Ayumi Shintani - Academia.edu (original) (raw)

Papers by Ayumi Shintani

Research paper thumbnail of A quick and easy delirium assessment for nonphysician research personnel

American Journal of Emergency Medicine, Jun 1, 2016

Objectives-Delirium in the emergency department (ED) is an emerging field of research. Most ED re... more Objectives-Delirium in the emergency department (ED) is an emerging field of research. Most ED research infrastructures utilize lay personnel to collect data, but delirium assessments that can be reliably performed by non-physicians are lacking. We evaluated the diagnostic performance of the modified Brief Confusion Assessment Method (modified bCAM) for this purpose. Methods-This was a secondary analysis of a prospective observational study than enrolled ED patients 65 years or older. The original bCAM was a brief (< 2 minutes) delirium assessment that assessed for inattention by asking the patient to recite the months backwards from December to July. It was modified by adding the Vigilance A ("squeeze my hand when you hear the letter 'A'") to the inattention assessment. The elements of the modified bCAM were performed by a research assistant (RA) and emergency physician. The reference standard for delirium was a psychiatrist

Research paper thumbnail of Acute Brain Dysfunction: Development and Validation of a Daily Prediction Model

Chest, Jan 23, 2018

To develop and validate a dynamic risk model to predict daily changes in acute brain dysfunction ... more To develop and validate a dynamic risk model to predict daily changes in acute brain dysfunction (i.e., delirium and coma), discharge and mortality in intensive care unit (ICU) patients. Using data from a multicenter prospective ICU cohort, we developed a daily Acute Brain Dysfunction-prediction model (ABD-pm) using multinomial logistic regression that estimated 15 transition probabilities (from 1 of 3 brain function states [normal, delirious, or comatose] to 1 of 5 possible outcomes [normal, delirious, comatose, ICU discharge, and dead]) using baseline and daily risk factors. Model discrimination was assessed using predictive characteristics such as negative predictive value [NPV]. Calibration was assessed by plotting empirical versus model-estimated probabilities. Internal validation was performed by bootstrap procedure. We analyzed data from 810 patients (6711 daily transitions). The ABD-pm included individual risk factors: mental status, age, pre-existing cognitive impairment, b...

Research paper thumbnail of Research Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study

Crit Care, 2007

Introduction Post-traumatic stress disorder (PTSD) has been identified in a significant portion o... more Introduction Post-traumatic stress disorder (PTSD) has been identified in a significant portion of intensive care unit (ICU) survivors. We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation.

Research paper thumbnail of A quick and easy delirium assessment for nonphysician research personnel

The American journal of emergency medicine, Jan 3, 2016

Delirium in the emergency department (ED) is an emerging field of research. Most ED research infr... more Delirium in the emergency department (ED) is an emerging field of research. Most ED research infrastructures utilize lay personnel to collect data, but delirium assessments that can be reliably performed by nonphysicians are lacking. We evaluated the diagnostic performance of the modified Brief Confusion Assessment Method (modified bCAM) for this purpose. This was a secondary analysis of a prospective observational study that enrolled ED patients 65years or older. The original bCAM was a brief (<2minutes) delirium assessment that assessed for inattention by asking the patient to recite the months backward from December to July. It was modified by adding the Vigilance A ("squeeze my hand when you hear the letter 'A'") to the inattention assessment. The elements of the modified bCAM were performed by a research assistant (RA) and emergency physician. The reference standard for delirium was a psychiatrist assessment performed within 3hours using Diagnostic and Stat...

Research paper thumbnail of The Impact of Lymphopenia on Delirium in ICU Patients

PLOS ONE, 2015

Background Immunosuppressed states may predispose patients to development of acute brain injury d... more Background Immunosuppressed states may predispose patients to development of acute brain injury during times of critical illness. Lymphopenia is a non-specific yet commonly used bedside marker of immunosuppressed states.

