinolysis observed with 2-chroloprocaine.

Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury.

Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ~4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury.

Development of venovenous extracorporeal blood purification circuits in rodents for sepsis.

BACKGROUND: Unlike pharmacologic interventions in sepsis, extracorporeal blood purification, which is widely used in septic patients, is not typically studied in experimental rodents. Most of the previous studies have performed extracorporeal blood purification in larger animals and typically use arteriovenous (AV) vascular access. We developed a venovenous (VV) purification model in the rat as an adjunct for the treatment of sepsis. METHODS: Using adult male Sprague-Dawley rats, we cannulated the femoral artery or vein and the jugular vein with P50 tubing and created an AV or VV circuit. Blood flow was maintained by arterial pressure in the AV circuit, whereas in the VV circuit the blood flow was regulated using a rotary pump. The safety of this circuit was evaluated using the changes of blood interleukin 6, rectal temperature, and 7-d survival with sham extracorporeal circulation (circuit connection without treatment) compared with the control (without circuit). The main side complications of this VV circuit were compared with those of the AV circuit. RESULTS: The differences in interleukin 6, body temperature, and cumulative survival were not statistically significant after extracorporeal circulation. The main complications of extracorporeal circulation occurred less often with VV compared with AV therapy: massive bleeding (2.5% versus 15%, P = 0.04); clot formation (2.5% versus 15%, P = 0.04). This VV circuit has been successfully used in different septic rodent models with different techniques (hemoadsorption and hemofiltration). CONCLUSIONS: VV blood purification in a rodent model appears to be effective and is safer than AV circuit.

Crystalloids vs. colloids: KO at the twelfth round?

CITATION: Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012, 367:1901-1911. BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kDa and a molar substitution ratio of 0.4 (130/0.4, Voluven; Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy. OBJECTIVE: We conducted a large-scale randomized controlled trial to evaluate the safety and efficacy of 6% HES(130/0.4) in 0.9% saline as compared with 0.9% saline alone for fluid resuscitation in a heterogeneous population of adult patients in the ICU. DESIGN: The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator-initiated, multicenter,prospective, blinded, parallel-group, randomized controlled trial. SETTING: The study was set at 32 hospitals in Australia and New Zealand. SUBJECTS: The subjects were adult patients (>18 years) who were admitted to the ICU and who required intravenous fluid above maintenance requirements determined by the treating clinician and supported by at least one objective physiological criterion. Patients were excluded if they received more than 1 L of 6% HES within 24 hours of screening or had one of the following:dialysis-dependent or impending dialysis renal failure,computed tomography evidence of non-traumatic intracranial hemorrhage (ICH) or severe traumatic ICH, creatinine of more than 3.9 mg/dL or urine output of less than 10 mL/hour for 12 hours, sodium of more than 160 meq/L, or chloride of more than 130 meq/L. Also excluded were females of childbearing age (unless proven not to be pregnant) and patients who had post-cardiac surgery status, liver transplant, or burns and those whose death was judged to be imminent or whose underlying disease process indicated a life expectancy of less than 90 days. INTERVENTION: If fluid was deemed necessary by the treating clinician by the parameters described above, the patient received 'study' fluid with identical packaging and appearance. The fluid was either 6% HES (130/0.4) in saline (Voluven) or 0.9% saline. OUTCOMES: Th e primary outcome was death within 90 days. Secondary outcomes were acute kidney injury (AKI) and failure and treatment with renal replacement therapy. RESULTS: A total of 597 (18.0%) of 3,315 patients in the HES group and 566 (17.0%) of 3,336 in the saline group died (relative risk (RR) in the HES group 1.06, 95% confidence interval (CI) 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. AKI--defined by RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria--occurred in few patients receiving HES (34.6%) compared with saline (38%) (RR 0.91, 95% CI 0.85 to 0.97). However, renal replacement therapy was used in 235 (7.0%) of 3,352 patients in the HES group and 196 (5.8%) of 3,375 in the saline group (RR 1.21, 95% CI 1.00 to 1.45; P=0.04). HES was significantly associated with more adverse events (5.3% versus 2.8%; P<0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, despite a lower overall rate of AKI, more patients who received resuscitation with HES were given renal replacement therapy. (The study was supported by the National Health and Medical Research Council of Australia; the Ministry of Health, New South Wales Government, Australia; and Fresenius Kabi; and by a Practitioner Fellowship from the National Health and Medical Research Council of Australia (to Drs Myburgh and Bellomo), by a Principal Research Fellowship from the National Health and Medical Research Council of Australia (to Dr Cass), and by a Practitioner Fellowship from the Medical Research Foundation of the Royal Perth Hospital (to Dr Webb); CHEST ClinicalTrials.gov number NCT00935168.).

