Biomarkers of human cardiopulmonary response after short-term exposures to medical laser generated particulate matter from simulated procedures: a pilot study

Objective We conducted an exposure chamber study in humans using a simulated clinical procedure lasing porcine tissue to demonstrate evidence of effects of exposure to laser generated particulate matter (LGPM). Methods We measured pre- and post-exposure changes in exhaled nitric oxide (eNO), spirometry, heart rate variability (HRV), and blood markers of inflammation in five volunteers. Results Change in pre- and post-exposure measurements of eNO and spirometry were unremarkable. Neutrophil and lymphocyte counts increased and fibrinogen levels decreased in four of the five subjects. Measures of HRV showed decreases in the standard deviation of normal between beat intervals and sequential five-minute intervals. Conclusion These data represent the first evidence of human physiologic response to LGPM exposure. Further exploration of coagulation effects and HRV are warranted

Oxygen affinity of hemoglobin and peripheral nerve degeneration in experimental diabetes

Peripheral neuropathy remains a major complication of diabetes. Numerous etiological theories of metabolic and/or vascular disturbances have been suggested including decreased endoneurial oxygen tension with presumed tissue hypoxia. Increases in the affinity of hemoglobin for oxygen (Hb-O2 affinity) may also produce tissue hypoxia and such Hb-O2 affinity changes have been implicated in the pathogenesis of diabetic microangiopathy. In order to test whether affinity hypoxia might contribute to the development of diabetic peripheral neuropathy, we have utilized a rat model of high and normal Hb-O2 affinity produced by backcrossing animals with increased and decreased levels of 2,3-diphosphoglycerate (DPG). Diabetes was induced in ten high and ten low DPG animals with a tail vein injection of 55 mg/kg streptozotocin (STZ). Five animals in each group were treated with 2.4 U protamine zinc insulin (PZI)/day while the remaining animals were untreated. All rats were killed after 30 days, sections of tibial and sural nerve were rapidly removed and processed for teased fiber analysis. A minimum of 125 axons were assessed per nerve for E degeneration (myelin ovoids) using the classification developed by Dyck et al. Untreated animals, regardless of DPG levels, demonstrated 0% neuropathy. In contrast, all insulin-treated animals showed degeneration (0.4-17%) that inversely correlated with the DPG level (r = -0.59, P 2 affinity) with its attendant effect on tissue oxygen release may play a role in the development of peripheral neuropathy in STZ-induced diabetic rats treated with insulin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29479/1/0000565.pd

Relationship between African-American Race and Delirium in the Intensive Care Unit

Objective Delirium is a highly prevalent syndrome of acute brain dysfunction among critically ill patients that has been linked to multiple risk factors such as age, pre-existing cognitive impairment, and use of sedatives; but to date the relationship between race and delirium is unclear. We conducted this study to identify whether African-American race is a risk factor for developing ICU delirium. Design A prospective cohort study. Setting Medical and Surgical ICUs of a university affiliated, safety-net hospital in Indianapolis, Indiana. Patients 2087 consecutive admissions with 1008 African-Americans admitted to the ICU services from May 2009 to August 2012. Interventions None Measurements and Main Results Incident delirium defined as first positive Confusion Assessment Method for the ICU (CAM-ICU) result after an initial negative CAM-ICU; and prevalent delirium defined as positive CAM-ICU on first CAM-ICU assessment. The overall incident delirium rate in African-Americans was 8.7% compared to 10.4% in Caucasians (P: 0.26). The prevalent delirium rate was 14% in both African-Americans and Caucasians (P: 0.95). Significant age and race interactions were detected for incident delirium (P: 0.02), but not for prevalent delirium (P: 0.3). The hazard ratio for incident delirium for African-Americans in the 18–49 years age group compared to Caucasians of similar age was 0.4 (0.1– 0.9). The hazard and odds ratios for incident and prevalent delirium in other groups were not different. Conclusions African-American race does not confer any additional risk for developing incident or prevalent delirium in the ICU. Instead younger African-Americans tend to have lower rates of incident delirium compared to similar age Caucasians

