Pharmacological Management Of Delirium Research Articles

The Relationship Between Intensive Care Unit (ICU) Delirium Severity and 2-Year Mortality

Background:Delirium is an acute brain dysfunction characterized by altered cognition, attention, and level of consciousness. The presence of delirium is associated with increased risk of mortality, neurocognitive decline, and physical impairment; however, the role of ICU delirium severity in long-term health outcomes is less understood.
 Objective:Characterize the relationship between delirium severity and mortality risk in ICU survivors 2-years after discharge.
 Methods:A secondary analysis was performed on patient data collected in two randomized controlled trials (Pharmacological Management of Delirium and Deprescribing in the Pharmacologic Management of Delirium, 2009-2015). Participants received delirium assessments twice daily during hospitalization via the Confusion Assessment Method for the ICU (CAM-ICU-7). Patients enrolled at Eskenazi Hospital with complete mortality data were included in this study. Mean delirium severity was categorized as rapidly resolving (0-2), mild to moderate (2.1-5), or severe (>5). Cox proportional hazard model was used to quantify mortality risk associated with delirium severity. Analyses were adjusted for patient demographics, comorbidities, and severity-of-disease.
 Results:The cohort (n=434) was 54.6% female and 48.6% African American with an average age of 59.8 (SD 16.4). The admission diagnosis was acute respiratory failure/sepsis in 47.9% of patients across medical (n=272), progressive (n=52), and surgical (n=110) ICU types. Approximately one third of the original cohort (n=143) died within 2 years of index discharge. In the multivariate analysis, patients with severe delirium (>5) had nearly twice the adjusted hazard ratio for 2-year mortality compared to patients with mild-moderate delirium (aHR 2.1 [95% CI, 1.3-3.4] and aHR 1.1 [95% CI, 0.7-1.6], p=0.008).
 Conclusion:Severe delirium during ICU stay was significantly associated with increased 2-year mortality risk in comparison to mild-moderate (subsyndromal) delirium.
 Impact:The relationship between delirium severity and 2-year mortality underscores the need for further research on the mechanisms underlying ICU delirium and specific interventions to improve long-term outcomes.

Risk factors for dementia in older intensive care unit (ICU) survivors.

As the number of older intensive care unit (ICU) survivors grows, there is an urgent need to identify modifiable risk factors for post-ICU dementia. We performed a secondary data analysis of 3144 ICU patients ≥ 50 years of age without a history of dementia or severe mental illness who were screened as part of the Pharmacological Management of Delirium (PMD) study. Delirium was assessed using the Confusion Assessment Method for the ICU. Dementia was identified using International Classification of Diseases Ninth and Tenth revision codes for dementia or prescription of anti-dementia medication. Average age (standard deviation) was 65.2±9.5 years; 50.4% were female; and 37.3% were Black. Analyses identified stroke (adjusted hazard ratio [HR] 2.49; 95% confidence interval [CI: 1.52, 4.07], P<0.001), and depression (adjusted HR 3.03; 95% CI [1.80, 5.10], P<0.001) as post-ICU risk factors for dementia. Future studies will need to examine whether interventions targeting post-ICU stroke and depression can lower dementia incidence in ICU survivors. Risk factors for post-intensive care unit (ICU) dementia were distinct from those of Alzheimer's disease. Cardiovascular risk factors were not associated with dementia in older ICU survivors. Post-ICU stroke was associated with a higher risk of dementia in older ICU survivors. Post-ICU depression was associated with a higher risk of dementia in older ICU survivors.

DELIRIUM: NARRATIVE REVIEW

Delirium is a neuropsychiatric syndrome characterized by acute onset of decits in attention and in multiple aspects of cognition. The prevalence of delirium varies considerably by patient group and setting, tending to be more common in hospitalized older adults or the critically ill. Three phenotypes of delirium are recognized depending on psychomotor activity (hyperactive, hypoactive, mixed). Its diagnosis is based on the criteria established in the DSM V, however we have diagnostic tools used in clinical practice such as 4A, CAM and ICDSC. The pharmacological management of delirium is still a matter of debate, treatments with antipsychotic drugs have been shown to reduce motor activity, but they do not seem to affect the dura

Delirium Severity Trajectories and Outcomes in ICU Patients. Defining a Dynamic Symptom Phenotype.

