Pratik P. Pandharipande

Lorazepam Is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients

Background:Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients’ transitioning into delirium. Methods:In this cohort study, the authors designed a priori an investigation to determine whether sedative and analgesic medications independently increased the probability of daily transition to delirium. Markov regression modeling (adjusting for 11 covariates) was used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 h. Results:Lorazepam was an independent risk factor for daily transition to delirium (odds ratio, 1.2 [95% confidence interval, 1.1–1.4]; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios. Increasing age and Acute Physiology and Chronic Health Evaluation II scores were also independent predictors of transitioning to delirium (multivariable P values < 0.05). Conclusions:Lorazepam administration is an important and potentially modifiable risk factor for transitioning into delirium even after adjusting for relevant covariates.

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 ≥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. (Crit Care Med 2010; 38:1513–1520

Delirium in the intensive care unit.

Delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients, occurring in up to 80% of the sickest intensive care unit (ICU) populations. Critically ill patients are subject to numerous risk factors for delirium. Some of these, such as exposure to sedative and analgesic medications, may be modified to reduce risk. Although dysfunction of other organ systems continues to receive more clinical attention, delirium is now recognized to be a significant contributor to morbidity and mortality in the ICU, and it is recommended that all ICU patients be monitored using a validated delirium assessment instrument. Patients with delirium have longer hospital stays and lower 6-month survival than do patients without delirium, and preliminary research suggests that delirium may be associated with cognitive impairment that persists months to years after discharge. Little evidence exists regarding the prevention and treatment of delirium in the ICU, but multicomponent interventions reduce the incidence of delirium in non-ICU studies. Strategies for the prevention and treatment of ICU delirium are the subjects of multiple ongoing investigations.

Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients.

BACKGROUND Although known to be an independent predictor of poor outcomes in medical intensive care unit (ICU) patients, limited data exist regarding the prevalence of and risk factors for delirium among surgical (SICU) and trauma ICU (TICU) patients. The purpose of this study was to analyze the prevalence of and risk factors for delirium in surgical and trauma ICU patients. METHODS SICU and TICU patients requiring mechanical ventilation (MV) >24 hours were prospectively evaluated for delirium using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the ICU (CAM-ICU). Those with baseline dementia, intracranial injury, or ischemic/hemorrhagic strokes that would confound the evaluation of delirium were excluded. Markov models were used to analyze predictors for daily transition to delirium. RESULTS One hundred patients (46 SICU and 54 TICU) were enrolled. Prevalence of delirium was 73% in the SICU and 67% in the TICU. Multivariable analyses identified midazolam [OR 2.75 (CI 1.43-5.26, p = 0.002)] exposure as the strongest independent risk factor for transitioning to delirium. Opiate exposure showed an inconsistent message such that fentanyl was a risk factor for delirium in the SICU (p = 0.007) but not in the TICU (p = 0.936), whereas morphine exposure was associated with a lower risk of delirium (SICU, p = 0.069; TICU p = 0.024). CONCLUSION Approximately 7 of 10 SICU and TICU patients experience delirium. In keeping with other recent data on benzodiazepines, exposure to midazolam is an independent and potentially modifiable risk factor for the transitioning to delirium.

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. Trial Registration: ClinicalTrials.gov, number NCT00096863.

Delirium and sedation in the intensive care unit: survey of behaviors and attitudes of 1384 healthcare professionals.