Deprescribing in the Pharmacologic Management of Delirium (de-PMD): A Randomized Trial in the Intensive Care Unit

OBJECTIVE: Benzodiazepines and anticholinergics are risk factors for delirium in the intensive care unit (ICU). We tested the impact of a deprescribing intervention on short-term delirium outcomes. DESIGN: Multi-site randomized clinical trial SETTING: ICU’s of three large hospitals PARTICIPANTS: Two hundred adults aged ≥ 18 years admitted to an ICU with delirium according to the Richmond Agitation Severity Scale and the Confusion Assessment Method for the ICU (CAM-ICU). Participants had a contraindication to haloperidol (seizure disorder or prolonged QT interval) or preference against haloperidol as a treatment for delirium, and were excluded for serious mental illness, stroke, pregnancy or alcohol withdrawal. Participants were randomized to a deprescribing intervention or usual care. The intervention included electronic alerts combined with pharmacist support to deprescribe anticholinergics and benzodiazepines. MEASUREMENTS: Primary outcomes were delirium duration measured by the CAM-ICU, and severity measured by the Delirium Rating Scale Revised-98 (DRS-R-98) and the CAM-ICU-7; secondary outcomes included adverse events and mortality. RESULTS: Participants had a mean age of 61.8 (standard deviation: 14.3) years, 59% female, and 52% African American with no significant differences in baseline characteristics between groups. No differences between groups were identified in the number exposed to anticholinergics (p=0.219) or benzodiazepines (p=0.566), the median total anticholinergic score (p=0.282), or the median total benzodiazepine dose in lorazepam equivalents (p=0.501). Neither median delirium/coma-free days (p=0.361) nor median change in delirium severity scores (p=0.582 for DRS-R-98; p=0.333 for CAM-ICU-7) were different between groups. No differences in adverse events or mortality were identified. CONCLUSIONS: When added to state-of-the-art clinical services, this deprescribing intervention had no impact on medication use in ICU participants. Given the age of the population, results of clinical outcomes may not be easily extrapolated to older adults. Nonetheless, improved approaches for deprescribing or preventing anticholinergics and benzodiazepines should be developed to determine the impact on delirium outcomes

The CAM-ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the Intensive Care Unit

OBJECTIVES: Delirium severity is independently associated with longer hospital stays, nursing home placement, and death in patients outside the ICU. Delirium severity in the ICU is not routinely measured because the available instruments are difficult to complete in critically ill patients. We designed our study to assess the reliability and validity of a new ICU delirium severity tool, the Confusion Assessment Method for the ICU-7 delirium severity scale. DESIGN: Observational cohort study. SETTING: Medical, surgical, and progressive ICUs of three academic hospitals. PATIENTS: Five hundred eighteen adult (≥ 18 yr) patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients received the Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale, and Delirium Rating Scale-Revised-98 assessments. A 7-point scale (0-7) was derived from responses to the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale items. Confusion Assessment Method for the ICU-7 showed high internal consistency (Cronbach's α = 0.85) and good correlation with Delirium Rating Scale-Revised-98 scores (correlation coefficient = 0.64). Known-groups validity was supported by the separation of mechanically ventilated and nonventilated assessments. Median Confusion Assessment Method for the ICU-7 scores demonstrated good predictive validity with higher odds (odds ratio = 1.47; 95% CI = 1.30-1.66) of in-hospital mortality and lower odds (odds ratio = 0.8; 95% CI = 0.72-0.9) of being discharged home after adjusting for age, race, gender, severity of illness, and chronic comorbidities. Higher Confusion Assessment Method for the ICU-7 scores were also associated with increased length of ICU stay (p = 0.001). CONCLUSIONS: Our results suggest that Confusion Assessment Method for the ICU-7 is a valid and reliable delirium severity measure among ICU patients. Further research comparing it to other delirium severity measures, its use in delirium efficacy trials, and real-life implementation is needed to determine its role in research and clinical practice

