Role of Quetiapine in the Prevention of ICU Delirium in Elderly Patients at a High Risk

Delirium is a mental state characterized by confusion and a disturbance in the level of consciousness, making it difficult for the person to focus, sustain attention, or remain attentive. The incidence of delirium ranges from 20–50% in non-ventilated patients and 60–80% in mechanically ventilated patients [1, 2]. Delirium increases the risk of mortality, morbidities including hospital stay and prolonged intensive care unit (ICU) [3, 4], functional disability, early dementia, delayed cognitive disorders [5] and increased costs [6].

Elderly is more vulnerable to acute stress than younger patients [7], because of age related diminution of physiological reserves, greater association of chronic disease in older adults. Assessing vulnerability and diminution of certain system could be quantitative e.g. serum creatinine in kidney function while others could be challenging as in brain vulnerability, Despite of the clinical frailty scale to assess the liability of geriatric population to adverse outcomes [8].

Moreover, hospitalization make delirium more common in elderly patients due to disturbance of patient’s daily home activities to a hospital room. Confusional states can be deteriorated by sensory impairment as well as unintended adverse consequences from interventions [9].

Multiple risk factors have role in the development of delirium [10, 11]. some of those are modifiable. These risk factors have an additive effect including but not limited to mechanical ventilation, high APACHE II score, multiorgan failure, polytrauma, certain medications such as opioids analgesics, pain, catheterization, age, hypertension, interruption in sleep patterns, and smoking [12, 13].

Reducing incidence and duration of delirium and consequently the associated adverse outcome could be not only through the activation of delirium and preventive strategies by correcting modifiable risk factors [14, 15]. But also, through adoption of a bundle of care by using evidence based interventions [13].

Delirium rooms have been designed in some hospital to deliver a specialized care for disoriented patients using the TADA approach (Tolerate, Anticipate, and Don’t Agitate) [16].

The American Geriatrics Society and the American College of Surgeons recommended in guidelines of the prevention and treatment of postoperative delirium, against the use physical or pharmacologic restraints (e.g., antipsychotics, benzodiazepines), since restraints, may increase the risk of falling in this population, unless there is concern for impending risk to the patient or caregivers [17, 18].

Delirium can be classified into two groups according to behavioral activity of psychomotor, that is hypoactive and hyperactive types. Hypoactive delirium is state of decreased consciousness, indifference, withdrawal and is often not diagnosed due to its vague manifestations. In contrast, hyperactive delirium is characterized by restlessness, emotional instability and a moving agitated state that can be easily recognized. Both categories are associated with negative clinical outcome and increased mortality rates [19].

The prevalence and consequences of the delirium, made the society of critical care medicine recommend the necessity of screening of the ICU patients with a screening tools [20], as Intensive Care Delirium Screening Checklist (ICDSC) [1] and the Confusion Assessment Method for the ICU (CAM-ICU) [21].

Quetiapine is atypical antipsychotic which stabilizes mood and reduce agitation by dopamine and serotonin antagonism. It could prevent delirium by its sedation features with lower extrapyramidal side effects.

The aim is to denote the effectiveness of Quetiapine as additive to preventive bundle of delirium in elderly patients with multiple risks for delirium.

A total of 90 elderly patients (above 60 years) were included in the study, 45 patients in each group. Age was significantly higher in Group C (P=0.02) but there was no statistical significance among the two groups regarding the gender and co-morbidities (P= 0.38 and P=0.5 respectively) (Table 2).

The qSOFA score was higher in group Q with median (IQR) of 3 (1–6) in comparison to group C with median (IQR) of 3 (1–4). The length of the hospital stay were higher in group Q than group C with a median and IQR of 15 (10–19) versus 10 (5–14) in group C (Table 2). Apart from immobilization (P=0.0004), infection (P=0.0001) and visual impairment (P=0.0008), all other comparable risks of ICU delirium showed no statistical significance among the studied groups (Table 3).

There was a significant difference between the two groups regarding the incidence of delirium as shown in table 3. In those who developed delirium, the severity of delirium were higher among group C as revealed by higher score for CAM-ICU-7, however it was not statistically significant, where the median and IQR for CAM-ICU-7 were 2 (3) versus 2 (6) for group Q and group C respectively (P=0.37) and ICDSE score 0 (2) versus 0 (4) among group Q and group C respectively (P=0.06) as shown in table 4. The type of delirium as well were different with the hypoactive type being the dominant form in group Q whereas the hyperactive form was the commonest form in group C (Table 5). The interrater reliability between CAM-ICU-7 and ICDSE showed a kappa 0.98 denoting excellent correlation between the two scores.

