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Objectives: To measure the impact of full versus partial ABCDE bundle implementation on specific cost centers and related resource utilization. Design: Retrospective cohort study. Setting: Two medical ICUs within Montefiore Health System (Bronx, NY). Patients: Four hundred and seventy-two mechanically ventilated patients admitted to the medical ICUs during a hospitalization which began and ended between January 1, 2013 and December 31, 2013. Interventions: The full (A)wakening, (B)reathing, (C)oordination, (D)elirium Monitoring/Management and (E)arly Mobilization bundle was implemented in the intervention ICU while a portion of the bundle (A, B, and D components) was implemented in the comparison ICU. Measurements and Main Results: Relative to the comparison ICU, implementation of the entire bundle in the intervention ICU was associated with a 27.3% (95% CI: 9.9%, 41.3%; P = 0.004) decrease in total hospital laboratory costs and a 2,888.6% (95% CI: 77.9%, 50,113.2%; P = 0.018) increase in total hospital physical therapy costs. Cost of total hospital medications, diagnostic radiology and respiratory therapy were unchanged. Relative to the comparison ICU, total hospital resource use decreased in the intervention ICU (incidence rate ratio [95% CI], laboratory: 0.68 [0.54, 0.87], P = 0.002; diagnostic radiology: 0.75 [0.59, 0.96], P = 0.020). Conclusions: Full ABCDE bundle implementation resulted in a decrease in total hospital laboratory costs and total hospital laboratory and diagnostic resource utilization while leading to an increase in physical therapy costs.

Rationale: How to provide advanced respiratory support for coronavirus disease (COVID-19) to maximize population-level survival while optimizing mechanical ventilator access is unknown. Objectives: To evaluate the use of high-flow nasal cannula for COVID-19 on population-level mortality and ventilator availability. Methods: We constructed dynamical (deterministic) simulation models of high-flow nasal cannula and mechanical ventilation use for COVID-19 in the United States. Model parameters were estimated through consensus based on published literature, local data, and experience. We had the following two outcomes: 1) cumulative number of deaths and 2) days without any available ventilators. We assessed the impact of various policies for the use of high-flow nasal cannula (with or without “early intubation”) versus a scenario in which high-flow nasal cannula was unavailable. Results: The policy associated with the fewest deaths and the least time without available ventilators combined the use of high-flow nasal cannula for patients not urgently needing ventilators with the use of early mechanical ventilation for these patients when at least 10% of ventilator supply was not in use. At the national level, this strategy resulted in 10,000–40,000 fewer deaths than if high-flow nasal cannula were not available. In addition, with moderate national ventilator capacity (30,000–45,000 ventilators), this strategy led to up to 25 (11.8%) fewer days without available ventilators. For a 250-bed hospital with 100 mechanical ventilators, the availability of 13, 20, or 33 high-flow nasal cannulas prevented 81, 102, and 130 deaths, respectively. Conclusions: The use of high-flow nasal cannula coupled with early mechanical ventilation when supply is sufficient results in fewer deaths and greater ventilator availability.

Background Prone position ventilation (PPV) is recommended for patients with severe acute respiratory distress syndrome, but it remains underused. Interprofessional simulation-based training for PPV has not been described. Objectives To evaluate the impact of a novel interprofessional simulation-based training program on providers’ perception of and comfort with PPV and the program’s ability to help identify unrecognized safety issues (“latent safety threats”) before implementation. Methods A prospective observational quality improvement study was done in the medical intensive care unit of an academic medical center. Registered nurses, physicians, and respiratory therapists were trained via a didactic session, simulations, and structured debriefings during which latent safety threats were identified. Participants completed anonymous surveys before and after training. Results A total of 73 providers (37 nurses, 18 physicians, 18 respiratory therapists) underwent training and completed surveys. Before training, only 39% of nurses agreed that PPV would be beneficial to patients with severe acute respiratory distress syndrome, compared with 96% of physicians and 70% of respiratory therapists (P < .001). Less than half of both nurses and physicians felt comfortable taking care of prone patients. After training, perceived benefit increased among all providers. Comfort taking care of proned patients and managing cardiac arrest increased significantly among nurses and physicians. Twenty novel latent safety threats were identified. Conclusion Interprofessional simulation-based training may improve providers’ perception of and comfort with PPV and can help identify latent safety threats before implementation.