Effectiveness of implementing a wake up and breathe program on sedation and delirium in the ICU

OBJECTIVES: Mechanically ventilated critically ill patients receive significant amounts of sedatives and analgesics that increase their risk of developing coma and delirium. We evaluated the impact of a "Wake-up and Breathe Protocol" at our local ICU on sedation and delirium. DESIGN: A pre/post implementation study design. SETTING: A 22-bed mixed surgical and medical ICU. PATIENTS: Seven hundred two consecutive mechanically ventilated ICU patients from June 2010 to January 2013. INTERVENTIONS: Implementation of daily paired spontaneous awakening trials (daily sedation vacation plus spontaneous breathing trials) as a quality improvement project. MEASUREMENTS AND MAIN RESULTS: After implementation of our program, there was an increase in the mean Richmond Agitation Sedation Scale scores on weekdays of 0.88 (p < 0.0001) and an increase in the mean Richmond Agitation Sedation Scale scores on weekends of 1.21 (p < 0.0001). After adjusting for age, race, gender, severity of illness, primary diagnosis, and ICU, the incidence and prevalence of delirium did not change post implementation of the protocol (incidence: 23% pre vs 19.6% post; p = 0.40; prevalence: 66.7% pre vs 55.3% post; p = 0.06). The combined prevalence of delirium/coma decreased from 90.8% pre protocol implementation to 85% postimplementation (odds ratio, 0.505; 95% CI, 0.299-0.853; p = 0.01). CONCLUSIONS: Implementing a "Wake Up and Breathe Program" resulted in reduced sedation among critically ill mechanically ventilated patients but did not change the incidence or prevalence of delirium

Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19

Background: Delirium incidence, duration and severity in patients admitted to the intensive care unit (ICU) due to COVID-19 is not known. Methods: We conducted an observational study at two large urban academic Level 1 trauma centers. Consecutive patients admitted to the ICU with a positive SARS-CoV-2 nasopharyngeal swab polymerase chain reaction test from March 1st, 2020 to April 27, 2020, were included. Individuals younger than 18 years of age, without any documented delirium assessments (CAM-ICU), or without a discharge disposition were excluded. The primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. Outcomes were assessed for up to the first 14 days of ICU stay. Results: Of 243 consecutive patients with confirmed COVID-19 admitted to the ICU, 144 met eligibility criteria and were included in the analysis. Delirium occurred in 73.6% (106/144) and delirium or coma occurred in 76.4% (110/144). Sixty-three percent of patients were positive for delirium on the first CAM-ICU assessment. The median duration of delirium and coma was 7 days (IQR: 3-10), and the median delirium duration was 5 days (IQR: 2-7). The median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium. Mechanical ventilation was associated with greater odds of developing delirium (OR: 42.1, 95%CI: 13.0-137.1). Mortality was 26.4% in patients with delirium compared to 15.8% in patients without delirium. Conclusions: 73.6% of patients admitted to the ICU with COVID-19 experience delirium that persists for approximately 1 week. Invasive mechanical ventilation is significantly associated with odds of delirium. Clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with COVID-19.Babar Khan, Sujuan Gao, and Anthony Perkins are supported through NIA R01 AG 055391, R01 AG 052493 and NHLBI R01 HL131730. Anthony Perkins is also supported by NIA grants 1K23AG062555-01 and R01AG056325. Roberto Machado is supported by 1R01HL111656, 1R01HL127342 and 1R01HL133951. Sophia Wang is supported by K23AG062555-01. Edward Marcantonio is supported by grants R01AG044518 and K24AG035075 from the NIA. Malaz Boustani received funding from NIA R01AG034205 and disclosed that he has ownership equity in two for profit companies, Preferred Population Health Management and RestUp. The products and services of the two companies are not related to the research activities of the paper

Mortality Rates in a Diverse Cohort of Mechanically Ventilated Patients With Novel Coronavirus in the Urban Midwest