Rationale: Delirium severity and duration are independently associated with higher mortality and morbidity. No studies to date have described a delirium trajectory by integrating both severity and duration.Objectives: The primary aim was to develop delirium trajectories by integrating symptom severity and duration. The secondary aim was to investigate the association among trajectory membership, clinical characteristics, and 30-day mortality.Methods: A secondary analysis of the PMD (Pharmacologic Management of Delirium) randomized control trial (ClinicalTrials.gov Identifier: NCT00842608; N = 531) was conducted. The presence of delirium and symptom severity were measured at least daily for 7 days using the Confusion Assessment Method for the intensive care unit (CAM-ICU) and CAM-ICU-7 (on a scale of 0-7, with 7 being the most severe). Delirium trajectories were defined using an innovative, data-driven statistical method (group-based trajectory modeling [GBTM]) and SAS v9.4.Results: A total of 531 delirious participants (mean age 60 yr [standard deviation = 16], 55% female, and 46% African American) were analyzed. Five distinct delirium trajectories were described (CAM-ICU-7: mean [standard deviation]); mild-brief (CAM-ICU-7: 0.5 [0.5]), severe-rapid recovers (CAM-ICU-7: 2.1 [1.0]), mild-accelerating (CAM-ICU-7: 2.2 [0.9]), severe-slow recovers (CAM-ICU-7: 3.9 [0.9]), and severe-nonrecovers (CAM-ICU-7: 5.9 [1.0]). Baseline cognition and race were associated with trajectory membership. Trajectory membership independently predicted 30-day mortality while controlling for age, sex, race, cognition, illness severity, and comorbidities.Conclusions: This secondary analysis described five distinct delirium trajectories based on delirium symptom severity and duration using group-based trajectory modeling. Trajectory membership predicted 30-day mortality.

ASSOCIATION BETWEEN INFLAMMATORY BIOMARKERS IN PATIENTS WITH ICU DELIRIUM AND TWO-YEAR DIAGNOSIS OF MCI OR ADRD

Introduction Delirium is characterized by acute onset of fluctuation in attention and cognition and is present in 60–87% of older adults in the intensive care unit (ICU).1 Delirium is associated with subsequent Alzheimer's disease (AD) and other related dementias (ADRD), but underlying mechanisms connecting the two disorders are poorly understood.2 Previous work has established a relationship between inflammatory biomarkers and delirium. Our study tested the hypothesis that inflammatory biomarkers measured during an episode of delirium would correlate with a diagnosis of mild cognitive impairment (MCI) or ADRD within two years of discharge from the ICU. Methods We performed a secondary data analysis of delirious patients enrolled in the Pharmacologic Management of Delirium (PMD) Trial l.3 ICD-9 codes for MCI and ADRD in the two years after discharge were obtained from the Indiana Network for Patient Care database. Prescriptions for memantine or anti-cholinesterase inhibitors were counted as evidence of MCI or ADRD. Patients who died at discharge or who had a prior diagnosis of MCI or dementia were excluded. To test for the association of the biomarkers, we used proportional hazards regression to model the time to dementia/MCI diagnosis. Patients who died were censored at their time of death. We performed a sensitivity analysis with logistic regression for patients who did not die during follow-up. Results were similar to the survival analysis, so we only report results from the proportional hazards regression. Models were adjusted for age, gender, race, Apache II, Charlson score, sepsis diagnosis, and usual care. Results A total of 251 patients were included in the analysis. Of these, 231 patients had blood samples collected on Day 1 post randomization to the PMD study, and 149 patients had blood samples collected on Day 8 or upon discharge, whichever was sooner. Within two years of ICU discharge, 12 patients were diagnosed with ADRD, and 43 were diagnosed with MCI. There was no association between inflammatory biomarkers (IL-6, IL-8, IL-10, TNF-Alpha, CRP) drawn on Day 1 and a diagnosis of MCI or ADRD. There was a trend toward significance for higher levels of interleukin-6 (IL-6) drawn at Day 8/discharge and a diagnosis of MCI or ADRD (p = 0.077). Conclusions This preliminary study suggests that higher levels of IL-6 may be associated with a diagnosis of MCI or ADRD after ICU discharge in patients with delirium. However, future larger-scale studies are needed to study the relationship between inflammatory biomarkers in patients with delirium and the subsequent development of MCI and ADRD. This research was funded by S.W. is supported by NIA 2P30AG010133 and NCATS UL1TR001108 (Project Development Team). L.S. is supported by NIA P30AG024827. B.K. is supported by NHLBI R01HL131730, and NIA R01AG055391. M.B. is supported by NIA R01AG034205. The authors declare no relevant financial interests related to this manuscript.

