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.

Duration of cardiopulmonary resuscitation and phenotype of post-cardiac arrest brain injury.

BACKGROUND: Patients resuscitated from cardiac arrest have variable severity of primary hypoxic ischemic brain injury (HIBI). Signatures of primary HIBI on brain imaging and electroencephalography (EEG) include diffuse cerebral edema and burst suppression with identical bursts (BSIB). We hypothesize distinct phenotypes of primary HIBI are associated with increasing cardiopulmonary resuscitation (CPR) duration. METHODS: We identified from our prospective registry of both in-and out-of-hospital CA patients treated between January 2010 to January 2020 for this cohort study. We abstracted CPR duration, neurological examination, initial brain computed tomography gray to white ratio (GWR), and initial EEG pattern. We considered four phenotypes on presentation: awake; comatose with neither BSIB nor cerebral edema (non-malignant coma); BSIB; and cerebral edema (GWR ≤ 1.20). BSIB and cerebral edema were considered as non-mutually exclusive outcomes. We generated predicted probabilities of brain injury phenotype using localized regression. RESULTS: We included 2,440 patients, of whom 545 (23%) were awake, 1,065 (44%) had non-malignant coma, 548 (23%) had BSIB and 438 (18%) had cerebral edema. Only 92 (4%) had both BSIB and edema. Median CPR duration was 16 [IQR 8-28] minutes. Median CPR duration increased in a stepwise manner across groups: awake 6 [3-13] minutes; non-malignant coma 15 [8-25] minutes; BSIB 21 [13-31] minutes; cerebral edema 32 [22-46] minutes. Predicted probability of phenotype changes over time. CONCLUSIONS: Brain injury phenotype is related to CPR duration, which is a surrogate for severity of HIBI. The sequence of most likely primary HIBI phenotype with progressively longer CPR duration is awake, coma without BSIB or edema, BSIB, and finally cerebral edema.

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.

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.

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.

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.

Effects of hyperbaric oxygen therapy on biochemical and histological parameters of muscle groups in proximity to the distracted rat tibia.

We investigated the effect of hyperbaric oxygen therapy (HBOT) on rat muscles during tibial distraction osteogenesis (DO) at normal and hyperdistraction rates. Animals in groups 1 and 2 were distracted by 0.5 mm/day and those in groups 3 and 4 by 1 mm/day. Groups 2 and 4 received HBOT during distraction. Group 5 served as control. Superoxide dismutase (SOD; U/g protein), malondialdehyde (nmol/g protein), glutathione (mmol/g protein), and protein levels (g/dl) were determined. SOD was significantly higher in group 2 (4.59 ± 0.97) than in controls (2.19 ± 0.7) (P = 0.0001), and lower in group 4 (3.74 ± 1.70) than in group 2 (P=0.011). Malondialdehyde was significantly higher in group 2 (0.72 ± 0.23) than in controls (0.38 ± 0.10) (P=0.005). Total protein levels were better preserved with HBOT in distracted muscles: group 2 (3.24 ± 0.37) vs. group 1 (1.88 ± 0.60), and group 4 (3.45 ± 0.70) vs. group 3 (2.03 ± 0.75) (both P=0.0001). Numbers of fibres were lower in group 1 (4.88 ± 0.59) than in group 2 (6.07 ± 0.86), and in group 3 (5.13 ± 0.36) than in group 4 (6.14 ± 0.74) (both P=0.001). Numbers of nuclei were higher in group 1 (11.29 ± 2.47) than in group 2 (9.03 ± 1.53) (P=0.04), and in group 3 (12.43 ± 3.32) than in group 4 (9.08 ± 1.58) (P=0.001). Fibres and nuclei with HBOT were similar to those of controls. HBOT decreased the inflammatory cell infiltrate for group 1 (19.8 ± 8.54) vs. group 2 (4.2 ± 2.53) and group 3 (36.54 ± 11.29) vs. group 4 (21.5 ± 9.23) (both P=0.001). HBOT improves the adaptation of distracted muscle by increasing fibres and antioxidants while decreasing inflammation.

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.

A trial of intracranial pressure monitoring in traumatic brain injury.

BACKGROUND: Intracranial pressure (ICP) monitoring is considered the standard of care for severe traumatic brain injury (TBI) and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed. OBJECTIVE: The objective was to compare efficacy of guideline-based management in which a protocol for monitoring intraparenchymal ICP was used (ICP group) or a protocol in which treatment was based on imaging and clinical examination (exam group). DESIGN: A multicenter randomized controlled trial was conducted. SETTING: The trial was set in ICUs in Bolivia or Ecuador. SUBJECTS: Patients had severe TBI (n = 324) and were 13 years of age or older. INTERVENTIONS: Patients were randomly allocated to ICP monitoring or clinical exam-based monitoring. OUTCOMES: The primary outcome was a composite of survival time, impaired consciousness, functional status at 3 and 6 months, and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of the protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and was calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). RESULTS: There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score 56 in the pressure-monitoring group versus 53 in the imaging-clinical examination group; P = 0.49). Six-month mortality rates were 39% in the pressure-monitoring group and 41% in the imaging-clinical examination group (P = 0.60). The median lengths of stay in the ICU were similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging-clinical examination group; P = 0.25), although the number of days of brain-specific treatments (for example, administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging-clinical examination group than in the pressure-monitoring group (4.8 versus 3.4, P = 0.002). The distributions of serious adverse events were similar in the two groups. CONCLUSIONS: For patients with severe TBI, care focused on maintaining monitored ICP at 20 mmHg or less was not shown to be superior to care based on imaging and clinical examination.

Cumulative effect of low-level laser therapy and low-intensity pulsed ultrasound on bone repair in rats.