Research paper thumbnail of Elevated serum creatine phosphokinase is associated with mortality and inotropic requirement in critically injured adults

Injury, 2014

Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, inc... more Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, increasing oxidative stress. Creatine phosphokinase (CPK) elevation is a marker for free myoglobin after myocyte damage. Since oxidative injury is a key mechanism of injury-related organ dysfunction, we hypothesised that serum CPK levels correlate with mortality and need for inotropic medication and duration of inotropic support, i.e. shock, among critically injured patients. We conducted a retrospective review of 17,847 patients admitted to a single Trauma Intensive Care Unit over 9 years. 2583 patients with serum CPK levels were included in the analysis. Patient data were collected continuously into an electronic ICU repository. Univariate analysis was accomplished using Spearman correlation and the Mann–Whitney U test. Propensity score adjustment models accounting for potential confounders were used to assess the independent effect of CPK level on mortality, need for inotropic support, a...

Research paper thumbnail of Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients

Critical care (London, England), 2005

Delirium occurs in most ventilated patients and is independently associated with more deaths, lon... more Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients. A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes. Of 261 patients, 125 (48%) experienced at least o...

Research paper thumbnail of Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury

Kidney International, 2015

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselect... more Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Research paper thumbnail of Statins and delirium during critical illness: a multicenter, prospective cohort study

Critical care medicine, 2014

Since statins have pleiotropic effects on inflammation and coagulation that may interrupt deliriu... more Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium. Multicenter, prospective cohort study. Medical and surgical ICUs in two large tertiary care hospitals in the United States. Patients with acute respiratory failure or shock. None. We measured statin exposure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confusion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51-70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19-31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin u...

Research paper thumbnail of Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation

International Psychogeriatrics, 2011

ABSTRACTBackground:Delirium occurs frequently in the intensive care unit (ICU), but its pathophys... more ABSTRACTBackground:Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF-1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness.Methods:Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF-1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assess...

Research paper thumbnail of Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients

Intensive Care Medicine, 2009

The pathophysiology of delirium remains elusive though neurotransmitters and their precursor larg... more The pathophysiology of delirium remains elusive though neurotransmitters and their precursor large neutral amino acids (LNAAs) may play a role. This pilot study investigated whether alterations of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr), plasma levels were associated with a higher risk of transitioning to delirium in critically ill patients. Methods-Plasma LNAA concentrations were determined on days 1 and 3 in mechanically ventilated (MV) patients from the MENDS randomized controlled trial (dexmedetomidine vs. lorazepam sedation). Three independent variables were calculated by dividing the plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the Confusion Assessment Method in ICU (CAM-ICU). Markov regression models were used to analyze the independent associations between plasma LNAA ratios and transition to delirium after adjusting for important covariates. Results-The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24 to 32). Patients with either high or very low tryptophan to LNAA ratios (p=0.0003), and tyrosine to LNAA ratios (p=0.02) were at increased risk of transitioning to delirium, after adjusting for potential confounders. Phenylalanine levels were not associated with transition to delirium (p=0.27). Older age and exposure to fentanyl were also associated with a higher probability of transitioning to delirium.

Research paper thumbnail of Associations of markers of inflammation and coagulation with delirium during critical illness

Intensive Care Medicine, 2012

Research paper thumbnail of The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*

Critical Care Medicine, 2012

Objectives-Plasma tryptophan levels are associated with delirium in critically ill patients. Alth... more Objectives-Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients. Design, Setting, and Patients-This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients. Measurements and Main Results-Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6-3.1) and 2.1 (95% confidence interval 1.0-3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively).