To measure the impact of staged implementation of full versus partial ABCDE bundle on mechanical ventilation duration, ICU and hospital lengths of stay, and cost.Prospective cohort study.Two medical ICUs within Montefiore Healthcare Center (Bronx, NY).One thousand eight hundred fifty-five mechanically ventilated patients admitted to ICUs between July 2011 and July 2014.At baseline, spontaneous (B)reathing trials (B) were ongoing in both ICUs; in period 1, (A)wakening and (D)elirium (AD) were implemented in both full and partial bundle ICUs; in period 2, (E)arly mobilization and structured bundle (C)oordination (EC) were implemented in the full bundle (B-AD-EC) but not the partial bundle ICU (B-AD).In the full bundle ICU, 95% patient days were spent in bed before EC (period 1). After EC was implemented (period 2), 65% of patients stood, 54% walked at least once during their ICU stay, and ICU-acquired pressure ulcers and physical restraint use decreased (period 1 vs 2: 39% vs 23% of patients; 30% vs 26% patient days, respectively; p0.001 for both). After adjustment for patient-level covariates, implementation of the full (B-AD-EC) versus partial (B-AD) bundle was associated with reduced mechanical ventilation duration (-22.3%; 95% CI, -22.5% to -22.0%; p0.001), ICU length of stay (-10.3%; 95% CI, -15.6% to -4.7%; p = 0.028), and hospital length of stay (-7.8%; 95% CI, -8.7% to -6.9%; p = 0.006). Total ICU and hospital cost were also reduced by 24.2% (95% CI, -41.4% to -2.0%; p = 0.03) and 30.2% (95% CI, -46.1% to -9.5%; p = 0.007), respectively.In a clinical practice setting, the addition of (E)arly mobilization and structured (C)oordination of ABCDE bundle components to a spontaneous (B)reathing, (A)wakening, and (D) elirium management background led to substantial reductions in the duration of mechanical ventilation, length of stay, and cost.

Objectives ABCDEF bundle implementation in the Intensive Care Unit (ICU) is associated with dose dependent improvements in patient outcomes. The objective was to compare nurse attitudes about the ABCDEF bundle to self-reported adherence to bundle components. Research methodology/design Cross-sectional study. Setting Nurses providing direct patient care in 28 ICUs within 18 hospitals across the United States. Main outcome measures 53-item survey of attitudes and practice of the ABCDEF bundle components was administered between November 2011 and August 2015 (n = 1661). Results We did not find clinically significant correlations between nurse attitudes and adherence to A wakening trials, B reathing trials, and sedation protocol adherence (rs = 0.05–0.28) or sedation plan discussion during rounds and A wakening and B reathing trial C oordination (rs = 0.19). D elirium is more likely to be discussed during rounds when ICU physicians and nurse managers facilitate delirium reduction (rs = 0.27–0.36). E arly mobilization is more likely to occur when ICU physicians, nurse managers, staffing, equipment, and the ICU environment facilitate early mobility (rs = 0.36–0.47). Physician leadership had the strongest correlation with reporting an ICU environment that facilitates ABCDEF bundle implementation (rs = 0.63–0.74). Conclusions Nurse attitudes about bundle implementation did not predict bundle adherence. Nurse manager and physician leadership played a large role in creating a supportive ICU environment.

Rationale: Both acute respiratory distress syndrome (ARDS) and intensive care unit (ICU) delirium are associated with significant morbidity and mortality. However, the risk of delirium and its impact on mortality in ARDS patients is unknown.Objectives: To determine if ARDS is associated with a higher risk for delirium compared with respiratory failure without ARDS, and to determine the association between ARDS and in-hospital mortality after adjusting for delirium.Methods: Prospective observational cohort study of adult ICU patients admitted to two urban academic hospitals.Measurements and Main Results: Delirium was assessed daily using the Confusion Assessment Method for the ICU and Richmond Agitation and Sedation Scale. Of the 564 patients in our cohort, 48 had ARDS (9%). Intubated patients with ARDS had the highest prevalence of delirium compared with intubated patients without ARDS and nonintubated patients (73% vs. 52% vs. 21%, respectively; P