Somnolence was the most common side effect of Quetiapine (25%) followed by dry mouth (18%) as shown in figure 1.

Fig. 1.

The side effects of Quetiapine among the patients in group Q

Prevention of delirium is a paradigm, a lot of studies have been proposed to decrease or even prevent the poor outcome associated with it, various pharmacological agent and techniques were proposed.

Studies showed that delirium could be prevented in patients undergoing surgery by prevention of pain. In one study ketamine used during cardiac surgeries of 58 elderly patients was associated with a lower rate of postoperative delirium (3%) [23]. But Ketamine still cannot be considered for general usage in prevention of postoperative delirium as further studies are needed with larger sample size, avoid incorporation of nonpharmacologic delirium preventative strategies, and recording long-term outcomes [24].

Not only testing the introduction or use of a pharmacological agent was proposed but the avoidance of certain classes of pharmacological agent was studied to contribute in prevention of delirium.

For example, certain opioids especially pethidine should be avoided in elderly and persons who are susceptible to delirium, as in multiple prospective studies it was associated with an increased risk for delirium [25, 26]. Accordingly, it was recommended for those patients with chronic pain to switch to long-acting opioids such as methadone [27]. Unfortunately, the use of protocols to manage pain result in reducing the severity and duration of delirium, but not its incidence [28] or other postoperative mishaps [23,24,25,26].

Special concerns was directed for elderly population with or without dementia as well as in post stroke setting, where multiple attempts were done to prevent delirium. The potential benefit from using cholinesterase inhibitors (e.g., rivastigmine and donepezil) have been suggested [29, 30], antipsychotic agents and others were all investigated.

However, clinical trials failed to prove decrease incidence and prevalence of delirium in those patients received these medications, moreover the side effects were greater [30].

Low dose of antipsychotic drugs in critical care setting had been studied for prevention of delirium with good results regarding its incidence, severity and duration [31]. However, in one study, it showed increased severity and longer duration of delirium [32].

In the current study, A low dose of Quetiapine decrease the delirium significantly where 11 patients developed delirium versus 22 patients in group C, although there was no a statistically significance difference in most of the risk factors considered in this study and a higher qSOFA in group Q with a median of 3 (1–6) versus 3 (1–4).

The severity of delirium were higher among group C as revealed by higher score for CAM-ICU-7, however it wasn’t statistically significant. Moreover, the dominant type of delirium was the hypoactive type in group Q (9 patients in group Q versus 5 patients in group C) whereas the hyperactive form is the commonest form in group C (2 patients in group Q versus 17 patients in group C). The difference in the age among the two groups may contribute to the difference in the incidence of delirium and the use of quetiapine affects the type of delirium where the hypoactive form was the dominant.

A limited side effect from using Quetiapine was recorded mainly somnolence (25%) followed by dry mouth (18%).

A systematic review and meta-analysis showed that such treatment decreased the incidence of delirium only without reduction of its severity, duration or adverse events [33].It comes to the result that, second generation antipsychotics were found to be more effective than haloperidol. In one study, postoperative low prophylactic dose of dexmedetomidine (0.1 mcg/kg per hour) lowered the incidence of delirium (9% versus 23%; OR 0.35, 95% CI 0.22–0.54). Similar results were supported from different studies [34], side effects of dexmedetomidine were dose dependent bradycardia and hypotension [35].However, these studies weren’t minded with these age group.

The longer length of the hospital stay was higher in group Q than in group C, may be due to higher infection, immobilization and qSOFA in group Q.

The interrater reliability between CAM-ICU-7 and ICDSC showing a kappa 0.98 denoting excellent correlation between the two score in elderly patients. These results match a study by Krewulak et al. [36] where it concluded that the agreement between both for delirium measurement was moderate (kappa = 0.51) and fair for measurement of less than clinical threshold symptoms of delirium (kappa = 0.21), however the current study didn’t include subclinical symptoms.

This study has limitations as it didn’t measure the poor outcome associated with delirium, and the significant difference in age group among the two patients’ population may affect the outcome.

In conclusion, prophylactic low dose of Quetiapine in elderly population in the preventive bundle could reduce the incidence of delirium with a low incidence of a major side effect, as well as CAM-ICU-7 is as effective as ICDSC in monitoring and early diagnosis of delirium.