Research paper thumbnail of Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality

Critical Care Medicine, 2008

Objectives-This study investigates the possibility of a relationship between oversedation and mor... more Objectives-This study investigates the possibility of a relationship between oversedation and mortality in mechanically ventilated patients. The presence of burst suppression, a pattern of severely decreased brain wave activity on the electroencephalogram, may be unintentionally induced by heavy doses of sedatives. Burst suppression has never been studied as a potential risk factor for death in patients without a known neurologic disorder or injury. Design: Post hoc-analysis of a prospectively observational cohort study. Setting-Medical intensive care units of a tertiary care, university-based medical center. Patients-A total of 125 mechanically ventilated, adult, critically ill patients. Measurements and Main Results-A validated arousal scale (Richmond Agitation-Sedation Scale) was used to measure sedation level, and the bispectral index monitor was used to capture electroencephalogram data. Burst suppression occurred in 49 of 125 patients (39%). For analysis, the patients were divided into those with burst suppression (49 of 125, 39%) and those without burst suppression (76 of 125, 61%). All baseline variables were similar between the two groups, with the overall cohort demonstrating a high severity of illness (Acute Physiology and Chronic Health Evaluation II scores of 27.4 ± 8.2) and 98% receiving sedation. Of those with burst suppression, 29 of 49 (59%) died within 6 months compared with 25 of 76 (33%) who did not demonstrate burst suppression. Using time-dependent Cox regression to adjust for clinically important covariates (age, Charlson comorbidity score, baseline dementia, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, coma, and delirium), patients who experienced burst suppression were found to have a statistically significant higher 6-month mortality [Hazard's ratio = 2.04, 95% confidence interval, 1.12-3.70, p = 0.02]. Conclusion-The presence of burst suppression, which was unexpectedly high in this medical intensive care unit population, was an independent predictor of increased risk of death at 6 months. This association should be studied prospectively on a larger scale in mechanically ventilated, critically ill patients.

Research paper thumbnail of Delirium as a predictor of long-term cognitive impairment in survivors of critical illness

Critical Care Medicine, 2010

After participating in this educational activity, the participant should be better able to: 1. As... more After participating in this educational activity, the participant should be better able to: 1. Assess risk factors and predictors of long-term cognitive impairment following critical illness. 2. Measure presence or absence of delirium in the intensive care unit. 3. Counsel families about risk for long-term cognitive impairment in mechanically ventilated intensive care unit patients with delirium.

Research paper thumbnail of Diurnal sedative changes during intensive care

Critical Care Medicine, 2012

Objective-To determine whether benzodiazepine and propofol doses are increased at night and wheth... more Objective-To determine whether benzodiazepine and propofol doses are increased at night and whether daytime and nighttime sedative doses are associated with delirium, coma, and delayed liberation from mechanical ventilation. Design-Single-center, prospective cohort study nested within the Awakening and Breathing Controlled randomized trial

Research paper thumbnail of Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients*

Critical Care Medicine, 2010

; for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group *Se... more ; for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group *See also p. 2413.

Research paper thumbnail of Costs associated with delirium in mechanically ventilated patients*