Objectives: Differences in mortality rates previously reported in critically ill patients with coronavirus disease 2019 have increased the need for additional data on mortality and risk factors for death. We conducted this study to describe length of stay, mortality, and risk factors associated with in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019. Design: Observational study. Setting: Two urban, academic referral hospitals in Indianapolis, Indiana. Patients or Subjects: Participants were critically ill patients 18 years old and older, admitted with coronavirus disease 2019 between March 1, 2020, and April 27, 2020. Interventions: None. Measurements and Main Results: Outcomes included in-hospital mortality, duration of mechanical ventilation, and length of stay. A total of 242 patients were included with mean age of 59.6 years (sd, 15.5 yr), 41.7% female and 45% African American. Mortality in the overall cohort was 19.8% and 20.5% in the mechanically ventilated subset. Patients who died were older compared with those that survived (deceased: mean age, 72.8 yr [sd, 10.6 yr] vs patients discharged alive: 54.3 yr [sd, 14.8 yr]; p < 0.001 vs still hospitalized: 59.5 yr [sd, 14.4 yr]; p < 0.001) and had more comorbidities compared with those that survived (deceased: 2 [0.5–3] vs survived: 1 [interquartile range, 0–1]; p = 0.001 vs still hospitalized: 1 [interquartile range, 0–2]; p = 0.015). Older age and end-stage renal disease were associated with increased hazard of in-hospital mortality: age 65–74 years (hazard ratio, 3.1 yr; 95% CI, 1.2–7.9 yr), age 75+ (hazard ratio, 4.1 yr; 95% CI, 1.6–10.5 yr), and end-stage renal disease (hazard ratio, 5.9 yr; 95% CI, 1.3–26.9 yr). The overall median duration of mechanical ventilation was 9.3 days (interquartile range, 5.7–13.7 d), and median ICU length of stay in those that died was 8.7 days (interquartile range, 4.0–14.9 d), compared with 9.2 days (interquartile range, 4.0–14.0 d) in those discharged alive, and 12.7 days (interquartile range, 7.2–20.3 d) in those still remaining hospitalized. Conclusions: We found mortality rates in mechanically ventilated patients with coronavirus disease 2019 to be lower than some previously reported with longer lengths of stay.Drs. Perkins, Gao, and Khan are supported through National Institutes of Health (NIH)-National Institute on Aging (NIA) R01 AG 055391, R01 AG 052493, and National Heart, Lung, and Blood Institute R01 HL131730. Dr. Twigg is supported through NIH-NIA U01 AG060900. The remaining authors have disclosed that they do not have any potential conflicts of interest

Marked Differences in Human Melanoma Antigen-Specific T Cell Responsiveness after Vaccination Using a Functional Microarray

BACKGROUND: In contrast to many animal model studies, immunotherapeutic trials in humans suffering from cancer invariably result in a broad range of outcomes, from long-lasting remissions to no discernable effect. METHODS AND FINDINGS: In order to study the T cell responses in patients undergoing a melanoma-associated peptide vaccine trial, we have developed a high-throughput method using arrays of peptide-major histocompatibility complexes (pMHC) together with antibodies against secreted factors. T cells were specifically immobilized and activated by binding to particular pMHCs. The antibodies, spotted together with the pMHC, specifically capture cytokines secreted by the T cells. This technique allows rapid, simultaneous isolation and multiparametric functional characterization of antigen-specific T cells present in clinical samples. Analysis of CD8+ lymphocytes from ten melanoma patients after peptide vaccination revealed a diverse set of patient- and antigen-specific profiles of cytokine secretion, indicating surprising differences in their responsiveness. Four out of four patients who showed moderate or greater secretion of both interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) in response to a gp100 antigen remained free of melanoma recurrence, whereas only two of six patients who showed discordant secretion of IFNγ and TNFα did so. CONCLUSION: Such multiparametric analysis of T cell antigen specificity and function provides a valuable tool with which to dissect the molecular underpinnings of immune responsiveness and how this information correlates with clinical outcome