Medical practices display power law behaviors similar to spoken languages.

BACKGROUND: Medical care commonly involves the apprehension of complex patterns of patient derangements to which the practitioner responds with patterns of interventions, as opposed to single therapeutic maneuvers. This complexity renders the objective assessment of practice patterns using conventional statistical approaches difficult. METHODS: Combinatorial approaches drawn from symbolic dynamics are used to encode the observed patterns of patient derangement and associated practitioner response patterns as sequences of symbols. Concatenating each patient derangement symbol with the contemporaneous practitioner response symbol creates "words" encoding the simultaneous patient derangement and provider response patterns and yields an observed vocabulary with quantifiable statistical characteristics. RESULTS: A fundamental observation in many natural languages is the existence of a power law relationship between the rank order of word usage and the absolute frequency with which particular words are uttered. We show that population level patterns of patient derangement: practitioner intervention word usage in two entirely unrelated domains of medical care display power law relationships similar to those of natural languages, and that-in one of these domains-power law behavior at the population level reflects power law behavior at the level of individual practitioners. CONCLUSIONS: Our results suggest that patterns of medical care can be approached using quantitative linguistic techniques, a finding that has implications for the assessment of expertise, machine learning identification of optimal practices, and construction of bedside decision support tools.

SuRxgWell: study protocol for a randomized controlled trial of telemedicine-based digital cognitive behavioral intervention for high anxiety and depression among patients undergoing elective hip and knee arthroplasty surgery.

BACKGROUND: Mood disorders (anxiety, depression), sleep disorders, and catastrophizing lead to increased post-operative pain perception, increase in postoperative opioid consumption, decreased engagement with physical activity, and increased resource utilization in surgical patients. Psychosocial disorders significantly affect postoperative outcome. Unfortunately, studies focused on perioperative psychological assessment and treatment are scarce. We propose to test whether digital cognitive behavioral intervention (dCBI) can help surgical patients. dCBI such as RxWell™ is a proven treatment for mood disorders in medical patients such as reducing depression in patients with inflammatory bowel disease. We hypothesize that RxWell™ will also be effective in surgical patients. This study aims to test whether RxWell™ can improve preoperative mood disorders and subsequently reduce postoperative pain and opioid requirement in patients scheduled for primary total hip and knee arthroplasty (THA, TKA). We named the trial as the SuRxgWell trial. METHODS: This is a randomized, controlled trial that will enroll primary and unilateral THA or TKA patients with anxiety and/or depression symptoms before surgery to receive the SuRxgWell dCBI program and investigate its impact on postoperative outcomes including postoperative pain, anxiety, depression, sleep disorder, and catastrophizing. After signing an informed consent, subjects will be screened using the PROMIS questionnaires, and subjects with a T-score of ≥ 60 on the short Patient-Reported Outcomes Measurement Information System (PROMIS) 4a Anxiety and/or short PROMIS 4a Depression questionnaires will be randomized to either usual care (control group) or the cognitive behavioral intervention, RxWell™, plus usual care (intervention group). The control group will receive information on how to locate tools to address anxiety and depression, whereas the intervention group will have access to SuRxgWell 1 month prior to surgery and up to 3 months after surgery. The allocation will be 3:1 (intervention to control). Investigators will be blinded, but research coordinators approaching patients and research subjects will not. The primary outcome will be day of surgery anxiety or depression symptoms measured with the PROMIS Short Form v1.0 -Anxiety 4a/Depression and Generalized Anxiety Disorder Measure (GAD-7) and Patient Health Questionnaire (PHQ-8). Secondary end points include measuring other health-related quality of life outcomes including sleep disturbance, fatigue, ability to participate in social roles, pain interference, cognitive function, pain catastrophizing, and physical function. Other secondary outcomes include collecting data about preoperative and postoperative pain scores, and pain medication usage, and orthopedic functional recovery at baseline, day of surgery, and 1, 2, and 3 months after the surgery with the Pain Catastrophizing Scale, the Knee injury and Osteoarthritis Outcome Score (KOOS), and Hip injury and Osteoarthritis Outcome Score (HOOS). In addition, subjects will be asked to complete a GAD-7 and PHQ-8 questionnaires bi-weekly (via the RxWell™ app for the interventional group or REDCAP for the control group). Data about postsurgical complications, and resource utilization will also be recorded. We will also receive monthly reports measuring the usage and engagement of RxWell use for each participant randomized to that arm. The primary hypotheses will be assessed with intention-to-treat estimates, and differences in primary outcome will be tested using independent two sample t-tests. This trial is registered to the ClinicalTrials.gov database (NCT05658796) and supported by the DAPM, UPMC Health Plan, and the NIH. DISCUSSION: Our trial will evaluate the feasibility of digital cognitive behavioral intervention as a perioperative tool to improve anxiety and depression before and after major orthopedic surgery in comparison to education. If digital cognitive behavioral intervention proves to be effective, this might have important clinical implications, reducing the incidence of chronic postsurgical pain and improving outcomes.