Critical Care Medicine, 2004

elirium is an acute disturbance of consciousness and cognition that fluctuates in severity (1). A... more elirium is an acute disturbance of consciousness and cognition that fluctuates in severity (1). Also known as acute encephalopathy (2), delirium occurs as many as eight of ten mechanically ventilated medical intensive care unit (ICU) patients. Although most clinicians consider ICU delirium an expected event that is iatrogenic and without consequence (3), it has recently been shown to be associated with increased length of stay, medical complications, and poor outcomes including increased mortality (4-8). What is not known, however, are the costs associated with the development of ICU delirium. The ICU is an expensive part of the healthcare system, accounting for 1% of the annual U.S. gross domestic product (9). The average cost of ICU care is estimated to be between 20,000and20,000 and 20,000and30,000 per patient (10-12). Some of the costs of critical care are due to complications such as ventilator-associated pneumonia (13, 14) and catheter-related bloodstream infection (15). Because of the significant clinical and economic impact of these conditions, efforts have been made to identify risk factors for their development and interventions to reduce their incidence. On the other hand, little is known about the economic impact of delirium in critically ill patients, despite the fact that it occurs in the majority of those treated in the ICU (6, 7). We conducted this investigation to determine the costs associated with delirium in mechanically ventilated medical ICU patients. MATERIALS AND METHODS Patients. The institutional review board approved this study, and informed consent was obtained from patients or their surrogate. Enrollment criteria included any adult, mechanically ventilated patient admitted to the medical or coronary ICUs of Vanderbilt University's 631-bed medical center from February 2000 to May 2001. During the study period, 555 mechanically ventilated patients Objective: To determine the costs associated with delirium in mechanically ventilated medical intensive care unit patients. Design: Prospective cohort study. Setting: A tertiary care academic hospital. Patients: Patients were 275 consecutive mechanically ventilated medical intensive care unit patients. Interventions: We prospectively examined patients for delirium using the Confusion Assessment Method for the Intensive Care Unit. Measurements and Main Results: Delirium was categorized as "ever vs. never" and by a cumulative delirium severity index. Costs were determined from individual ledger-level patient charges using cost-center-specific cost-to-charge ratios and were reported in year 2001 U.S. dollars. Fifty-one of 275 patients (18.5%) had persistent coma and died in the hospital and were excluded from further analysis. Of the remaining 224 patients, delirium developed in 183 (81.7%) and lasted a median of 2.1 (interquartile range, 1-3) days. Baseline demographics were similar between those with and without delirium. Intensive care unit costs (median, interquartile range

Research paper thumbnail of Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients

Critical Care, 2011

Introduction: Non-intensive care unit (ICU) cohorts have shown an association between inflammator... more Introduction: Non-intensive care unit (ICU) cohorts have shown an association between inflammatory disturbances and delirium, though these relationships have not been studied in critically ill patients. This study sought to investigate the relationship between two inflammatory biomarkers, procalcitonin and C-reactive protein (CRP), and duration of acute brain dysfunction in ventilated patients. Methods: Patients enrolled in the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial were assessed daily for delirium using the Confusion Assessment Method-ICU. Plasma levels of procalcitonin and CRP were obtained within 24 hours of enrollment. Proportional odds logistic regression was used to examine the association between procalcitonin and CRP separately with delirium/coma-free days, adjusting for age, acute physiology score (APS) of the Acute Physiology And Chronic Health Evaluation (APACHE) II, sedation group (dexmedetomidine vs. lorazepam), and sepsis. Secondary analyses examined the association of these markers with other organ dysfunctions and 28-day survival. Results: Eighty-seven patients were included in this analysis. The median age of the patients was 60 years with APACHE II scores of 28; 68% had sepsis within 48 hours of admission. Higher levels of procalcitonin were associated with fewer delirium/coma-free days [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04], whereas higher CRP levels showed trends towards fewer delirium/coma-free days (OR, 0.6; 95% CI, 0.3 to 1.1; P = 0.08). Similar relationships were found regardless of the presence of sepsis. No associations were found between procalcitonin or CRP with 28-day survival (P = 0.40 and 0.16, respectively). Conclusions: In our pilot study, high baseline inflammatory biomarkers predicted prolonged periods of acute brain dysfunction, implicating inflammation as an important mechanism in the pathophysiology of delirium and coma during critical illness, irrespective of whether patients had sepsis or not.

Research paper thumbnail of Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

Critical Care, 2010

After publication of our article [1], we noted typographical errors in our tables and in the labe... more After publication of our article [1], we noted typographical errors in our tables and in the labelling of Figure 3. Th ere have been no changes to the results or their interpretation. In Tables 1, 2 and 3 the number of dexmedetomidine patients without sepsis should read 21 instead of the published 20. Th e numbers in the corresponding text are correct. Th e corrected tables can be found overleaf. In Figure 3, in the "Patients at risk" table below the Kaplan-Meier curve, the dexmedetomidine and lorazepam labels are incorrect. Th e top row should be labeled lorazepam and the bottom row should be labeled dexmedetomidine. Th e corrected fi gure can be found overleaf.