Objective:A 2001 survey found that most healthcare professionals considered intensive care unit (ICU) delirium as a serious problem, but only 16% used a validated delirium screening tool. Our objective was to assess beliefs and practices regarding ICU delirium and sedation management. Design and Setting:Between October 2006 and May 2007, a survey was distributed to ICU practitioners in 41 North American hospitals, seven international critical care meetings and courses, and the American Thoracic Society e-mail database. Study Participants:A convenience sample of 1384 healthcare professionals including 970 physicians, 322 nurses, 23 respiratory care practitioners, 26 pharmacists, 18 nurse practitioners and physicians’ assistants, and 25 others. Results:A majority [59% (766 of 1300)] estimated that more than one in four adult mechanically ventilated patients experience delirium. More than half [59% (774 of 1302)] screen for delirium, with 33% of those respondents (258 of 774) using a specific screening tool. A majority of respondents use a sedation protocol, but 29% (396 of 1355) still do not. A majority (76%, 990 of 1309) has a written policy on spontaneous awakening trials (SATs), but the minority of respondents (44%, 446 of 1019) practice spontaneous awakening trials on more than half of ICU days. Conclusions:Delirium is considered a serious problem by a majority of healthcare professionals, and the percent of practitioners using a specific screening tool has increased since the last published survey data. Although most respondents have adopted specific sedation protocols and have an approved approach to stopping sedation daily, few report even modest compliance with daily cessation of sedation.

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

IntroductionBenzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.MethodsIn 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.ResultsOf 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).ConclusionsIn 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 RegistrationNCT00095251.

Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients

Objective: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. Design: Prospective, observational cohort study. Setting: A 541‐bed, community‐based teaching hospital. Patients: Fifty‐three mechanically ventilated intensive care unit patients. Interventions: None. Measurements and Main Results: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4−). APOE4+ patients were younger (53.2 ± 21.9 vs. 65.4 ± 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4− patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4− patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82–29.51, p = .005). Conclusions: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.

Bench-to-bedside review: Delirium in ICU patients - importance of sleep deprivation

Delirium occurs frequently in critically ill patients and has been associated with both short-term and long-term consequences. Efforts to decrease delirium prevalence have been directed at identifying and modifying its risk factors. One potentially modifiable risk factor is sleep deprivation. Critically ill patients are known to experience poor sleep quality with severe sleep fragmentation and disruption of sleep architecture. Poor sleep while in the intensive care unit is one of the most common complaints of patients who survive critical illness. The relationship between delirium and sleep deprivation remains controversial. However, studies have demonstrated many similarities between the clinical and physiologic profiles of patients with delirium and sleep deprivation. This article aims to review the literature, the clinical and neurobiologic consequences of sleep deprivation, and the potential relationship between sleep deprivation and delirium in intensive care unit patients. Sleep deprivation may prove to be a modifiable risk factor for the development of delirium with important implications for the acute and long-term outcome of critically ill patients.

Diagnosing delirium in critically ill children: Validity and reliability of the Pediatric Confusion Assessment Method for the Intensive Care Unit*

Objective:To validate a diagnostic instrument for pediatric delirium in critically ill children, both ventilated and nonventilated, that uses standardized, developmentally appropriate measurements. Design and Setting:A prospective observational cohort study investigating the Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU) patients in the pediatric medical, surgical, and cardiac intensive care unit of a university-based medical center. Patients:A total of 68 pediatric critically ill patients, at least 5 years of age, were enrolled from July 1, 2008, to March 30, 2009. Interventions:None. Measurements:Criterion validity including sensitivity and specificity and interrater reliability were determined using daily delirium assessments with the pCAM-ICU by two critical care clinicians compared with delirium diagnosis by pediatric psychiatrists using Diagnostic and Statistical Manual, 4th Edition, Text Revision criteria. Results:A total of 146 paired assessments were completed among 68 enrolled patients with a mean age of 12.2 yrs. Compared with the reference standard for diagnosing delirium, the pCAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66–93%), a specificity of 99% (95% confidence interval, 95–100%), and a high interrater reliability (&kgr; = 0.96; 95% confidence interval, 0.74–1.0). Conclusions:The pCAM-ICU is a highly valid reliable instrument for the diagnosis of pediatric delirium in critically ill children chronologically and developmentally at least 5 yrs of age. Use of the pCAM-ICU may expedite diagnosis and consultation with neuropsychiatry specialists for treatment of pediatric delirium. In addition, the pCAM-ICU may provide a means for delirium monitoring in future epidemiologic and interventional studies in critically ill children.