Sedative Plasma Concentrations and Delirium Risk in Critical Illness.

BACKGROUND: The relationship between plasma concentration of sedatives and delirium is unknown. OBJECTIVE: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. METHODS: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. RESULTS: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). CONCLUSIONS: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.

Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury.

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.

Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation.

OBJECTIVE: Survivors of critical illness are frequently left with long-lasting disability. The association between delirium and disability in critically ill patients has not been described. We hypothesized that the duration of delirium in the ICU would be associated with subsequent disability and worse physical health status following a critical illness. DESIGN: Prospective cohort study nested within a randomized controlled trial of a paired sedation and ventilator weaning strategy. SETTING: A single-center tertiary-care hospital. PATIENTS: One hundred twenty-six survivors of a critical illness. MEASUREMENTS AND MAIN RESULTS: Confusion Assessment Method for the ICU, Katz activities of daily living, Functional Activities Questionnaire (measuring instrumental activities of daily living), Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score, and Awareness Questionnaire were used. Associations between delirium duration and outcomes were determined via proportional odds logistic regression with generalized estimating equations (for Katz activities of daily living and Functional Activities Questionnaire scores) or via generalized least squares regression (for Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score and Awareness Questionnaire scores). Excluding patients who died prior to follow-up but including those who withdrew or were lost to follow-up, we assessed 80 of 99 patients (81%) at 3 months and 63 of 87 patients (72%) at 12 months. After adjusting for covariates, delirium duration was associated with worse activities of daily living scores (p = 0.002) over the course of the 12-month study period but was not associated with worse instrumental activities of daily living scores (p = 0.15) or worse Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score (p = 0.58). Duration of delirium was also associated with lower Awareness Questionnaire Motor/Sensory Factors scores (p 0.02). CONCLUSION: In the setting of critical illness, longer delirium duration is independently associated with increased odds of disability in activities of daily living and worse motor-sensory function in the following year. These data point to a need for further study into the determinants of functional outcomes in ICU survivors.

Statins and delirium during critical illness: a multicenter, prospective cohort study.

OBJECTIVE: 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. DESIGN: Multicenter, prospective cohort study. SETTING: Medical and surgical ICUs in two large tertiary care hospitals in the United States. PATIENTS: Patients with acute respiratory failure or shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 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 use was associated with reduced delirium (p < 0.01). This association was modified by sepsis and study day; for example, statin use was associated with reduced delirium among patients with sepsis on study day 1 (odds ratio, 0.22; 95% CI, 0.10-0.49) but not among patients without sepsis on day 1 (odds ratio, 0.92; 95% CI, 0.46-1.84) or among those with sepsis later, for example, on day 13 (odds ratio, 0.70; 95% CI, 0.35-1.41). Prehospital statin use was not associated with delirium (odds ratio, 0.86; 95% CI, 0.44-1.66; p = 0.18), yet the longer a prehospital statin user's statin was held in the ICU, the higher the odds of delirium (overall p < 0.001 with the odds ratio depending on sepsis status and study day due to significant interactions). CONCLUSIONS: In critically ill patients, ICU statin use was associated with reduced delirium, especially early during sepsis; discontinuation of a previously used statin was associated with increased delirium.

Delirium in the cardiovascular ICU: exploring modifiable risk factors.

OBJECTIVE: Delirium, an acute organ dysfunction, is common among critically ill patients leading to significant morbidity and mortality; its epidemiology in a mixed cardiology and cardiac surgery ICU is not well established. We sought to determine the prevalence and risk factors for delirium among cardiac surgery ICU patients. DESIGN: Prospective observational study. SETTING: Twenty-seven-bed medical-surgical cardiac surgery ICU. PATIENTS: Two hundred consecutive patients with an expected cardiac surgery ICU length of stay >24 hrs. INTERVENTIONS: None. MEASUREMENTS: Baseline demographic data and daily assessments for delirium using the validated and reliable Confusion Assessment Method for the ICU were recorded, and quantitative tracking of delirium risk factors were conducted. Separate analyses studied the role of admission risk factors for occurrence of delirium during the cardiac surgery ICU stay and identified daily occurring risk factors for the development of delirium on a subsequent cardiac surgery ICU day. MAIN RESULTS: Prevalence of delirium was 26%, similar among cardiology and cardiac surgical patients. Nearly all (92%) exhibited the hypoactive subtype of delirium. Benzodiazepine use at admission was independently predictive of a three-fold increased risk of delirium (odds ratio 3.1 [1, 9.4], p = 0.04) during the cardiac surgery ICU stay. Of the daily occurring risk factors, patients who received benzodiazepines (2.6 [1.2, 5.7], p = 0.02) or had restraints or devices that precluded mobilization (2.9 [1.3, 6.5], p < 0.01) were more likely to have delirium the following day. Hemodynamic status was not associated with delirium. CONCLUSIONS: Delirium occurred in one in four patients in the cardiac surgery ICU and was predominately hypoactive in subtype. Chemical restraints via use of benzodiazepines or the use of physical restraints/restraining devices predisposed patients to a greater risk of delirium, pointing to areas of quality improvement that would be new to the vast majority of cardiac surgery ICUs.