Active smokers are prevalent in hospitalized and critically ill patients. Cigarette smoking and nicotine withdrawal may increase delirium in these populations. This systematic review aims to determine whether active cigarette smoking increases the risk for delirium in hospitalized and intensive care unit (ICU) patients.A systematic search of English-, Spanish-, and French-language articles published from 1966 to April 2013 was performed. Studies were included if they measured cigarette smoking as a risk factor and delirium as an outcome in adult hospitalized or ICU patients. Methodologic quality of studies was assessed using both the validated Newcastle Ottawa Scale and an additional evidence-based quality rating scale.A total of 14 cohort studies of surgical and ICU populations were included in the review. No studies in non-ICU inpatients were identified. The incidence of delirium ranged from 9 to 52%, and the prevalence of active smokers ranged from 9 to 44%. The quality of assessment for active smoking varied widely. None of the studies used biochemical measures to determine cigarette smoke exposure. Of the six studies restricting the smoking group to active smokers only, active smoking was independently associated with delirium in one study, trended toward an association in one study, and showed a dose response in one study. Quantitative summary measures were not calculated due to study heterogeneity and missing data.There is currently insufficient evidence to determine if cigarette smoking is a risk factor for delirium. Future studies should consider using biochemical measures of cigarette smoke exposure to objectively quantify smoking behavior.

Although expert communication between intensive care unit clinicians with patients or surrogates improves patient- and family-centered outcomes, fellows in critical care medicine do not feel adequately trained to conduct family meetings.We aimed to develop, implement, and evaluate a communication skills program that could be easily integrated into a U.S. critical care fellowship.We developed four simulation cases that provided communication challenges that critical care fellows commonly face. For each case, we developed a list of directly observable tasks that could be used by faculty to evaluate fellows during each simulation. We developed a didactic curriculum of lectures/case discussions on topics related to palliative care, end-of-life care, communication skills, and bioethics; this month-long curriculum began and ended with the fellows leading family meetings in up to two simulated cases with direct observation by faculty who were not blinded to the timing of the simulation. Our primary measures of effectiveness were the fellows' self-reported change in comfort with leading family meetings after the program was completed and the quality of the communication as measured by the faculty evaluators during the family meeting simulations at the end of the month.Over 3 years, 31 critical care fellows participated in the program, 28 of whom participated in 101 family meeting simulations with direct feedback by faculty facilitators. Our trainees showed high rates of information disclosure during the simulated family meetings. During the simulations done at the end of the month compared with those done at the beginning, our fellows showed significantly improved rates in: (1) verbalizing an agenda for the meeting (64 vs. 41%; Chi-square, 5.27; P = 0.02), (2) summarizing what will be done for the patient (64 vs. 39%; Chi-square, 6.21; P = 0.01), and (3) providing a follow-up plan (60 vs. 37%; Chi-square, 5.2; P = 0.02). More than 95% of our participants (n = 27) reported feeling "slightly" or "much" more comfortable with discussing foregoing life-sustaining treatment and leading family discussions after the month-long curriculum.A communication skills program can be feasibly integrated into a critical care training program and is associated with improvements in fellows' skills and comfort with leading family meetings.

OBJECTIVES:: Cigarette smoke exposure has recently been found to be associated with increased susceptibility to trauma-and transfusion-associated acute respiratory distress syndrome. We sought to determine 1) the incidence of cigarette smoke exposure in a diverse multicenter sample of acute respiratory distress syndrome patients and 2) whether cigarette smoke exposure is associated with severity of lung injury and mortality in acute respiratory distress syndrome. DESIGN:: Analysis of the Albuterol for the Treatment of Acute Lung Injury and Omega Acute Respiratory Distress Syndrome Network studies. SETTING:: Acute Respiratory Distress Syndrome Network hospitals. PATIENTS:: Three hundred eighty-one patients with acute respiratory distress syndrome. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanol, a validated tobacco-specific marker, was measured in urine samples from subjects enrolled in two National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network randomized controlled trials. Urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels were consistent with active smoking in 36% of acute respiratory distress syndrome patients and with passive smoking in 41% of nonsmokers (vs 20% and 40% in general population, respectively). Patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels in the active smoking range were younger and had a higher incidence of alcohol misuse, fewer comorbidities, lower severity of illness, and less septic shock at enrollment compared with patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels. Despite this lower severity of illness, the severity of lung injury did not significantly differ based on biomarker-determined smoking status. Cigarette smoke exposure was not significantly associated with death after adjusting for differences in age, alcohol use, comorbidities, and severity of illness. CONCLUSIONS:: In this first multicenter study of biomarker-determined cigarette smoke exposure in acute respiratory distress syndrome patients, we found that active cigarette smoke exposure was significantly more prevalent among acute respiratory distress syndrome patients compared to population averages. Despite their younger age, better overall health, and lower severity of illness, smokers by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol had similar severity of lung injury as patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol. These findings suggest that active cigarette smoking may increase susceptibility to acute respiratory distress syndrome in younger, healthier patients. © 2014 by the Society of Critical Care Medicine and Lippincott Williams and Wilkins.