Reliability of the Telemedicine Examination in the Neurologic Diagnosis of Death.

OBJECTIVE: To determine whether telemedicine technology can be used to reliably determine the neurologic diagnosis of death (NDD) in patients with catastrophic brain injury (CBI). METHODS: We included a convenience sample of patients with CBI at a single academic medical center from November 2016 through June 2018. We simultaneously performed brain death evaluation at the bedside and remotely via telemedicine. Remote examiners were neurointensivists who were experienced and knowledgeable in the NDD. In addition to standard clinical examination, we used quantitative pupillometry to evaluate pupil size and reactivity. We determined the proportion of agreement for each NDD examination element and the overall diagnosis of brain death between bedside and remote examiners. RESULTS: Twenty-nine patients with mean age 46 ± 18 years underwent 30 paired NDD examinations. Twenty-eight (97%) patients met the NDD criteria and were pronounced dead. One patient did not meet the NDD criteria and died after withdrawal of life support. With the exception of qualitative assessment of pupillary reactivity, we observed excellent agreement (97%-100% across NDD examination elements) between bedside and remote examiners and 97% agreement on the overall diagnosis of brain death. Unlike qualitative pupillary assessment, quantitative pupillometry was consistently interpretable by remote examiners. CONCLUSIONS: Our results suggest that remote telemedicine technology can be used to verify the findings of bedside examiners performing NDD examinations when a pupillometer is used to assess pupillary reactivity. When performed by neurocritical care experts, the telemedicine NDD examination has potential to facilitate timely and accurate certification of brain death in patients with CBI. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the concordance of neurologic diagnosis of death by telemedicine and bedside examiners.

Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation.

Reactive oxygen species have been shown to play a significant role in hyperoxia-induced acute lung injury, in part, by inducing apoptosis of pulmonary endothelium. However, the signaling roles of phospholipid oxidation products in pulmonary endothelial apoptosis have not been studied. Using an oxidative lipidomics approach, we identified individual molecular species of phospholipids involved in the apoptosis-associated peroxidation process in a hyperoxic lung. C57BL/6 mice were killed 72 h after exposure to hyperoxia (100% oxygen). We found that hyperoxia-induced apoptosis (documented by activation of caspase-3 and -7 and histochemical terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of pulmonary endothelium) was accompanied by nonrandom oxidation of pulmonary lipids. Two anionic phospholipids, mitochondria-specific cardiolipin (CL) and extramitochondrial phosphatidylserine (PS), were the two major oxidized phospholipids in hyperoxic lung. Using electrospray ionization mass spectrometry, we identified several oxygenation products in CL and PS. Quantitative assessments revealed a significant decrease of CL and PS molecular species containing C(18:2), C(20:4), C(22:5), and C(22:6) fatty acids. Similarly, exposure of mouse pulmonary endothelial cells (MLEC) to hyperoxia (95% oxygen; 72 h) resulted in activation of caspase-3 and -7 and significantly decreased the content of CL molecular species containing C(18:2) and C(20:4) as well as PS molecular species containing C(22:5) and C(22:6). Oxygenated molecular species were found in the same two anionic phospholipids, CL and PS, in MLEC exposed to hyperoxia. Treatment of MLEC with a mitochondria-targeted radical scavenger, a conjugate of hemi-gramicidin S with nitroxide, XJB-5-131, resulted in significantly lower oxidation of both CL and PS and a decrease in hyperoxia-induced changes in caspase-3 and -7 activation. We speculate that cytochrome c driven oxidation of CL and PS is associated with the signaling role of these oxygenated species participating in the execution of apoptosis and clearance of pulmonary endothelial cells, thus contributing to hyperoxic lung injury.

Toll-like receptor 4-myeloid differentiation factor 88 signaling contributes to ventilator-induced lung injury in mice.

BACKGROUND: The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood. METHODS: Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels. RESULTS: Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV. CONCLUSIONS: TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.