Atypical sleep in ventilated patients: empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria.

OBJECTIVES: Standard sleep scoring criteria may be unreliable when applied to critically ill patients. We sought to quantify typical and atypical polysomnographic findings in critically ill patients and to begin development and reliability testing of methodology to characterize the atypical polysomnographic tracings that confound standard sleep scoring criteria. DESIGN: Prospective convenience sample. SETTING: Two academic, tertiary care medical centers. PATIENTS: Thirty-seven critically ill, mechanically ventilated, medical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mechanically ventilated subjects were monitored by continuous polysomnography. After noting frequent atypical polysomnographic findings (i.e., lack of stage N2 markers, the presence of polymorphic delta, burst suppression, or isoelectric electroencephalography), attempts to use standard sleep scoring criteria alone were abandoned. Atypical polysomnographic findings were characterized and used to develop a modified scoring system. Polysomnographic data were scored manually via this revised scoring scheme. Of 37 medical ICU patients enrolled, 36 experienced atypical sleep, which accounted for 85% of all recorded data, with 5.1% normal sleep and 9.4% wake. Coupling observed patient arousal levels with polysomnographic characteristics revealed that standard polysomnographic staging criteria did not reliably determine the presence or absence of sleep. Rapid eye movement occurred in only five patients (14%). The revised scoring system incorporating frequently seen atypical characteristics yielded very high interrater reliability (weighted κ = 0.80; bootstrapped 95% CI, [0.48, 0.89]). CONCLUSIONS: Analysis of polysomnographic data revealed profound deficiencies in standard scoring criteria due to a predominance of atypical polysomnographic findings in ventilated patients. The revised scoring scheme proved reliable in sleep staging and may serve as a building block in future work.

Association between endothelial dysfunction and acute brain dysfunction during critical illness.

BACKGROUND: Acute brain dysfunction (delirium and coma) during critical illness is prevalent and costly, but the pathophysiology remains unclear. The relationship of acute brain dysfunction with endothelial function, which is impaired in critical illness and may contribute to alterations in cerebral blood flow and blood-brain barrier permeability, has not been studied. This study sought to determine whether systemic endothelial dysfunction is associated with acute brain dysfunction during critical illness. METHODS: In this prospective cohort study, adult medical/surgical intensive care unit patients in shock and/or respiratory failure were enrolled. Endothelial function was assessed at enrollment using peripheral artery tonometry to calculate the reactive hyperemia index, with lower reactive hyperemia index indicative of worse endothelial function. Patients were assessed for coma and delirium with the Richmond Agitation-Sedation Scale and Confusion Assessment Method for the Intensive Care Unit. Multivariable linear regression was used to analyze the association between reactive hyperemia index and (1) delirium/coma-free days among all patients and (2) delirium duration among survivors, both over a 14-day period. RESULTS: One hundred forty-seven patients with median age of 57 yr and median Acute Physiology and Chronic Health Evaluation II score of 26 were enrolled. After adjusting for age, severity of illness, severe sepsis, preexisting cognitive function, medical versus surgical intensive care unit admission, and prehospital statin use, lower reactive hyperemia index (worse systemic endothelial function) was associated with fewer delirium/coma-free days (P = 0.02) and more delirium days (P = 0.05). CONCLUSIONS: In this study, critically ill patients with lower vascular reactivity indicative of worse systemic endothelial function had increased duration of acute brain dysfunction.

Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation and delirium.