Delirium is a form of acute brain injury that occurs in up to 80% of critically ill patients. It is a source of enormous societal and financial burdens due to increased mortality, prolonged intensive care unit (ICU) and hospital stays, and long-term neuropsychological and functional deficits in ICU survivors. These poor outcomes are not only independently associated with the development of delirium but are also associated with increasing delirium duration. Therefore, interventions should strive both to prevent the occurrence of ICU delirium and to limit its persistence. Both patient-centered and ICU-acquired risk factors need to be addressed early in the ICU course to maximize the efficacy of prevention strategies and to improve long-term outcomes of ICU patients. In this article, we review strategies for early detection of patients who are delirious and who are at high risk for developing delirium, and we present a clinically useful ICU delirium prevention and reduction strategy for clinicians to incorporate into their daily practice.

From the Authors: We thank Dr. Manthous for his comments regarding our article (1). Dr. Manthous offered some interesting hypotheses on reasons for the continued use of heavy sedation in mechanically ventilated patients, despite strong evidence demonstrating improved outcomes with a lighter and more targeted approach. We wholeheartedly agree with his view that there is an urgent need for greater adoption of guideline-concordant sedation practices. In addition to a need to address knowledge gaps and clinical inertia at an individual physician level, changing sedation practices requires education and a transformation in the attitudes and behaviors of the entire multidisciplinary ICU team to a “less is more” sedation culture. One of the first steps in improving ICU-level sedation practices involves a close examination of barriers specific to each ICU setting and a systematic, multidisciplinary team–based approach to plan, educate, and implement these new practices. Effective approaches to tackling these barriers and implementing best evidence-based practices have been widely published in the quality improvement literature. The Plan-Do-Study-Act (PDSA) framework is an example of an iterative approach that we have used to effectively implement delirium monitoring and sedation protocols (2). For example, a team could plan to implement a sedation protocol (Plan), implement the protocol (Do), determine if the protocol actually reduced sedative use (Study), and determine how refine the sedation protocol based on the findings (Act). In addition, a number of excellent resources for clinicians interested in implementing these changes are easily accessible online. These include (1) http://www.icudelirium.org/ by the Vanderbilt ICU Delirium and Cognitive Impairment and Study Group, (2) http://www.iculiberation.org/Pages/default.aspx by the Society of Critical Care Medicine, and (3) http://www.ihi.org/resources/Pages/Tools/PlanDoStudyActWorksheet.aspx from the Institute for Healthcare Improvement. Finally, with the clear and convincing evidence that clinical outcomes can be further improved by coordinating sedation lightening with ventilator weaning trials and early mobilization, waking up our critically ill patients should be considered the first step in rehabilitating our ICU patients (3, 4). Quality initiatives on ICU sedation should serve as a gateway toward implementing these multicomponent nonpharmacologic delirium prevention and reduction strategies. While we should learn from our past missteps, history has also shown us that we are capable of changing our practices to better care for our patients (5). As one of the five key concepts featured in the interdisciplinary Critical Care Societies Collaborative “Choosing Wisely” list, a critical reappraisal of our sedation practices is now under the national spotlight (6). Let us heed this call to action and ensure that these conversations and changes are occurring in our ICUs.

