Considering Causes for Hypoactive Delirium

Prior cognitive impairment, such as dementia, is a significant risk factor for hypoactive delirium (Avelino-Silva, Campora, Curiati, & Jacob-Filho, 2017; Davis et al., 2015; Peritogiannis, Bolosi, Lixouriotis, & Rizos, 2015). Susceptibility to acute insults increases with underlying cognitive or neurodegenerative pathology (Davis et al., 2015). Synaptic loss related to dementia is a strong correlate of cognitive decline and neuronal pathology occurring years before signs of impairment (Avelino-Silva et al., 2017). The progressive degeneration represents significant brain disconnectivity and quantifiable loss of “brain reserve,” or ability to compensate (Avelino-Silva et al., 2017; Numan et al., 2017; Rowe et al., 2015).

Although synaptic disconnection is a major contributor to delirium, other aspects of dementia, such as activation of the immune system and cholinergic dysfunction, are also likely contributors (Avelino-Silva et al., 2017; Davis et al., 2015; Numan et al., 2017). These factors contribute to the overall brain function frailty and simply reveal the degenerating brain’s inability to compensate during times of overwhelming acute stress, such as critical illness (Avelino-Silva et al., 2017; Davis et al., 2015). Therefore, while not the cause, delirium may unmask an underlying neurodegenerative process such as dementia. These underlying neurodegenerative processes in turn, increase the susceptibility to delirium. Because prior cognitive impairment increases the brain’s vulnerability, nurses should closely monitor any patient admitted with a history of dementia, brain injury or other cerebral conditions.

Factors associated with medication related hypoactive delirium include the number of medications or polypharmacy (generally > 3), the drug’s anticholinergic potential, and the use of psychoactive medications (Kruskal-Wallis test: 17.39, p<0.005) (Horacek, Krnacova, Prasko, & Latalova, 2016). The number of agents is associated with the pharmacokinetic and pharmacodynamic effects of combining agents (e.g., drug-drug interactions, metabolic inhibitions, and additive negative effects) (Mulkey, Hardin, et al., 2018). Therefore, nurses should suspect the development delirium in patients with more than three medications such as those with multiple co-morbidities or advanced age.

Medications with psychoactive activity (i.e., opiates, benzodiazepines and anticholinergics) contribute to as much as 75% of hypoactive delirium (Horacek et al., 2016; Numan et al., 2017). Sedative agents contribute through several mechanisms. Sedatives decrease the amount of acetylcholine causing an acetylcholine deficiency. This deficiency results in a disruption of the blood-brain barrier’s (BBB) ability to act as a filter, meaning the ability to restrict what crosses over from central circulation into cerebral circulation is impaired, therefore, neuronal damage is enhanced. Anticholinergics are also associated with a subsequent increase in symptom severity (Maldonado, 2008). Even after adjusting for physical impairment and admission diagnosis, anticholinergic drugs can double the risk for hypoactive delirium in acutely ill older adults.

Among sedatives, GABAergic medications (i.e. lorazepam and propofol) are the most significant and frequent culprits causing hypoactive delirium. Propofol has a higher incidence because it significantly reduces the brain's information integration capacity (Bilotta et al., 2013). Additionally, lorazepam increases the daily risk for delirium transition (Maldonado, 2008). Meagher (2011) found 15/35 or 42% of transitions into the hypoactive subtype were preceded by increased benzodiazepine dosing. In turn, benzodiazepine antagonists have been shown to reverse coma and improve hypoactive delirium, particularly in hepatic encephalopathy. Delirium has been found to increase length of time requiring mechanical ventilation [OR 7.0 (4.7-10.5)] more frequently than sedative use alone [OR 2.9 (1.8-4.6)]. These alterations result in sensory overload and a disruption of the circadian rhythm, thereby, interfering with physiologic sleep patterns (Numan et al., 2017). Therefore, polypharmacy, anticholinergics and/or use of psychoactive drugs are one of the primary risk factors that quadruple the risk for developing hypoactive delirium (Rowe et al., 2015). Nurses need to be aware of the increased risk for developing delirium in patients with receiving sedatives, psychoactives or any anticholinergic medications.

Illness, trauma, and surgical procedures offer several triggering factors: anesthetic use, extensive tissue trauma, blood loss and anemia, blood transfusions, hypoxia, and initiating the inflammatory process (Horacek et al., 2016). van den Boogaard (2012) found hypoactive delirium increased ICU length of stay (LOS) from 1-5 days to 2-9 days and hospital LOS from 1-5 days to 8-32 days. The severity of the initial injury or underlying medical condition, mechanical ventilation and high Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) scores are significantly directly correlated with hypoactive delirium (Adamis, Meagher, Rooney, Mulligan, & McCarthy, 2017).

In a recent meta-analysis, mortality rates were significantly higher in individuals with reduced levels of consciousness admitted with respiratory conditions (38%). Respiratory conditions were found to increase the odds of developing delirium (OR 3.35 [2.59, 4.33] higher than cardiac at 5.4% (OR 10.00 [3.6, 27.76], endocrine at 2.5% (OR 25.6 [4.05, 161.73]) or gastrointestinal at 5.9% with odds ratios of 11.26 [4.34, 29.25] conditions (Todd et al., 2017). The more intense the insult, the more pronounced the response.