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. SETTING: Saint Thomas Hospital in Nashville, TN, from 2004 to 2006. PATIENTS: Adult patients receiving mechanical ventilation for >12 hrs with continuous recording of hourly sedation dosing. INTERVENTIONS: We measured hourly doses of benzodiazepine and propofol exposure during the daytime (7 AM to 11 PM) and nighttime (11 PM to 7 AM) for 5 days. We quantified nighttime dose increases by subtracting the average hourly daytime dose on the preceding day from subsequent average hourly nighttime dose. We used multivariable logistic regression to determine whether daytime and nighttime dose increases were independently associated with delirium, coma, and delayed liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Among 140 patients, the median Acute Physiology and Chronic Health Evaluation II score was 27 (interquartile range 22-33). Among those receiving the sedatives, benzodiazepine and propofol doses were increased at night on 40% and 41% of patient-days, respectively. Of 485 patient-days, delirium was present on 160 (33%) and coma on 206 (42%). In adjusted models, greater daytime benzodiazepine dose was independently associated with failed spontaneous breathing trial and extubation, and subsequent delirium (p<.02 for all). Nighttime increase in benzodiazepine dose was associated with failed spontaneous breathing trial (p<.01) and delirium (p=.05). Daytime propofol dose was marginally associated with subsequent delirium (p=.06). CONCLUSIONS: Nearly half of mechanically ventilated intensive care unit patients received greater doses of sedation at night, a practice associated with failed spontaneous breathing trials, coma, and delirium. Over the first 5 days in our study, patients spent 75% of their time in coma or delirium, outcomes that may be reduced by efforts to decrease sedative exposure during both daytime and nighttime hours in the intensive care unit.

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

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). CONCLUSIONS: Increased kynurenine pathway activation, assessed by plasma kynurenine and kynurenine/tryptophan ratio, was associated with fewer days alive and without acute brain dysfunction in intensive care unit patients. Future studies are warranted to clarify this relationship and investigate potential therapeutic interventions.

Cognitive and physical rehabilitation of intensive care unit survivors: results of the RETURN randomized controlled pilot investigation.

BACKGROUND: Millions of patients who survive medical and surgical general intensive care unit care every year experience newly acquired long-term cognitive impairment and profound physical and functional disabilities. To overcome the current reality in which patients receive inadequate rehabilitation, we devised a multifaceted, in-home, telerehabilitation program implemented using social workers and psychology technicians with the goal of improving cognitive and functional outcomes. METHODS: This was a single-site, feasibility, pilot, randomized trial of 21 general medical/surgical intensive care unit survivors (8 controls and 13 intervention patients) with either cognitive or functional impairment at hospital discharge. After discharge, study controls received usual care (sporadic rehabilitation), whereas intervention patients received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period via a social worker or master's level psychology technician utilizing telemedicine to allow specialized multidisciplinary treatment. Interventions over 12 wks included six in-person visits for cognitive rehabilitation and six televisits for physical/functional rehabilitation. Outcomes were measured at the completion of the rehabilitation program (i.e., at 3 months), with cognitive functioning as the primary outcome. Analyses were conducted using linear regression to examine differences in 3-month outcomes between treatment groups while adjusting for baseline scores. RESULTS: Patients tolerated the program with only one adverse event reported. At baseline both groups were well-matched. At 3-month follow-up, intervention group patients demonstrated significantly improved cognitive executive functioning on the widely used and well-normed Tower test (for planning and strategic thinking) vs. controls (median [interquartile range], 13.0 [11.5-14.0] vs. 7.5 [4.0-8.5]; adjusted p < .01). Intervention group patients also reported better performance (i.e., lower score) on one of the most frequently used measures of functional status (Functional Activities Questionnaire at 3 months vs. controls, 1.0 [0.0 -3.0] vs. 8.0 [6.0-11.8], adjusted p = .04). CONCLUSIONS: A multicomponent rehabilitation program for intensive care unit survivors combining cognitive, physical, and functional training appears feasible and possibly effective in improving cognitive performance and functional outcomes in just 3 months. Future investigations with a larger sample size should be conducted to build on this pilot feasibility program and to confirm these results, as well as to elucidate the elements of rehabilitation contributing most to improved outcomes.

The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study*.