Research paper thumbnail of A quick and easy delirium assessment for nonphysician research personnel

American Journal of Emergency Medicine, Jun 1, 2016

Objectives-Delirium in the emergency department (ED) is an emerging field of research. Most ED re... more Objectives-Delirium in the emergency department (ED) is an emerging field of research. Most ED research infrastructures utilize lay personnel to collect data, but delirium assessments that can be reliably performed by non-physicians are lacking. We evaluated the diagnostic performance of the modified Brief Confusion Assessment Method (modified bCAM) for this purpose. Methods-This was a secondary analysis of a prospective observational study than enrolled ED patients 65 years or older. The original bCAM was a brief (< 2 minutes) delirium assessment that assessed for inattention by asking the patient to recite the months backwards from December to July. It was modified by adding the Vigilance A ("squeeze my hand when you hear the letter 'A'") to the inattention assessment. The elements of the modified bCAM were performed by a research assistant (RA) and emergency physician. The reference standard for delirium was a psychiatrist

Research paper thumbnail of Acute Brain Dysfunction: Development and Validation of a Daily Prediction Model

Chest, Jan 23, 2018

To develop and validate a dynamic risk model to predict daily changes in acute brain dysfunction ... more To develop and validate a dynamic risk model to predict daily changes in acute brain dysfunction (i.e., delirium and coma), discharge and mortality in intensive care unit (ICU) patients. Using data from a multicenter prospective ICU cohort, we developed a daily Acute Brain Dysfunction-prediction model (ABD-pm) using multinomial logistic regression that estimated 15 transition probabilities (from 1 of 3 brain function states [normal, delirious, or comatose] to 1 of 5 possible outcomes [normal, delirious, comatose, ICU discharge, and dead]) using baseline and daily risk factors. Model discrimination was assessed using predictive characteristics such as negative predictive value [NPV]. Calibration was assessed by plotting empirical versus model-estimated probabilities. Internal validation was performed by bootstrap procedure. We analyzed data from 810 patients (6711 daily transitions). The ABD-pm included individual risk factors: mental status, age, pre-existing cognitive impairment, b...

Research paper thumbnail of Research Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study

Crit Care, 2007

Introduction Post-traumatic stress disorder (PTSD) has been identified in a significant portion o... more Introduction Post-traumatic stress disorder (PTSD) has been identified in a significant portion of intensive care unit (ICU) survivors. We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation.

Research paper thumbnail of A quick and easy delirium assessment for nonphysician research personnel

The American journal of emergency medicine, Jan 3, 2016

Delirium in the emergency department (ED) is an emerging field of research. Most ED research infr... more Delirium in the emergency department (ED) is an emerging field of research. Most ED research infrastructures utilize lay personnel to collect data, but delirium assessments that can be reliably performed by nonphysicians are lacking. We evaluated the diagnostic performance of the modified Brief Confusion Assessment Method (modified bCAM) for this purpose. This was a secondary analysis of a prospective observational study that enrolled ED patients 65years or older. The original bCAM was a brief (<2minutes) delirium assessment that assessed for inattention by asking the patient to recite the months backward from December to July. It was modified by adding the Vigilance A ("squeeze my hand when you hear the letter 'A'") to the inattention assessment. The elements of the modified bCAM were performed by a research assistant (RA) and emergency physician. The reference standard for delirium was a psychiatrist assessment performed within 3hours using Diagnostic and Stat...

Research paper thumbnail of The Impact of Lymphopenia on Delirium in ICU Patients

PLOS ONE, 2015

Background Immunosuppressed states may predispose patients to development of acute brain injury d... more Background Immunosuppressed states may predispose patients to development of acute brain injury during times of critical illness. Lymphopenia is a non-specific yet commonly used bedside marker of immunosuppressed states.

