Intravenous Infusion of Low Dose Ketamine Versus Dexmedetomedine for Delirium Treatment in Acute Heart Failure

Overview

Delirium is an acute, fluctuating disturbance in attention and cognition that commonly complicates the course of critically ill patients, particularly those admitted with acute heart failure (AHF). Its occurrence in the intensive care unit (ICU) is associated with prolonged mechanical ventilation, longer ICU and hospital stays, increased morbidity and mortality, and substantial healthcare costs. In patients with AHF, the risk of delirium is amplified by factors such as cerebral hypoperfusion, systemic inflammation, sedative exposure, and multi-organ dysfunction. Therefore, effective prevention and early management of delirium in this population are critical to improving outcomes. Dexmedetomidine, a selective α2-adrenoceptor agonist, has gained wide use in ICU sedation due to its anxiolytic and analgesic properties and minimal respiratory depression. Several randomized controlled trials and meta-analyses have demonstrated that dexmedetomidine-based sedation reduces the incidence and duration of delirium compared with traditional sedatives such as benzodiazepines or propofol. However, its use in AHF patients may be limited by dose-dependent bradycardia and hypotension, potentially compromising hemodynamic stability in an already fragile population. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, possesses unique properties that may offer an alternative approach to delirium prevention. At subanesthetic (low) doses, ketamine provides analgesia, maintains respiratory drive, and exerts sympathomimetic effects that support blood pressure and cardiac output-features that may be advantageous in AHF. Emerging evidence from cardiac surgery and critical care studies suggests that low-dose ketamine infusion might reduce delirium incidence through anti-inflammatory and neuroprotective mechanisms, although data remain limited and heterogeneous. Given the hemodynamic fragility of AHF patients and the need for sedatives that balance safety and delirium treatment, a direct comparison between low-dose ketamine and dexmedetomidine is warranted. This study aims to evaluate and compare the efficacy and safety of these two agents in treating delirium among AHF patients admitted to the ICU. By addressing this gap, the study seeks to identify a sedation strategy that optimizes cognitive and hemodynamic outcomes in this high-risk population.

Delirium is a serious cognitive disturbance marked by fluctuating levels of consciousness, impaired attention, altered perception, and disruptions in memory and cognitive function. It affects roughly 18% to 25% of patients in hospitals, with higher incidence rates seen in critically ill individuals. Delirium is both prevalent and associated with a substantial healthcare burden. While 30% to 40% of cases are preventable, its occurrence leads to greater disability, functional decline, higher morbidity and mortality rates, and increased healthcare expenses, making it a major public health concern. Delirium and heart failure (HF) are closely linked, especially among older adults and critically ill patients. The relationship is bidirectional and multifactorial, with heart failure increasing the risk of delirium, and delirium worsening heart failure outcomes. Heart failure (HF) is a well-established independent risk factor for delirium. Some studies have observed increased prevalence of delirium among nursing home residents which was associated with a 3-fold increase in mortality within 60 days. Another study reported that HF independently predicts postoperative delirium, which is linked to higher hospital mortality and extended hospital stays. One more study, studying patients with congestive HF, found that delirium was independently associated with higher rates of 30- and 90-day readmissions as well as increased short-term mortality. Delirium in these patients was also related to elevated heart rate, increased serum B-type natriuretic peptide, and the presence of basal rales, suggesting that activation of the renin-angiotensin-aldosterone system may contribute to impaired cerebral metabolism and perfusion, partially accounting for its occurrence. Heart failure can precipitate delirium through multiple mechanisms including cerebral hypoperfusion due to reduced cardiac output, systemic inflammation with elevated cytokines disrupting blood-brain barrier function, hypoxia from pulmonary congestion and low oxygen saturation, electrolyte and metabolic disturbances (e.g., hyponatremia, uremia), medication effects, including diuretics, and antiarrhythmics. All these mechanisms are supported by clinical and experimental studies. On the other hand, delirium has a profound impact on patients with heart failure (HF), significantly worsening clinical outcomes and quality of life. Evidence shows that delirium is associated with a marked increase in mortality, with a recent meta-analysis demonstrating nearly doubled in-hospital mortality, as well as increased 90-day and 1-year mortality among HF patients. It also contributes to a fourfold higher risk of 30-day hospital readmission, often driven by poor medication adherence, cognitive impairment, and functional decline. In acute decompensated HF, delirium is linked to longer hospital stays, prolonged ICU admissions, and higher healthcare costs due to complications and the need for extended care. Beyond hospitalization, delirium impairs functional recovery, as affected patients show reduced improvement in activities of daily living (ADLs) and a greater likelihood of long-term dependence. Collectively, delirium represents a major determinant of poor prognosis in HF and underscores the importance of early recognition, prevention, and multidisciplinary management. Management of delirium in patients with heart failure involves both preventive and therapeutic strategies aimed at minimizing risk factors, reducing incidence, and improving outcomes. Prevention focuses on early identification of high-risk individuals through standardized screening tools such as the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Non-pharmacological measures remain the cornerstone, including orientation protocols, sleep hygiene promotion, early mobilization, ensuring adequate hydration and nutrition, correction of electrolyte imbalances, and minimizing polypharmacy, particularly sedatives and anticholinergic drugs. The use of structured care bundles such as the ABCDEF bundle (Assess pain, Both spontaneous awakening and breathing trials, Choice of sedation, Delirium monitoring, Early mobility, and Family engagement) has demonstrated significant reductions in delirium incidence and improved survival in critically ill patients, including those with cardiac disease. Treatment is initiated once delirium is diagnosed and includes both supportive care and targeted interventions. Addressing underlying precipitants such as hypoxia, infection, metabolic disturbances, or medication effects is essential. Non-pharmacological approaches should be prioritized, with environmental optimization (adequate lighting, noise reduction, frequent reorientation) playing a crucial role. Pharmacological therapy is generally reserved for severe cases associated with agitation or risk of harm. Low-dose antipsychotics such as haloperidol or atypical agents like quetiapine may be considered, though caution is needed in heart failure due to potential QT prolongation and arrhythmogenic risk. Dexmedetomidine, an α2-adrenergic agonist, has shown promise in reducing delirium duration and maintaining hemodynamic stability compared with benzodiazepines, making it a suitable option in the ICU setting. Emerging evidence also suggests that low-dose ketamine may play a role in delirium treatment particularly in patients with acute heart failure, though further research is warranted. A multidisciplinary approach integrating cardiology, intensive care, clinical pharmacy, and nursing teams is critical for optimizing prevention and treatment strategies in this vulnerable population.