OBJECTIVE: Evidence is emerging that delirium duration is a predictor of long-term cognitive impairment in intensive care unit survivors. Relationships between 1) delirium duration and brain white matter integrity, and 2) white matter integrity and long-term cognitive impairment are poorly understood and could be explored using magnetic resonance imaging. DESIGN, SETTING, PATIENTS: A two-center, prospective cohort study incorporating delirium monitoring, neuroimaging, and cognitive testing in intensive care unit survivors. MEASUREMENTS: Delirium was evaluated with the Confusion Assessment Method for the Intensive Care Unit and cognitive outcomes were tested at 3 and 12-month follow-up. Following the intensive care unit stay, fractional anisotropy, a measure of white matter integrity, was calculated quantitatively using diffusion tensor imaging with a 3-T magnetic resonance imaging scanner at hospital discharge and 3-month follow-up. We examined associations between 1) delirium duration and fractional anisotropy and 2) fractional anisotropy and cognitive outcomes using linear regression adjusted for age and sepsis. RESULTS: A total of 47 patients with a median age of 50 yrs completed the diffusion tensor imaging-magnetic resonance imaging protocol. Greater duration of delirium (3 vs. 0 days) was associated with lower fractional anisotropy (i.e., reduced fractional anisotropy = white matter disruption) in the genu (-0.02; p = .04) and splenium (-0.01; p = .02) of the corpus callosum and anterior limb of the internal capsule (-0.02; p =.01) at hospital discharge. These associations persisted at 3 months for the genu (-0.02; p =.02) and splenium (-0.01; p = .004). Lower fractional anisotropy in the anterior limb of internal capsule at discharge and in genu of corpus callosum at three months was associated with worse cognitive scores at 3 and 12 months. CONCLUSIONS: In this pilot investigation, delirium duration in the intensive care unit was associated with white matter disruption at both discharge and 3 months. Similarly, white matter disruption was associated with worse cognitive scores up to 12 months later. This hypothesis-generating investigation may help design future studies to explore these complex relationships in greater depth.

The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study*.

OBJECTIVE: Delirium duration is predictive of long-term cognitive impairment in intensive care unit survivors. Hypothesizing that a neuroanatomical basis may exist for the relationship between delirium and long-term cognitive impairment, we conducted this exploratory investigation of the associations between delirium duration, brain volumes, and long-term cognitive impairment. DESIGN, SETTING, AND PATIENTS: A prospective cohort of medical and surgical intensive care unit survivors with respiratory failure or shock. MEASUREMENTS: Quantitative high resolution 3-Tesla brain magnetic resonance imaging was used to calculate brain volumes at discharge and 3-month follow-up. Delirium was evaluated using the confusion assessment method for the intensive care unit; cognitive outcomes were tested at 3- and 12-month follow-up. Linear regression was used to examine associations between delirium duration and brain volumes, and between brain volumes and cognitive outcomes. RESULTS: A total of 47 patients completed the magnetic resonance imaging protocol. Patients with longer duration of delirium displayed greater brain atrophy as measured by a larger ventricle-to-brain ratio at hospital discharge (0.76, 95% confidence intervals [0.10, 1.41]; p = .03) and at 3-month follow-up (0.62 [0.02, 1.21], p = .05). Longer duration of delirium was associated with smaller superior frontal lobe (-2.11 cm(3) [-3.89, -0.32]; p = .03) and hippocampal volumes at discharge (-0.58 cm(3) [-0.85, -0.31], p < .001)--regions responsible for executive functioning and memory, respectively. Greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months (lower Repeatable Battery for the Assessment of Neuropsychological Status score -11.17 [-21.12, -1.22], p = .04). Smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months. CONCLUSIONS: These preliminary data show that longer duration of delirium is associated with smaller brain volumes up to 3 months after discharge, and that smaller brain volumes are associated with long-term cognitive impairment up to 12 months. We cannot, however, rule out that smaller preexisting brain volumes explain these findings.

Associations among perceived and objective disease knowledge and satisfaction with physician communication in patients with chronic kidney disease.