Many studies have assessed the effects of either low-level laser therapy (LLLT) or low-intensity pulsed ultrasound (LIPUS) on bone repair; however, an evaluation of the combination of these modalities (LLLT + LIPUS) has not yet been considered. The aim of this study was to demonstrate the effects of LLLT + LIPUS on bone repair. Male Wistar rats (n = 128; four groups of 32) were used; the animals underwent a partial tibial bone osteotomy. One group had the osteotomized limb treated with LLLT, the second group with LIPUS, and the third group with the combined treatment protocols of the LLLT and LIPUS groups; the fourth group received no further treatment (control). Each group was divided into two subgroups for assessment at two different time-points, 14 and 21 days. After the completion of treatment rats were sacrificed and the tibias submitted to a three-point bending test or to histomorphometric analysis. Histological evaluation showed increased bone trabeculae, increased vascularization, and decreased inflammation in the LLLT + LIPUS group. Mechanical evaluation revealed increased biomechanical properties including maximum force, maximum stress, and stiffness, in the LLLT + LIPUS group. Combined LLLT + LIPUS treatment enhanced bone healing both histologically and mechanically, shortening the length of the treatment period, when compared to treatment with LLLT or LIPUS alone.

MMP-8 genotypes influence the inflammatory response in human endotoxemia.

Clinical studies have reported associations between MMP-8 genotypes and clinical outcomes without exploring underlying mechanisms. This study aims to understand the influence of the rs1940475 SNP on downstream chemokine and cytokine response in human endotoxemia. Rs1940475 was genotyped in 44 healthy Caucasian males, who were challenged with an intravenous bolus of 2 ng/kg lipopolysaccharide (LPS). Plasma levels of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were measured at baseline and 2, 4, 6, and 24 h after LPS infusion with high-sensitivity enzyme immunoassays. Peak TNF levels at 2 h after LPS infusion were significantly higher in subjects with AA genotype compared to subjects with AG or GG genotypes (185 pg/mL [IQR, 154-234] vs. 94 pg/mL [IQR, 65-125] vs. 107 pg/mL [IQR, 80-241], respectively; p = 0.03 between groups). Peak IL-6 levels were trend-wise higher in subjects with AA genotype compared to those with AG or GG genotypes (566 pg/mL [IQR, 294-644] vs. 278 pg/mL [IQR, 184-539] and 329 pg/mL [IQR, 240-492], respectively; p = 0.15 between groups). In contrast, peak MIP-1α at 2 h was highest in GG genotype carriers compared to those with AG or AA genotypes (602 pg/mL [IQR, 449-727] vs. 389 pg/mL [IQR, 375-490] and 510 pg/mL [425-813], respectively; p < 0.03 between groups). AA genotype carriers had highest peak TNF and IL-6 levels after LPS challenge, whereas peak MIP-1α levels were highest in GG carriers. This indicates that the rs1940475 SNP modifies the host response to inflammatory stimuli, which may in part explain previously shown associations with clinical outcomes.

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.

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.).

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.

Functional role of intracellular labile zinc in pulmonary endothelium.

After iron, zinc is the most abundant essential trace metal. Intracellular zinc ([Zn](i)) is maintained across a wide range of cells and species in a tight quota (100 to 500 µM) by a dynamic process of transport, intracellular vesicular storage, and binding to a large number of proteins (estimated at 3-10% of human proteome). As such, zinc is an integral component of numerous metalloenzymes, structural proteins, and transcription factors. It is generally assumed that a vanishingly small component of [Zn](i,) referred to as free or labile zinc, and operationally defined as the pool sensitive to chelation (by agents such as N, N, N', N'-tetrakis [2-pyridylmethyl] ethylenediamine [TPEN]) and capable of detection by a variety of chemical and genetic sensors, participates in signal transduction pathways. Zinc deficiencies, per se, can arise from acquired (malnutrition, alcoholism) or genetic (mutations in molecules affecting zinc homeostasis, the informative and first example being acrodermatitis enteropathica) factors or as a component of various diseases (e.g., sickle cell disease, cystic fibrosis, sepsis). Hypozincemia has profound effects on developing humans, and all facets of physiological function (neuronal, endocrine, immunological) are affected, although considerably less is known regarding cardiovascular pathophysiology. In this review, we provide an update on current knowledge of molecular and cellular aspects of zinc homeostasis and then focus on implications of zinc signaling in pulmonary endothelium as it relates to programmed cell death, altered contractility, and septic and aseptic injury to this segment of the lung.

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths.

BACKGROUND: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. METHODS: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. RESULTS: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). CONCLUSIONS: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease.

Intensivist-led management of brain-dead donors is associated with an increase in organ recovery for transplantation.

The disparity between the number of patients in need of organ transplantation and the number of available organs is steadily rising. We hypothesized that intensivist-led management of brain dead donors would increase the number of organs recovered for transplantation. We retrospectively analyzed data from all consented adult brain dead patients in the year before (n = 35) and after (n = 43) implementation of an intensivist-led donor management program. Donor characteristics before and after implementation were similar. After implementation of the organ donor support team, the overall number of organs recovered for transplantation increased significantly (66 out of 210 potentially available organs vs. 113 out of 258 potentially available organs, p = 0.008). This was largely due to an increase in the number of lungs (8 out of 70 potentially available lungs vs. 21 out of 86 potentially available lungs; p = 0.039) and kidneys (31 out of 70 potentially available kidneys vs. 52 out of 86 potentially available kidneys; p = 0.044) recovered for transplantation. The number of hearts and livers recovered for transplantation did not change significantly. Institution of an intensivist-led organ donor support team may be a new and viable strategy to increase the number of organs available for transplantations.