Research paper thumbnail of Elevated serum creatine phosphokinase is associated with mortality and inotropic requirement in critically injured adults

Injury, 2014

Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, inc... more Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, increasing oxidative stress. Creatine phosphokinase (CPK) elevation is a marker for free myoglobin after myocyte damage. Since oxidative injury is a key mechanism of injury-related organ dysfunction, we hypothesised that serum CPK levels correlate with mortality and need for inotropic medication and duration of inotropic support, i.e. shock, among critically injured patients. We conducted a retrospective review of 17,847 patients admitted to a single Trauma Intensive Care Unit over 9 years. 2583 patients with serum CPK levels were included in the analysis. Patient data were collected continuously into an electronic ICU repository. Univariate analysis was accomplished using Spearman correlation and the Mann–Whitney U test. Propensity score adjustment models accounting for potential confounders were used to assess the independent effect of CPK level on mortality, need for inotropic support, a...

Research paper thumbnail of Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients

Critical care (London, England), 2005

Delirium occurs in most ventilated patients and is independently associated with more deaths, lon... more Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients. A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes. Of 261 patients, 125 (48%) experienced at least o...

Research paper thumbnail of Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury

Kidney International, 2015

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselect... more Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Research paper thumbnail of Statins and delirium during critical illness: a multicenter, prospective cohort study

Critical care medicine, 2014

Since statins have pleiotropic effects on inflammation and coagulation that may interrupt deliriu... more Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium. Multicenter, prospective cohort study. Medical and surgical ICUs in two large tertiary care hospitals in the United States. Patients with acute respiratory failure or shock. None. We measured statin exposure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confusion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51-70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19-31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin u...

Research paper thumbnail of Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation

International Psychogeriatrics, 2011

ABSTRACTBackground:Delirium occurs frequently in the intensive care unit (ICU), but its pathophys... more ABSTRACTBackground:Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF-1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness.Methods:Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF-1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assess...

Research paper thumbnail of Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients

Intensive Care Medicine, 2009

The pathophysiology of delirium remains elusive though neurotransmitters and their precursor larg... more The pathophysiology of delirium remains elusive though neurotransmitters and their precursor large neutral amino acids (LNAAs) may play a role. This pilot study investigated whether alterations of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr), plasma levels were associated with a higher risk of transitioning to delirium in critically ill patients. Methods-Plasma LNAA concentrations were determined on days 1 and 3 in mechanically ventilated (MV) patients from the MENDS randomized controlled trial (dexmedetomidine vs. lorazepam sedation). Three independent variables were calculated by dividing the plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the Confusion Assessment Method in ICU (CAM-ICU). Markov regression models were used to analyze the independent associations between plasma LNAA ratios and transition to delirium after adjusting for important covariates. Results-The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24 to 32). Patients with either high or very low tryptophan to LNAA ratios (p=0.0003), and tyrosine to LNAA ratios (p=0.02) were at increased risk of transitioning to delirium, after adjusting for potential confounders. Phenylalanine levels were not associated with transition to delirium (p=0.27). Older age and exposure to fentanyl were also associated with a higher probability of transitioning to delirium.

Research paper thumbnail of Associations of markers of inflammation and coagulation with delirium during critical illness

Intensive Care Medicine, 2012

Research paper thumbnail of The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*

Critical Care Medicine, 2012

Objectives-Plasma tryptophan levels are associated with delirium in critically ill patients. Alth... more Objectives-Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients. Design, Setting, and Patients-This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients. Measurements and Main Results-Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6-3.1) and 2.1 (95% confidence interval 1.0-3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively).