It is likely that patients with chronic kidney disease (CKD) have a limited understanding of their illness. Here we studied the relationships between objective and perceived knowledge in CKD using the Kidney Disease Knowledge Survey and the Perceived Kidney Disease Knowledge Survey. We quantified perceived and objective knowledge in 399 patients at all stages of non-dialysis-dependent CKD. Demographically, the patient median age was 58 years, 47% were women, 77% had stages 3-5 CKD, and 83% were Caucasians. The overall median score of the perceived knowledge survey was 2.56 (range: 1-4), and this new measure exhibited excellent reliability and construct validity. In unadjusted analysis, perceived knowledge was associated with patient characteristics defined a priori, including objective knowledge and patient satisfaction with physician communication. In adjusted analysis, older age, male gender, and limited health literacy were associated with lower perceived knowledge. Additional analysis revealed that perceived knowledge was associated with significantly higher odds (2.13), and objective knowledge with lower odds (0.91), of patient satisfaction with physician communication. Thus, our results present a mechanism to evaluate distinct forms of patient kidney knowledge and identify specific opportunities for education tailored to patients with CKD.

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

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.

Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial.

RATIONALE: Studies have shown that reducing sedation of critically ill patients shortens time on the ventilator and in the intensive care unit (ICU). Little is known, however, of how such strategies affect long-term cognitive, psychological, and functional outcomes. OBJECTIVES: To determine the long-term effects of a wake up and breathe protocol that interrupts and reduces sedative exposure in the ICU. METHODS: In this a priori planned substudy conducted at one tertiary care hospital during the Awakening and Breathing Controlled Trial, a multicenter randomized controlled trial, we assessed cognitive, psychological, and functional/quality-of-life outcomes 3 and 12 months postdischarge among 180 medical ICU patients randomized to paired daily spontaneous awakening trials with spontaneous breathing trials (SBTs) or to sedation per usual care plus daily SBTs. MEASUREMENTS AND MAIN RESULTS: Cognitive impairment was less common in the intervention group at 3-month follow-up (absolute risk reduction, 20.2%; 95% confidence interval, 1.5-36.1%; P = 0.03) but not at 12-month follow-up (absolute risk reduction, -1.9%; 95% CI, -21.3 to 27.1%; P = 0.89). Composite cognitive scores, alternatively, were similar in the two groups at 3-month and 12-month follow-up (P = 0.80 and 0.61, respectively), as were symptoms of depression (P = 0.59 and 0.82) and posttraumatic stress disorder (P = 0.59 and 0.97). Activities of daily living, functional status, and mental and physical quality of life were similar between groups throughout follow-up. CONCLUSIONS: In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00097630).

Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape.

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes.

Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.

OBJECTIVE: To test the hypothesis that duration of delirium in the intensive care unit is an independent predictor of long-term cognitive impairment after critical illness requiring mechanical ventilation. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit in a large community hospital in the United States. PATIENTS: Mechanically ventilated medical intensive care unit patients who were assessed daily for delirium while in the intensive care unit and who underwent comprehensive cognitive assessments 3 and 12 mos after discharge. MEASUREMENTS AND MAIN RESULTS: Of 126 eligible patients, 99 survived>or=3 months after critical illness; long-term cognitive outcomes were obtained for 77 (78%) patients. Median age was 61 yrs, 51% were admitted with sepsis/acute respiratory distress syndrome, and median duration of delirium was 2 days. At 3-mo and 12-mo follow-up, 79% and 71% of survivors had cognitive impairment, respectively (with 62% and 36% being severely impaired). After adjusting for age, education, preexisting cognitive function, severity of illness, severe sepsis, and exposure to sedative medications in the intensive care unit, increasing duration of delirium was an independent predictor of worse cognitive performance-determined by averaging age-adjusted and education-adjusted T-scores from nine tests measuring seven domains of cognition-at 3-mo (p=.02) and 12-mo follow-up (p=.03). Duration of mechanical ventilation, alternatively, was not associated with long-term cognitive impairment (p=.20 and .58). CONCLUSIONS: In this study of mechanically ventilated medical intensive care unit patients, duration of delirium (which is potentially modifiable) was independently associated with long-term cognitive impairment, a common public health problem among intensive care unit survivors.

Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial.

OBJECTIVE: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six tertiary care medical centers in the US. PATIENTS: One hundred one mechanically ventilated medical and surgical intensive care unit patients. INTERVENTION: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. MEASUREMENTS AND MAIN OUTCOMES: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). CONCLUSIONS: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.

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

INTRODUCTION: Benzodiazepines and alpha2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an alpha2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients. METHODS: In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis. RESULTS: Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11). CONCLUSIONS: In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results. TRIAL REGISTRATION: NCT00095251.

Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

BACKGROUND: Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs). METHODS: In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630. FINDINGS: One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5). INTERPRETATION: Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.