Pharmacological Management of Delirium in the Intensive Care Unit: A Randomized Pragmatic Clinical Trial.

Delirium in the intensive care units (ICUs) is prevalent, with both delirium duration and delirium severity associated with adverse outcomes. We designed a pragmatic trial to test the efficacy of a pharmacological management of delirium (PMD) bundle in improving delirium/coma-free days and reducing delirium severity among ICU patients. A randomized pragmatic clinical trial. Medical, surgical, and progressive ICUs of three tertiary care hospitals. A total of 351 critically ill patients. A multicomponent PMD bundle consisting of reducing the exposure to 20 definite anticholinergic medications and benzodiazepines and prescribing low-dose haloperidol. The primary outcomes were delirium/coma-free days, measured through the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU (CAM-ICU), and delirium severity, measured through Delirium Rating Scale-Revised-98 and the CAM-ICU-7. Secondary outcomes were in-hospital and posthospital discharge 30-day mortality, ICU and hospital lengths of stay, and delirium-related hospital complications. We randomized 351 critically ill delirious patients (mean age = 59.3 years [SD = 16.9 years]; 52% female, 42% African Americans) to receive the PMD bundle or usual care. There were no significant differences in median delirium/coma-free days at day 8 (PMD vs usual care = 4 [interquartile range {IQR} = 2-7] days vs 5 [IQR = 1-7] days; P = .888) or at day 30 (PMD vs usual care = 26 [IQR 19-29] days vs 26 [IQR, 14-29] days; P = .991). There were no significant differences for decrease in delirium severity at day 8, but at hospital discharge, the intervention group showed a greater reduction in delirium severity (mean decrease in CAM-ICU-7 score for PMD vs usual care = 3.2 [SD = 3.3] vs 2.5 [SD = 3.2]; P = .046). No differences were observed between groups for ICU and hospital lengths of stay, mortality, and delirium-related hospital complications. Similar results were observed when analyses were limited to patients 65 years or older and 75 years or older. Implementing the PMD bundle in the ICU did not reduce delirium duration or severity among critically ill patients. clinicaltrials.gov Identifier: NCT00842608. J Am Geriatr Soc 67:1057-1065, 2019.

Deprescribing in the Pharmacologic Management of Delirium: A Randomized Trial in the Intensive Care Unit.

Benzodiazepines and anticholinergics are risk factors for delirium in the intensive care unit (ICU). We tested the impact of a deprescribing intervention on short-term delirium outcomes. Multisite randomized clinical trial. ICUs of three large hospitals. Two hundred adults aged 18 years or older and admitted to an ICU with delirium, according to the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU (CAM-ICU). Participants had a contraindication to haloperidol (seizure disorder or prolonged QT interval) or preference against haloperidol as a treatment for delirium, and were excluded for serious mental illness, stroke, pregnancy, or alcohol withdrawal. Participants were randomized to a deprescribing intervention or usual care. The intervention included electronic alerts combined with pharmacist support to deprescribe anticholinergics and benzodiazepines. Primary outcomes were delirium duration measured by the CAM-ICU and severity measured by the Delirium Rating Scale Revised-98 (DRS-R-98) and the CAM-ICU-7; secondary outcomes included adverse events and mortality. Participants had a mean age of 61.8 (SD = 14.3) years, 59% were female, and 52% were African American, with no significant differences in baseline characteristics between groups. No differences between groups were identified in the number exposed to anticholinergics (P = .219) or benzodiazepines (P = .566), the median total anticholinergic score (P = .282), or the median total benzodiazepine dose in lorazepam equivalents (P = .501). Neither median delirium/coma-free days (P = .361) nor median change in delirium severity scores (P = .582 for DRS-R-98; P = .333 for CAM-ICU-7) were different between groups. No differences in adverse events or mortality were identified. When added to state-of-the-art clinical services, this deprescribing intervention had no impact on medication use in ICU participants. Given the age of the population, results of clinical outcomes may not be easily extrapolated to older adults. Nonetheless, improved approaches for deprescribing or preventing anticholinergics and benzodiazepines should be developed to determine the impact on delirium outcomes. J Am Geriatr Soc 67:695-702, 2019.

Pharmacologic Management of Delirium in the ICU: A Review of the Literature.

Conflicting data exists on the pharmacologic management of intensive care unit (ICU) delirium. This review appraises the current evidence of pharmacologic management of ICU delirium. A systematic literature search of MEDLINE and Embase was conducted to answer the population, intervention, comparison, and outcome (PICO) question of: "Does the use of a pharmacologic agent compared to standard of care or placebo improve ICU delirium in a critically ill patient population?" After application of the PICO question and the inclusion and exclusion criteria, 13 articles were included. Of these articles, 7 were prospective randomized controlled trials, 1 was a prospective nonrandomized controlled trial, and 5 were retrospective investigations. The included articles differed in the agents evaluated, primary outcome, and method of identifying delirium. The variability of outcomes illustrates the need for a large-scale investigation to further evaluate the role of pharmacologic management of ICU delirium.

Standardizing Management of Adults with Delirium Hospitalized on Medical-Surgical Units.

Delirium is common among inpatients aged 65 years and older and is associated with multiple adverse consequences, including increased length of stay (LOS). However, delirium is frequently unrecognized and poorly understood. At one hospital, baseline management of delirium on medical-surgical units varied greatly, and psychiatric consultations focused exclusively on crisis management. To implement a multidisciplinary program for rapid identification and proactive management of patients with delirium on medical-surgical units. A pilot from September 2010 to July 2012 included 920 unique patients, of whom 470 were seen by the delirium management team. A delirium management team included a redesigned role for consulting psychiatrists and a new clinical nurse specialist role; the team provided assistance with diagnosis and recommendations for nonpharmacologic and pharmacologic management of delirium. Multidisciplinary education focused on delirium identification and management and nurses' use of appropriate assessment tools. Electronic health record functions supported accurate problem list coding, referrals to the team, and standardized documentation. Length of stay. During the study period, average LOS in the target population decreased from 8.5 days to 6.5 days (p = 0.001); average LOS for the Medical Center remained stable. Compared with patients whose delirium was diagnosed during the baseline period, patients who received a delirium diagnosis during the pilot period had a higher illness burden and were likelier to have a history of delirium and diagnosed dementia. Program implementation was associated with reduced LOS among older inpatients with delirium. The delirium team is an effective model that can be quickly implemented with few additional resources.

The pharmacologic management of delirium in children and adolescents.

Delirium is a serious and common problem in severely medically ill patients of all ages. It has been less addressed in children and adolescents. Treatment of delirium is predicated on addressing its underlying cause. The management of its symptoms depends on the off-label use of antipsychotics, while avoiding agents that precipitate or worsen delirium. Olanzapine, quetiapine, and risperidone are presently considered first-line drugs, usually replacing haloperidol. Other agents have shown promise, including melatonin to address the sleep disturbance characteristic of delirium, and dexmedetomidine, an α2-agonist, that may facilitate lower doses of benzodiazepines and opioids that may worsen delirium.

N015 Dexmedetomidine in Management of Agitated Delirium in the Postoperative Cardiac Surgery Patient

Delirium is a reversible organic mental syndrome whose chief characteristic is anxiety. When excessive motor activity is associated with delirium it is referred to as agitated delirium. Delirium occurs in 80% of intensive care unit (ICU) patients and is associated with prolonged length of stay (LOS) and increased mortality. In the postoperative cardiac surgery patient agitated delirium can result in difficulty breathing causing ventilator dyssynchony, hypertension, tachycardia, and combative behaviour. The risk of prolonged ventilation and integrity of sternal incisions are very real complications.The diagnosis and pharmacological management of delirium is an important quality of care issue for the postop cardiac surgery patient. Pharmacoeconomics involves the right drug, the right dose, at the right time and by the right route. Typically neuroleptics such as haloperidol and a combination of benzodiazepines namely ativan are used to treat delirium but neither have any analgesia properties. Dexmedetomidine (Dex) has a rapid onset and provides sedation and analgesia with no respiratory depression and can be used as a bridge to weaning mechanical ventilation.A review of two challenging patients will be used to describe our experience using Dex as an alternative to managing postoperative delirium. The pharmacologic management in the cardiac surgical patient in these times of economic constraints has stimulated interest in early extubation or fast track pathways. A brief discussion on a study with Dex will be discussed. Delirium is a reversible organic mental syndrome whose chief characteristic is anxiety. When excessive motor activity is associated with delirium it is referred to as agitated delirium. Delirium occurs in 80% of intensive care unit (ICU) patients and is associated with prolonged length of stay (LOS) and increased mortality. In the postoperative cardiac surgery patient agitated delirium can result in difficulty breathing causing ventilator dyssynchony, hypertension, tachycardia, and combative behaviour. The risk of prolonged ventilation and integrity of sternal incisions are very real complications. The diagnosis and pharmacological management of delirium is an important quality of care issue for the postop cardiac surgery patient. Pharmacoeconomics involves the right drug, the right dose, at the right time and by the right route. Typically neuroleptics such as haloperidol and a combination of benzodiazepines namely ativan are used to treat delirium but neither have any analgesia properties. Dexmedetomidine (Dex) has a rapid onset and provides sedation and analgesia with no respiratory depression and can be used as a bridge to weaning mechanical ventilation. A review of two challenging patients will be used to describe our experience using Dex as an alternative to managing postoperative delirium. The pharmacologic management in the cardiac surgical patient in these times of economic constraints has stimulated interest in early extubation or fast track pathways. A brief discussion on a study with Dex will be discussed.

Delirium in the Intensive Care Unit

A significant portion of critical care patients experience delirium. This form of acute brain dysfunction is associated with increased hospital stay, increased mortality, and greater long-term cognitive deficits. Critical care nurses are on the frontline with these patients and can make a significant impact on patient outcomes, including reducing the negative outcomes and experience of delirium. It is, therefore, imperative that nurses be equipped with a solid knowledge base of understanding delirium, which includes what has been reported specifically unique to delirium in the intensive care unit. This article will provide an overview of delirium and describe an interdisciplinary model of care combining multiple evidence-based practice strategies that nurses can and should use to help systematically reduce modifiable delirium risk factors. In addition, this article will provide an overview of recent reports concerning pharmacologic management of delirium in the intensive care unit.

Delirium in the Intensive Care Unit

A significant portion of critical care patients experience delirium. This form of acute brain dysfunction is associated with increased hospital stay, increased mortality, and greater long-term cognitive deficits. Critical care nurses are on the frontline with these patients and can make a significant impact on patient outcomes, including reducing the negative outcomes and experience of delirium. It is, therefore, imperative that nurses be equipped with a solid knowledge base of understanding delirium, which includes what has been reported specifically unique to delirium in the intensive care unit. This article will provide an overview of delirium and describe an interdisciplinary model of care combining multiple evidence-based practice strategies that nurses can and should use to help systematically reduce modifiable delirium risk factors. In addition, this article will provide an overview of recent reports concerning pharmacologic management of delirium in the intensive care unit.