The combination of an intense insult such as an acute infection or trauma, and the associated systemic inflammatory response result in high levels of stress capable of altering BBB permeability. This leads to the initiation of a cerebral inflammatory response and release of cerebral cytokines (Kozak et al., 2017). As a result, there are shifts in extravascular fluid with potential to develop perivascular edema. With the formation of edema, there is a significant risk for diffuse microcirculatory impairment along with decreased perfusion and longer oxygen diffusion distances (Kozak et al., 2017).

Cerebral and systemic leukocyte activation (immune response) result in release of free oxygen radicals and enzymes exacerbating the systemic inflammatory response and further contributing to the evolution of hypoactive delirium (Bergeron, Dubois, Dumont, Dial, & Skrobik, 2001; Nguyen et al., 2014; van den Boogaard, Schoonhoven, Evers, et al., 2012). Therefore, delirium may represent a central nervous system manifestation of a systemic disease state that has crossed the BBB. Because critical illness increases physiologic stress on the brain, patients in critical care units are particularly vulnerable and should be routinely monitored for an appropriate standardized delirium screening tool (Mulkey, Roberson, Everhart, & Hardin, 2018).

Abnormal laboratory values can significantly increase the risk of hypoactive delirium in all populations OR 3.4 (1.3-8.7) (Bilotta et al., 2013; Horacek et al., 2016; Inouye et al., 2014). Alterations in sodium (sodium <130 or >150 mEq/L) and potassium (<3.0 or >6.0 mEq/L) levels (Pearson’s r=0.2189, P< 0.05), as well as other electrolyte, can lead to the mental status changes associated with delirium. While not clearly understood, sodium imbalances lead to cellular swelling, thereby impairing oxygen delivery (Maldonado, 2008). In the elderly, electrolyte abnormalities, especially hyponatremia, often caused by renal disease and chronic diuretic therapy should be promptly corrected (Bilotta et al., 2013). Patients with an increased risk electrolyte abnormalities such as those with renal impairment, diabetes, cirrhosis or the presence of electrolyte imbalances should be closely observed for signs and symptoms of delirium.

Dehydration, fluid deficits, prolonged fasting time (> 6 hours), and low serum albumin concentrations contribute because of hypoperfusion, both cerebral and renal (Horacek et al., 2016). This is thought to be due to increased drug and metabolite concentrations and decreased renal elimination of drugs, metabolites, and toxic by-products. Failure to correct hypoglycemia (<60 mg/dL), hyperglycemia (>300 mg/dL), and anemia (Hb <120g/L) are risk factors due to the effects on brain metabolism and oxygen transport. For example, Horace (2016) found low Hb levels (<120g/L) increased delirium duration by 11 hours. These alterations induce drug and hormone binding activity along with antioxidant and oxygen radical trapping and are correlated with cognitive impairment. Because of the associated impairment in cognitive performance these abnormalities are considered precipitating factors (Horacek et al., 2016).

Therefore, nurses should be suspicious for delirium in patients who have an increased risk for dehydration or anemia such as postoperative patients and those with acute bleeding.

Hypoxia and global mild ischemic illness injury often co-exist with critical illness, increasing oxidative failure. This correlates with a 17% increased risk for developing hypoactive as well as delirium progression (Bilotta et al., 2013; Maldonado, 2008; Stransky et al., 2011). Low hemoglobin, hematocrit, and pulse oximetry occur approximately 48 hours before the onset of oxidative stress with alterations being more severe in individuals experiencing hypoactive delirium (Maldonado, 2008; Stransky et al., 2011). Severe illness, combined with decreased oxygen supply and/or increased oxygen demand leads to decreased cerebral oxygen availability (Maldonado, 2008). Inadequate oxygenation leads to abnormal neurotransmitter function, ineffective elimination of neurotoxic byproducts, and alterations in electrolytes (Numan et al., 2017).

Rapid depletion of energy stores from cerebral ischemia result in cell death. These changes then result in reconfiguration of neuronal networks. For example, sepsis causes an oxygen supply and demand imbalance due to lower hemoglobin level, cerebral blood flow, and cerebral oxygen delivery (Nedergaard, Jensen, Stylsvig, Lauridsen, & Toft, 2016). In critically ill delirious patients, reduced cerebral blood flow and the associated imbalances increase the chronic hypoxic injury. Patients admitted with an acute respiratory distress or failure and those with a history of respiratory conditions such as asthma and COPD are at increased risk.

Nurses are the cornerstone to prevention and identification of hypoactive delirium and preventing the associated negative sequela. Because hypoactive delirium is more difficult to detect, nurses need to ensure they understand the clinical features and risk factors. For early accurate detection nurses should frequently assess individuals using an appropriate standardized tool. Maintaining consistency and accuracy of assessments has been identified as a significant challenge to obtaining ongoing accurate assessments. (See Table 2) Understanding factors that increase an individual’s risk for developing delirium will assist with identification, and selection of prevention and intervention strategies specific to the individual. Because medications can have a significant impact on delirium risk, medications and patient response should be reviewed on an ongoing basis. Serious consideration should be directed toward continuation of home medications, adequate pain management and reducing sedation to the minimum dose required.

Early mobility, limiting use of restraints, adequate hydration, and limiting interruptions to maintaining adequate nutrition are key to prevention and treatment of delirium. Finally, timing of care is also extremely important. Promoting quiet time consistent with circadian rhythms (2-4 am & 2-4 pm), uninterrupted sleep, establishing day and night routines and timing of care (i.e. giving up middle of the night bathing, timing of medication administration and routine lab/x-rays) will reduce risk and help resolve delirium. To assist in remembering key components of nursing care vital to delirium management, the following acronym Q-U-I-E-T has been provided. (See Table 3)