Active smoking and secondhand smoke (SHS) exposure can cause or worsen many acute and chronic cardiovascular and pulmonary diseases (1, 2). SHS is a combination of mainstream smoke (exhaled by smokers) and sidestream smoke given off by the burning end of the tobacco product. Even brief exposure to SHS has significant immediate effects on endothelial cell function, inflammation, and lung function (3). Despite public health efforts to discourage smoking, U.S. smoking prevalence has recently plateaued at 20%, and the number of smokers internationally is increasing (4, 5). In addition, even though smoking has been increasingly restricted in public places and workplaces, an estimated 40% of U.S. nonsmokers have biological evidence of significant SHS exposure (6). Thus, cigarette smoke exposure remains an important cause of preventable chronic and acute disease in both smokers and those exposed to SHS. The association between recent tobacco smoke exposure and critical illness has been poorly studied. The lack of accurate methods to quantify exposure to tobacco smoke, and SHS in particular, in the critically ill has been a major hindrance. Historically, studies have commonly used questionnaires to measure exposure to tobacco smoke. This method is particularly difficult to use in the intensive care unit, because most critically ill patients have altered levels of consciousness or are endotracheally intubated or both. When patients are unable to provide a history, surrogate and chart reporting are often substituted; however, these sources can be subject to social desirability bias and are frequently inaccurate, out of date, or missing (7–9). Thus, to study the effects of cigarette smoke exposure on the incidence or outcomes of critical illness, a more quantitative approach to measuring cigarette smoke exposure in critically ill patients is needed. Biomarkers of cigarette smoke exposure quantify the biologically active dose of nicotine and toxins to which patients have been exposed, overcoming the subjectivity and inaccuracy of self-reporting or surrogate reporting. Such markers have been used to distinguish active and passive smokers from nonsmokers in epidemiologic studies and to establish causal relationships between both active smoking and SHS exposure and cardiovascular and lung disease (1, 10, 11). Nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a potent lung carcinogen), and their metabolites are markers specific for tobacco exposure in smokers, smokeless tobacco users, and nonsmokers exposed to SHS. Determining the optimal biomarker or combination of biomarkers for measuring cigarette smoke exposure in critically ill patients will be key for future studies of this population. The primary objective of our study was to compare cigarette smoke exposure, as measured by biomarkers, to exposure by self-report in a cohort of critically ill patients. A secondary objective was to determine how well biomarkers of exposure taken from different biological specimens (serum, urine, hair, and nails) correlate with each other in this population.

Objectives To measure the prevalence and incidence of delirium in older adults as they transition from the emergency department (ED) to the inpatient ward, and to determine the association between delirium during early hospitalisation and subsequent clinical deterioration. Design Prospective cohort study. Setting Urban tertiary care hospital in Bronx, New York. Participants Adults aged 65 years or older admitted to the inpatient ward from the ED (n=260). Measurements Beginning in the ED, delirium was assessed daily for 3 days, using the Confusion Assessment Method for the Intensive Care Unit. Outcomes (1) Clinical deterioration, defined as unanticipated intensive care unit (ICU) admission or in-hospital death (primary outcome); (2) decline in discharge status, defined as discharge to higher level of care, hospice or in-hospital death. Results 38 of 260 participants (15%) were delirious at least once during the first 3 days of hospitalisation. Of the 29 (11%) patients with delirium in the ED (ie, hospital day 1), delirium persisted into hospital day 2 in 72% (n=21), and persisted for all 3 days in 52% (n=15). In multivariate analyses, as little as 1 episode of delirium during the first 3 days was associated with increased odds of unanticipated ICU admission or in-hospital death (adjusted OR 8.07 (95% CI 1.91 to 34.14); p=0.005). Delirium that persisted for all 3 days was associated with a decline in discharge status, even after adjusting for factors such as severity of illness and baseline cognitive impairment (adjusted OR 4.70 (95% CI 1.41 to 15.63); p=0.012). Conclusions Delirium during the first few days of hospitalisation was associated with poor outcomes in older adults admitted from the ED to the inpatient ward. These findings suggest the need for serial delirium monitoring that begins in the ED to identify a high-risk population that may benefit from closer follow-up and intervention.

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer.

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [3H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose- and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal.