State of the science in pediatric ICU delirium: An integrative review.

Delirium is a complication of critical illness associated with poor outcomes. Although widely studied in adults, comparatively little is understood about delirium in pediatric intensive care units (ICUs). The purpose of this integrative review is to determine the extent and nature of current evidence, identify gaps in the literature, and outline future areas for investigation of pediatric ICU delirium. Eligible articles included research reports of delirium in pediatric ICU samples published in English since 2009. After an extensive literature search and consideration for inclusion/exclusion criteria, 22 articles were chosen for review. Delirium was highly prevalent in the ICU. Delirium episodes developed early in hospitalization, lasted several days, and consisted of hypoactive or mixed motor subtypes. Frequently identified independent risk factors included young age, developmental delay, mechanical ventilation, and benzodiazepine exposure. Pediatric delirium was independently associated with increased length of stay, costs, and mortality. The long-term cognitive, psychological, and functional morbidities associated with pediatric delirium remain largely unknown. Few researchers have implemented interventions to prevent or manage delirium. There was little evidence for the efficacy or safety of pharmacological management. Multicomponent delirium bundles may significantly decrease delirium incidence. Key quality issues among studies included variation in delirium screening, low levels of evidence (i.e., observational studies), and limited ability to determine intervention efficacy in quasi-experimental designs. Although the quantity and quality of pediatric delirium research has rapidly increased, further studies are needed to understand the long-term effects of pediatric delirium and determine the efficacy and safety of interventions for prevention and management.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

In a Model of Neuroinflammation Designed to Mimic Delirium, Quetiapine Reduces Cortisol Secretion and Preserves Reversal Learning in the Attentional Set Shifting Task.

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine's beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production. Graphical Abstract.

Transcutaneous electrical acupoint stimulation for prevention of postoperative delirium in geriatric patients with silent lacunar infarction: a preliminary study.

PURPOSE: This study aims to investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative delirium (POD) in elderly patients with silent lacunar infarct and preliminarily to determine the relationship among TEAS, blood-brain barrier (BBB), neuroinflammation, and POD. PATIENTS AND METHODS: Sixty-four-old patients with silent lacunar infarct were randomly divided into two groups: group TEAS and control group (group C). Patients in the group TEAS received TEAS (disperse-dense waves; frequency, 2/100 Hz) on acupoints Hegu and Neiguan of both sides starting from 30 minutes before induction of anesthesia until the end of surgery, and the intensity was the maximum current that could be tolerated. In group C, electrodes were placed on the same acupoints before anesthesia induction, but no current was given. At 0 minute before the treatment of TEAS, 30 minutes after skin incision, and after completion of surgery (T1-3), blood samples were extracted to detect the concentration of serum tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and S100ß. We assessed patients for delirium and coma twice daily in the first 3 postoperative days using the Confusion Assessment Method for the intensive care unit and the Richmond Agitation-Sedation Scale. RESULTS: This study preliminarily suggests that TEAS can reduce the development of POD in elderly patients with silent lacunar infarction (6.3% vs 25.0%; P=0.039). Compared with the baseline value at T1, the serum concentrations of IL-6, TNF-α, MMP-9, and S100ß were significantly increased at T2-3 in both the groups (P<0.05). Compared with group TEAS, serum levels of TNF-α and IL-6 were higher at T2-3 and serum levels of MMP-9 and S100ß were higher at T3 in group C (P<0.05). The intraoperative anesthetic consumptions were less in group TEAS than group C. CONCLUSION: TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduce the neuroinflammation by lowering the permeability of BBB.

Functional connectivity of the circadian clock and neural substrates of sleep-wake disturbance in delirium.

A possible mechanism of disrupted circadian rhythms in delirium was identified using resting-state functional connectivity. Thirty-four delirious patients and 38 non-delirious controls were scanned for resting-state functional MRI. Seed-based connectivity of the suprachiasmatic nucleus was compared between the groups. In delirious patients functional connectivity from the circadian clock was increased to the dorsal anterior cingulate cortex and decreased to the posterior cingulate cortex, parahippocampal gyrus, cerebellum, and thalamus. A dysregulation of the default mode network and mental coordination processing areas by the circadian clock may be the underlying pathophysiology of sleep-wake cycle disturbance and symptom fluctuation in delirium.

Do nutrients play a role in delirium?

PURPOSE OF REVIEW: This study will review the biologic roles of thiamine, niacin, folic acid, cobalamin, antioxidants, lipids, glucose, and water and their implications as contributors or causal agents in the development of delirium, particularly if deficiencies or excesses exist. RECENT FINDINGS: Knowledge on how overall nutritional status and individual nutrients predispose or directly lead to the development of delirium is currently very limited. Most studies in the area of nutrition and cognition still describe mental status changes using the term dementia and do not specifically address nutrition and delirium. However, as the brain pathophysiology that accompanies delirium has been furthered elucidated, it has become clear that nutritional imbalances can lead to these same physiologic changes in neuronal tissue. SUMMARY: Delirium, characterized by an acute change in mental status along with diminished awareness and attention and disturbances in memory, language, or perception, confers high rates of morbidity and mortality and can be difficult to both diagnose and treat. Although the cause of delirium is often multifactorial, nutritional status and nutrients may play a role in predisposing or directly causing this acute cognitive dysfunction. Many nutritional deficiencies or excesses (i.e., B vitamins, antioxidants, glucose, water, lipids) have been shown to alter the way one thinks and restoring the balance in many of these nutrients can lead to resolution of delirium.

Bright light therapy as part of a multicomponent management program improves sleep and functional outcomes in delirious older hospitalized adults.

OBJECTIVE: Delirium is associated with poor outcomes following acute hospitalization. A specialized delirium management unit, the Geriatric Monitoring Unit (GMU), was established. Evening bright light therapy (2000-3000 lux; 6-10 pm daily) was added as adjunctive treatment, to consolidate circadian activity rhythms and improve sleep. This study examined whether the GMU program improved sleep, cognitive, and functional outcomes in delirious patients. METHOD: A total of 228 patients (mean age = 84.2 years) were studied. The clinical characteristics, delirium duration, delirium subtype, Delirium Rating Score (DRS), cognitive status (Chinese Mini-Mental State Examination), functional status (modified Barthel Index [MBI]), and chemical restraint use during the initial and predischarge phase of the patient's GMU admission were obtained. Nurses completed hourly 24-hour patient sleep logs, and from these, the mean total sleep time, number of awakenings, and sleep bouts (SB) were computed. RESULTS: The mean delirium duration was 6.7 ± 4.6 days. Analysis of the delirium subtypes showed that 18.4% had hypoactive delirium, 30.2% mixed delirium, and 51.3% had hyperactive delirium. There were significant improvements in MBI scores, especially for the hyperactive and mixed delirium subtypes (P < 0.05). Significant improvements were noted on the DRS sleep-wake disturbance subscore, for all delirium-subtypes. The mean total sleep time (7.7 from 6.4 hours) (P < 0.05) and length of first SB (6.0 compared with 5.3 hours) (P < 0.05) improved, with decreased mean number of SBs and awakenings. The sleep improvements were mainly seen in the hyperactive delirium subtype. CONCLUSION: This study shows initial evidence for the clinical benefits (longer total sleep time, increased first SB length, and functional gains) of incorporating bright light therapy as part of a multicomponent delirium management program. The benefits appear to have occurred mainly in patients with hyperactive delirium, which merits further in-depth, randomized controlled studies.

Bowel obstruction and delirium: managing difficult symptoms at the end of life.

Palliative care has become an essential component of oncology care, with a focus on maximizing quality of life and optimizing function, as well as promoting pain and symptom management. This article focuses on the care of a patient experiencing bowel obstruction and delirium, two common issues in patients with advanced cancer, and demonstrates the integration of palliative care and oncology care to achieve an individualized care plan. Management focuses on identifying and treating reversible causes and improving quality of life while respecting the patient's values and goals. Sometimes the causes are not easily identified or treatment of the cause may impair quality of life, at least temporarily. At other times, the causes may be irreversible and the focus is exclusively on quality of life. Determination of best care for individual patients requires synthesis of data from holistic assessment, including the patient's goals of care and values, as well as knowledge of the patient's disease state with evidence-based approaches to management.

Sleep and delirium in ICU patients: a review of mechanisms and manifestations.

Sleep deprivation and delirium are conditions commonly encountered in intensive care unit patients. Sleep in these patients is characterized by sleep fragmentation, an increase in light sleep, and a decrease of both slow wave sleep and rapid eye movement sleep. The most common types of delirium in this population are hypoactive and mixed-type. Knowledge about the mechanisms of sleep and delirium has evolved over time, but these phenomena are not yet well understood. What is known, however, is that different areas in the brainstem transmit information to the thalamus and cortex necessary for sleep-wake regulation. Delirium is related to an imbalance in the synthesis, release, and inactivation of some neurotransmitters, particularly acetylcholine and dopamine. The relationship between sleep deprivation and delirium has been studied for many years and has been viewed as reciprocal. The link between them may be ascribed to shared mechanisms. An imbalance in neurotransmitters as well as alteration of melatonin production may contribute to the pathogenesis of both phenomena. A better understanding of the mechanisms and factors that contribute to sleep deprivation and delirium can guide the development of new methods and models for prevention and treatment of these problems and consequently improve patient outcomes.