Research paper thumbnail of Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality

Critical Care Medicine, 2008

Objectives-This study investigates the possibility of a relationship between oversedation and mor... more Objectives-This study investigates the possibility of a relationship between oversedation and mortality in mechanically ventilated patients. The presence of burst suppression, a pattern of severely decreased brain wave activity on the electroencephalogram, may be unintentionally induced by heavy doses of sedatives. Burst suppression has never been studied as a potential risk factor for death in patients without a known neurologic disorder or injury. Design: Post hoc-analysis of a prospectively observational cohort study. Setting-Medical intensive care units of a tertiary care, university-based medical center. Patients-A total of 125 mechanically ventilated, adult, critically ill patients. Measurements and Main Results-A validated arousal scale (Richmond Agitation-Sedation Scale) was used to measure sedation level, and the bispectral index monitor was used to capture electroencephalogram data. Burst suppression occurred in 49 of 125 patients (39%). For analysis, the patients were divided into those with burst suppression (49 of 125, 39%) and those without burst suppression (76 of 125, 61%). All baseline variables were similar between the two groups, with the overall cohort demonstrating a high severity of illness (Acute Physiology and Chronic Health Evaluation II scores of 27.4 ± 8.2) and 98% receiving sedation. Of those with burst suppression, 29 of 49 (59%) died within 6 months compared with 25 of 76 (33%) who did not demonstrate burst suppression. Using time-dependent Cox regression to adjust for clinically important covariates (age, Charlson comorbidity score, baseline dementia, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, coma, and delirium), patients who experienced burst suppression were found to have a statistically significant higher 6-month mortality [Hazard's ratio = 2.04, 95% confidence interval, 1.12-3.70, p = 0.02]. Conclusion-The presence of burst suppression, which was unexpectedly high in this medical intensive care unit population, was an independent predictor of increased risk of death at 6 months. This association should be studied prospectively on a larger scale in mechanically ventilated, critically ill patients.

Research paper thumbnail of Delirium as a predictor of long-term cognitive impairment in survivors of critical illness

Critical Care Medicine, 2010

After participating in this educational activity, the participant should be better able to: 1. As... more After participating in this educational activity, the participant should be better able to: 1. Assess risk factors and predictors of long-term cognitive impairment following critical illness. 2. Measure presence or absence of delirium in the intensive care unit. 3. Counsel families about risk for long-term cognitive impairment in mechanically ventilated intensive care unit patients with delirium.

Research paper thumbnail of Diurnal sedative changes during intensive care

Critical Care Medicine, 2012

Objective-To determine whether benzodiazepine and propofol doses are increased at night and wheth... more Objective-To determine whether benzodiazepine and propofol doses are increased at night and whether daytime and nighttime sedative doses are associated with delirium, coma, and delayed liberation from mechanical ventilation. Design-Single-center, prospective cohort study nested within the Awakening and Breathing Controlled randomized trial

Research paper thumbnail of Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients*

Critical Care Medicine, 2010

; for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group *Se... more ; for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group *See also p. 2413.

Research paper thumbnail of Costs associated with delirium in mechanically ventilated patients*