Quality Control Measures and Validation in Gene Association Studies: Lessons for Acute Illness.

Acute illness is a complex constellation of responses involving dysregulated inflammatory and immune responses, which are ultimately associated with multiple organ dysfunction. Gene association studies have associated single-nucleotide polymorphisms (SNPs) with clinical and pharmacological outcomes in a variety of disease states, including acute illness. With approximately 4 to 5 million SNPs in the human genome and recent studies suggesting that a large portion of SNP studies are not reproducible, we suggest that the ultimate clinical utility of SNPs in acute illness depends on validation and quality control measures. To investigate this issue, in December 2018 and January 2019 we searched the literature for peer-reviewed studies reporting data on associations between SNPs and clinical outcomes and between SNPs and pharmaceuticals (i.e., pharmacogenomics) published between January 2011 to February 2019. We review key methodologies and results from a variety of clinical and pharmacological gene association studies, including trauma and sepsis studies, as illustrative examples on current SNP association studies. In this review article, we have found three key points which strengthen the potential accuracy of SNP association studies in acute illness and other diseases: providing evidence of following a protocol quality control method such as the one in Nature Protocols or the OncoArray QC Guidelines; enrolling enough patients to have large cohort groups; and validating the SNPs using an independent technique such as a second study using the same SNPs with new patient cohorts. Our survey suggests the need to standardize validation methods and SNP quality control measures in medicine in general, and specifically in the context of complex disease states such as acute illness.

Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1.

RATIONALE: Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option. OBJECTIVES: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI. METHODS: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines. MEASUREMENTS AND MAIN RESULTS: Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilation-dependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferator-activated receptor (PPAR)-gamma, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO. CONCLUSIONS: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1.

Neutrophil elastase is needed for neutrophil emigration into lungs in ventilator-induced lung injury.

Mechanical ventilation, often required to maintain normal gas exchange in critically ill patients, may itself cause lung injury. Lung-protective ventilatory strategies with low tidal volume have been a major success in the management of acute respiratory distress syndrome (ARDS). Volutrauma causes mechanical injury and induces an acute inflammatory response. Our objective was to determine whether neutrophil elastase (NE), a potent proteolytic enzyme in neutrophils, would contribute to ventilator-induced lung injury. NE-deficient (NE-/-) and wild-type mice were mechanically ventilated at set tidal volumes (10, 20, and 30 ml/kg) with 0 cm H2O of positive end-expiratory pressure for 3 hours. Lung physiology and markers of lung injury were measured. Neutrophils from wild-type and NE-/- mice were also used for in vitro studies of neutrophil migration, intercellular adhesion molecule (ICAM)-1 cleavage, and endothelial cell injury. Surprisingly, in the absence of NE, mice were not protected, but developed worse ventilator-induced lung injury despite having lower numbers of neutrophils in alveolar spaces. The possible explanation for this finding is that NE cleaves ICAM-1, allowing neutrophils to egress from the endothelium. In the absence of NE, impaired neutrophil egression and prolonged contact between neutrophils and endothelial cells leads to tissue injury and increased permeability. NE is required for neutrophil egression from the vasculature into the alveolar space, and interfering with this process leads to neutrophil-related endothelial cell injury.

The effect of frailty on HAI response to influenza vaccine among community-dwelling adults ≥ 50 years of age.

The immune response to vaccine antigens is less robust in older adults because of changes in the aging immune system. Frailty, the multi-dimensional syndrome marked by losses in function and physiological reserve, is increasingly prevalent with advancing age. Frailty accelerates this immunosenescence but the consequence of frailty on immune response specific to influenza vaccine among older adults, is mixed. An observational, prospective study of 114 adults was conducted in the fall of 2013 to assess the association of physical frailty with immune response to standard dose influenza vaccine in community-dwelling adults ≥ 50 years of age. Participants were stratified by age (<65 years and ≥65 years), and vaccine strain (Influenza A/H1N1, A/H3N2 and B) was analyzed separately adjusting for body mass index (BMI) and baseline log2 hemagglutination inhibition (HAI) titers. Overall, immune responses were lower among those ≥65 years of age than those <65 years. Among those ≥65 years there were no significant differences between frail and non-frail individuals in seroprotection or seroconversion for any influenza strain. Frail individuals <65 years of age compared with non-frail individuals were more likely to be seroprotected and to seroconvert post vaccination. Linear regression models show the same pattern of significant differences between frail and non-frail for those <65 years but no significant differences between frailty groups for those ≥65 years. Additional research may elucidate the reasons for the differences observed between younger frail and non-frail adults.