Pharmacological Management of Delirium in Hospitalized Adults – A Systematic Evidence Review

Despite the significant burden of delirium among hospitalized adults, there is no approved pharmacologic intervention for delirium. This systematic review evaluates the efficacy and safety of pharmacologic interventions targeting either prevention or management of delirium. We searched Medline, PubMed, the Cochrane Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) information systems from January 1966 to October 2008. We included randomized, controlled trials comparing pharmacologic compounds either to each other or placebo. We excluded non-comparison trials, studies with patients aged < 18 years, a history of an Axis I psychiatric disorder, and patients with alcohol-related delirium. Three reviewers independently extracted the data for participants, interventions and outcome measures, and critically appraised each study using the JADAD scale. We identified 13 studies that met our inclusion criteria and evaluated 15 compounds: second-generation antipsychotics, first-generation antipsychotics, cholinergic enhancers, an antiepileptic agent, an inhaled anesthetic, injectable sedatives, and a benzodiazepine. Four trials evaluated delirium treatment and suggested no differences in efficacy or safety among the evaluated treatment methods (first and second generation antipsychotics). Neither cholinesterase inhibitors nor procholinergic drugs were effective in preventing delirium. Multiple studies, however, suggest either shorter severity and duration, or prevention of delirium with the use of haloperidol, risperidone, gabapentin, or a mixture of sedatives in patients undergoing elective or emergent surgical procedures. The existing limited data indicates no superiority for second-generation antipsychotics over haloperidol in managing delirium. Although preliminary results suggest delirium prevention may be accomplished through various mechanisms, further studies are necessary to prove effectiveness.

Tackling agitated delirium – the tip of the iceberg

Reade et al. studied 20 agitated intubated patients in a pilot open-label trial comparing the efficacy of dexmedetomidine versus haloperidol in facilitating extubation. While the study design had limitations, which are outlined by the authors themselves in the paper published in this issue of Critical Care, the study demonstrated an impressive reduction in time to extubation and length of stay. Dexmedetomidine is a promising sedative agent that acts via α2-receptors and has been shown to decrease prevalence and duration of delirium in mechanically ventilated patients. Haloperidol is the recommended and standard drug to treat delirium, largely based on large case series and reports. Delirium is a common, underdiagnosed and serious problem in intensive care unit patients. Agitated delirious patients are at risk of immediate adverse events as well as prolonged respiratory support. All delirious patients are at risk of poor cognitive outcomes. Further research is needed into the pharmacological management of delirium, including the use of dexmedetomidine in the management of agitation and the clinical efficacy of haloperidol.

The Pharmacological Management of Delirium in Critical Illness

A growing body of evidence has shown that critical illness and associated treatments can lead to de novo neurological degradation manifesting as delirium or acute brain dysfunction. Many survivors further suffer from long-term cognitive impairment (LTCI), months to years after their critical illness, affecting their functional quality of life. Recent data have demonstrated that delirium is an independent risk factor for increased morbidity and mortality in the critically ill and may also predispose patients to long-term cognitive impairment. Delirium, therefore, may represent a critical point for intervention and treatment in critically ill patients. The pathogenesis of delirium is multifactorial and is considered to be related to several physiological and possibly iatrogenic processes. Due to its complexity, the optimum pharmacological treatment by which to manage delirium is not fully understood; however, recent investigations have proposed several plausible protocols. In this review, we examine evidence pertaining to the pharmacological treatment of delirium in the context of acute critical illness.

PERIOPERATIVE HALOPERIDOL USAGE FOR DELIRIUM MANAGEMENT

To the Editor: Kalisvaart et al. address an important question regarding the pharmacological management of delirium in the older adult.1 Research in this area is limited, and randomized, placebo-controlled trials are lacking. Although not approved by the Food and Drug Administration for this indication, antipsychotic usage has been in clinical practice2 and supported by the American Psychiatric Association for management of delirium.3 As evidence mounts for adverse effects of antipsychotic agents in dementia patients,4 evidence for overall beneficial effect in the delirium population becomes ever more important. Although understandably underpowered, the study appears to be well designed, has practical implications, and makes me consider using prophylactic low doses of haloperidol in perioperative patients at higher risk for delirium. It also validates previously published patient risk profiles that can be incorporated into the preoperative risk evaluation.5 However, the conclusion that haloperidol reduces the length of stay appears misleading. In Table 1, the hospital days were not statistically different between the two groups. Table 3 shows a difference of 5.5 days in the delirium subgroup analysis, which was 15.8% of the total number of patients. Therefore, prophylactic haloperidol does not reduce length of stay overall but may reduce length of stay for the minority who develop delirium. Financial Disclosure: None. Author Contributions: Michael Wang was the sole author. Sponsors Role: None.