Delirium and its treatment.

Delirium occurs at rates ranging from 10% to 30% of all hospital admissions. It is a negative prognostic indicator, often leading to longer hospital stays and higher mortality. The aetiology of delirium is multifactorial and many causes have been suggested. The stress-diathesis model, which posits an interaction between the underlying vulnerability and the nature of the precipitating factor, is useful in understanding delirium. Preventing delirium is the most effective strategy for reducing its frequency and complications. Environmental strategies are valuable but are often underutilized, while remedial treatment is usually aimed at specific symptoms of delirium. Antipsychotics are the mainstay of pharmacological treatment and have been shown to be effective in treating symptoms of both hyperactive and hypoactive delirium, as well as generally improving cognition. Haloperidol is considered to be first-line treatment as it can be administered via many routes, has fewer active metabolites, limited anticholinergic effects and has a lower propensity for sedative or hypotensive effects compared with many other antipsychotics. Potential benefits of atypical compared with typical antipsychotics include the lower propensity to cause over-sedation and movement disorder. Of the second-generation antipsychotics investigated in delirium, most data support the use of risperidone and olanzapine. Other drugs (e.g. aripiprazole, quetiapine, donepezil and flumazenil) have been evaluated but data are limited. Benzodiazepines are the drugs of choice (in addition to antipsychotics) for delirium that is not controlled with an antipsychotic (and can be used alone for the treatment of alcohol and sedative hypnotic withdrawal-related delirium). Lorazepam is the benzodiazepine of choice as it has a rapid onset and shorter duration of action, a low risk of accumulation, no major active metabolites and its bioavailability is more predictable when it is administered both orally and intramuscularly.

Update on the neuropathogenesis of delirium.

Delirium has been considered a syndrome of generalized dysfunction of higher cortical functions due to its breadth of symptoms and associated diffuse slowing on electroencephalogram. Advances in neuropsychiatry have revealed differences between brain regions, including the hemispheres, which may underlie the constellation of symptoms among different psychiatric disorders. For example, different neural pathways are involved in major depression and obsessive-compulsive disorder, including lateralization to one or the other hemisphere. In this article the author proposes that delirium, too, involves particular neural pathways and that lateralization to the right may be relevant. Structural and functional neuroimaging reports and recent neuropsychological studies support this lateralization. Prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex may play a significant role in subserving delirium symptoms and may be the 'final common pathway' for delirium from a variety of etiologies. The final common pathway may be responsible for certain 'core symptoms' (disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, and language abnormalities), while other symptoms (delusions, hallucinations, illusions, and affective lability) may occur depending on the etiology causing delirium. An imbalance in the cholinergic and dopaminergic neurotransmitter systems is most commonly implicated in causing delirium, and could both account for delirium symptoms and be consistent with the neuroanatomical pathways being implicated.

ECT as a therapeutic option in severe brain injury.

Electroconvulsive therapy (ECT) is a safe, highly effective, and rapidly acting treatment for certain major psychiatric illnesses, most notably severe mood disorders. Disturbances in mood and behavior as symptoms of delirium may complicate recovery from traumatic brain injury, but virtually no data exist on the role of ECT as a treatment modality in such clinical situations. We describe a patient with severe, unremitting, agitated behavior following a severe closed head injury from a motor vehicle accident. The initial Glasgow Coma Scale score was 3, with computed tomographic evidence of bilateral frontal and left thalamic contusions. After awakening from a 21-day coma, the patient failed to improve beyond a Ranchos Los Amigos level 4 recovery stage. He exhibited persistent severe agitation with vocal outbursts and failed to assist in performing activities of daily living. His difficulties proved unresponsive to combined behavioral therapy and multiple trials of various psychopharmacologic agents. As an intervention of "last resort," he then received six brief-pulse, bilateral ECT treatments that resulted in marked lessening of his agitation and improvement in his ability to express his needs and participate in his self-care. Also, following the ECT, he showed a markedly enhanced response to psychopharmacologic agents. These findings may have important clinical implications for treatment of prolonged delirium after traumatic brain injury.