A novel method of continuous measurement of head of bed elevation in ventilated patients.

OBJECTIVE: We developed a novel pressure transducer-based method of continuous measurement of head of bed elevation. Following validation of the method we hypothesized that head of bed angles would be at or above 30 degrees among mechanically ventilated patients throughout the day due to a hospital-wide initiative on ventilator-associated pneumonia prevention and standardized electronic order entry system to keep head of bed at an angle of 30 degrees or greater. DESIGN AND SETTING: Prospective observational study in university hospital intensive care units. PATIENTS AND PARTICIPANTS: Twenty-nine consecutive mechanically ventilated patients with no contraindications for semirecumbency. MEASUREMENTS AND RESULTS: We acquired 113 pairs of measurements on unused beds for validation of the method at angles between 3 degrees and 70 degrees. Correlation between transducer and protractor was fitted into a linear regression model (R2 = 0.98) with minimal variation of data along the line of equality. Bland-Altman analysis showed a mean difference of 1.6 degrees +/- 1.6 degrees. Ninety-six percent of differences were within 2 SD from the mean. This method was then used among 29 intubated patients to collect head of bed data over a 24-h period for 3 consecutive days. Contrary to our hypothesis, all patients had head of bed angles less than 30 degrees. CONCLUSIONS: Our results suggest that this method could be used with high reliability and patients in our institution were not kept even at 30 degrees. The results are in accord with those of a recent study which found that continued maintenance of previously suggested head of bed angles was difficult to attain clinically. This may lead us to reevaluate methods studying the impact of head of bed elevation in VAP prevention.

Attitudes of respiratory therapists and nurses about measures to prevent ventilator-associated pneumonia: a multicenter, cross-sectional survey study.

OBJECTIVE: To understand the reported practices of and adherence to evidence-based guidelines for the prevention of ventilator-associated pneumonia (VAP) among respiratory therapists (RTs) and registered nurses (RNs) in academic and nonacademic intensive care units. METHODS: We conducted a multicenter, cross-sectional survey. We first obtained demographic information about health care professionals in a nonidentifiable method. We next questioned the practice patterns of RTs and RNs for preventing VAP based on evidence-supported guidelines. The participants were RTs and RNs working in academic and nonacademic intensive care units; 278 respondents participated in this study (172 RTs and 106 RNs). There were no interventions. RESULTS: The 3 major findings were: (1) both the RTs and the RNs reported that they frequently practice VAP-prevention measures, (2) the rate of adherence to ineffective measures (eg, routine changes of the ventilator circuit, disposable catheters) is also relatively high, which suggests that the evidence is not translated into bedside practice, (3) a substantial proportion of participants did not know the VAP rate in their institution, which might make it difficult to convince bedside practitioners to apply evidence-based practice, and might reflect a lack of infection-control/surveillance programs at hospitals. CONCLUSION: Consumers, the Centers for Disease Control and Prevention, and other organizations are currently trying to implement mandatory reporting of hospital infections, including VAP rate. Without a definition of VAP suited to individual institutions, an organized data-collection and reporting method, and team-based approaches to preventing and treating VAP, hospitals may not be able to meet these requests and track improvement efforts. Prevention measures need to be translated to bedside practice to improve the outcomes of critically ill patients.

Skin and soft tissue necrosis from calcium chloride in a deicer.

Calcium chloride salt is the principle ingredient of many commercially available deicers. Calcium chloride melts snow and ice by its osmotic action. We present a case of skin and soft tissue necrosis associated with the use of a calcium chloride-containing deicer. Although calcium chloride is known to produce soft tissue necrosis if it extravasates during intravenous administration, necrosis and skin sloughing has rarely been described after topical exposure to this salt. Calcium chloride likely produces tissue injury from the heat liberated by mixing calcium chloride with water (exothermic reaction) and from direct calcium deposits in the skin (calcinosis cutis) and soft tissue.

Bedside ultrasonography in the differential diagnosis of pulmonary pathologies in the intensive care unit.

Among critically ill patients, opacification of a part or whole lung field on chest radiography may pose a challenge in the differential diagnosis of acute pulmonary pathologies (eg, pneumothorax, hemothorax, pleural effusion, atelectasis, and solid organ in thoracic cavity) and selection of treatment modalities. In cases in which clinical findings, history, and imaging studies are not conclusive, bedside ultrasonography may be invaluable in achieving a diagnosis. We present two cases in which portable ultrasonography at the bedside was critical to the diagnosis and subsequent management of the patient.