Critical Care Medicine, 2004

elirium is an acute disturbance of consciousness and cognition that fluctuates in severity (1). A... more elirium is an acute disturbance of consciousness and cognition that fluctuates in severity (1). Also known as acute encephalopathy (2), delirium occurs as many as eight of ten mechanically ventilated medical intensive care unit (ICU) patients. Although most clinicians consider ICU delirium an expected event that is iatrogenic and without consequence (3), it has recently been shown to be associated with increased length of stay, medical complications, and poor outcomes including increased mortality (4-8). What is not known, however, are the costs associated with the development of ICU delirium. The ICU is an expensive part of the healthcare system, accounting for 1% of the annual U.S. gross domestic product (9). The average cost of ICU care is estimated to be between 20,000and20,000 and 20,000and30,000 per patient (10-12). Some of the costs of critical care are due to complications such as ventilator-associated pneumonia (13, 14) and catheter-related bloodstream infection (15). Because of the significant clinical and economic impact of these conditions, efforts have been made to identify risk factors for their development and interventions to reduce their incidence. On the other hand, little is known about the economic impact of delirium in critically ill patients, despite the fact that it occurs in the majority of those treated in the ICU (6, 7). We conducted this investigation to determine the costs associated with delirium in mechanically ventilated medical ICU patients. MATERIALS AND METHODS Patients. The institutional review board approved this study, and informed consent was obtained from patients or their surrogate. Enrollment criteria included any adult, mechanically ventilated patient admitted to the medical or coronary ICUs of Vanderbilt University's 631-bed medical center from February 2000 to May 2001. During the study period, 555 mechanically ventilated patients Objective: To determine the costs associated with delirium in mechanically ventilated medical intensive care unit patients. Design: Prospective cohort study. Setting: A tertiary care academic hospital. Patients: Patients were 275 consecutive mechanically ventilated medical intensive care unit patients. Interventions: We prospectively examined patients for delirium using the Confusion Assessment Method for the Intensive Care Unit. Measurements and Main Results: Delirium was categorized as "ever vs. never" and by a cumulative delirium severity index. Costs were determined from individual ledger-level patient charges using cost-center-specific cost-to-charge ratios and were reported in year 2001 U.S. dollars. Fifty-one of 275 patients (18.5%) had persistent coma and died in the hospital and were excluded from further analysis. Of the remaining 224 patients, delirium developed in 183 (81.7%) and lasted a median of 2.1 (interquartile range, 1-3) days. Baseline demographics were similar between those with and without delirium. Intensive care unit costs (median, interquartile range

Research paper thumbnail of Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients

Critical Care, 2011

Introduction: Non-intensive care unit (ICU) cohorts have shown an association between inflammator... more Introduction: Non-intensive care unit (ICU) cohorts have shown an association between inflammatory disturbances and delirium, though these relationships have not been studied in critically ill patients. This study sought to investigate the relationship between two inflammatory biomarkers, procalcitonin and C-reactive protein (CRP), and duration of acute brain dysfunction in ventilated patients. Methods: Patients enrolled in the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial were assessed daily for delirium using the Confusion Assessment Method-ICU. Plasma levels of procalcitonin and CRP were obtained within 24 hours of enrollment. Proportional odds logistic regression was used to examine the association between procalcitonin and CRP separately with delirium/coma-free days, adjusting for age, acute physiology score (APS) of the Acute Physiology And Chronic Health Evaluation (APACHE) II, sedation group (dexmedetomidine vs. lorazepam), and sepsis. Secondary analyses examined the association of these markers with other organ dysfunctions and 28-day survival. Results: Eighty-seven patients were included in this analysis. The median age of the patients was 60 years with APACHE II scores of 28; 68% had sepsis within 48 hours of admission. Higher levels of procalcitonin were associated with fewer delirium/coma-free days [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04], whereas higher CRP levels showed trends towards fewer delirium/coma-free days (OR, 0.6; 95% CI, 0.3 to 1.1; P = 0.08). Similar relationships were found regardless of the presence of sepsis. No associations were found between procalcitonin or CRP with 28-day survival (P = 0.40 and 0.16, respectively). Conclusions: In our pilot study, high baseline inflammatory biomarkers predicted prolonged periods of acute brain dysfunction, implicating inflammation as an important mechanism in the pathophysiology of delirium and coma during critical illness, irrespective of whether patients had sepsis or not.

Research paper thumbnail of Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

Critical Care, 2010

After publication of our article [1], we noted typographical errors in our tables and in the labe... more After publication of our article [1], we noted typographical errors in our tables and in the labelling of Figure 3. Th ere have been no changes to the results or their interpretation. In Tables 1, 2 and 3 the number of dexmedetomidine patients without sepsis should read 21 instead of the published 20. Th e numbers in the corresponding text are correct. Th e corrected tables can be found overleaf. In Figure 3, in the "Patients at risk" table below the Kaplan-Meier curve, the dexmedetomidine and lorazepam labels are incorrect. Th e top row should be labeled lorazepam and the bottom row should be labeled dexmedetomidine. Th e corrected fi gure can be found overleaf.