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Quetiapine for delirium prophylaxis in high-risk critically ill patients
the surgeon xxx (xxxx) xxx
Quetiapine for delirium prophylaxis in high-risk critically ill patients Matthew P. Abraham a, Melisande Hinds b, Isson Tayidi a, David R. Jeffcoach a, James M. Corder c, Leslie A. Hamilton b, Christie M. Lawson c, Reagan W. Bollig c, R. Eric Heidel a, Brian J. Daley c, Jessica E. Taylor c,*, James C. McMillen b a
1924 Alcoa Highway, The University of Tennessee Graduate School of Medicine, Knoxville, TN, 37920, USA 1924 Alcoa Highway, Box 41, Department of Pharmacy, The University of Tennessee Medical Center, Knoxville, TN, 37920, USA c 1924 Alcoa Highway, Box U-11, Department of Surgery, Division of Trauma & Critical Care Surgery, The University of Tennessee Medical Center, Knoxville, TN, 37920, USA b
article info
abstract
Article history:
Background: Delirium is common in patients admitted to the surgical trauma intensive care
Received 24 October 2019
unit (ICU), and the risk factors for these patients differ from medical patients. Given the
Received in revised form
morbidity and mortality associated with delirium, efforts to prevent it may improve patient
26 January 2020
outcomes, but previous efforts pharmacologically have been limited by side effects and
Accepted 21 February 2020
insignificant results. We hypothesized that scheduled quetiapine could reduce the inci-
Available online xxx
dence of delirium in this population. Methods: The study included 71 adult patients who were at high-risk for the development of
Keywords:
delirium (PRE-DELIRIC Score 50%, history of dementia, alcohol misuse, or drug abuse).
Delirium
Patients were randomized to receive quetiapine 12.5 mg every 12 h for delirium or no
Quetiapine
pharmacologic prophylaxis within 48 h of admission to the ICU. The primary end point was
Surgery
the incidence of delirium during admission to the ICU. Secondary end points included time
Intensive care unit
to onset of delirium, ICU and hospital length of stay (LOS), ICU and hospital mortality, duration of mechanical ventilation, and adverse events. Results: The incidence of delirium during admission to the ICU was 45.5% (10/22) in the quetiapine group and 77.6% (38/49) in the group that did not receive pharmacological prophylaxis. The mean time to onset of delirium was 1.4 days for those who did not receive prophylaxis versus 2.5 days for those who did (p ¼ 0.06). The quetiapine group significantly reduced ventilator duration from 8.2 days to 1.5 days (p ¼ 0.002). Conclusions: The findings suggested that scheduled, low-dose quetiapine is effective in preventing delirium in high-risk, surgical trauma ICU patients. © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Delirium is an acute onset of fluctuations in mental status characterized by changes in levels of consciousness and
inattentiveness that result from physiological stress.1,2 Poor outcomes have been associated with the presence of delirium, including increased morbidity, higher mortality, a nonfavorable discharge status, increased intensive care unit (ICU) and hospital lengths of stay, and costlier
* Corresponding author. E-mail addresses: [email protected] (M.P. Abraham), [email protected] (M. Hinds), [email protected] (I. Tayidi), [email protected] (D.R. Jeffcoach), [email protected] (J.M. Corder), [email protected] (L.A. Hamilton), cmlawson78@gmail. com (C.M. Lawson), [email protected] (R.W. Bollig), [email protected] (R.E. Heidel), [email protected] (B.J. Daley), jtaylor4@utmck. edu (J.E. Taylor), [email protected] (J.C. McMillen). https://doi.org/10.1016/j.surge.2020.02.002 1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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hospitalizations.3,4 Understanding risk factors related to the development of delirium can aid clinicians in identifying patients who are at high-risk for the deleterious outcomes associated with the development of delirium. Early prediction of the development of delirium in critically ill patients can facilitate the use of preventative measures aimed at reducing incidence of ICU delirium among patients who are categorized as high-risk. More recently, atypical antipsychotics are beginning to replace the neuroleptic agents such as haloperidol for the treatment of psychiatric conditions as a result of their more favorable safety profile.5 In 2018 the Society of Critical Care Medicine (SCCM) published Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU, known as the PADIS Guidelines. Based on the guidelines, the SCCM suggests not to use haloperidol, atypical antipsychotics, dexmedetomidine, statins or ketamine for prevention of delirium. Although the guidelines suggest not use the above mentioned pharmacologic interventions, the quality of evidence is low.6 Scheduled quetiapine was compared to placebo in a pilot analysis for the treatment of delirium in critically ill patients requiring as needed haloperidol.7 The study showed that quetiapine was associated with a shorter time to resolution of delirium, a reduced duration of delirium, and a more favorable disposition at hospital discharge.7 Despite the prevalence of delirium in injured patients admitted to the trauma ICU,1 the majority of the literature reviewing delirium focuses on elderly hospitalized medical and surgical patients. In comparison, there is little literature that focuses on delirium in the trauma population, which typically consists of a relatively young subgroup of patients. Additionally, surgical populations have been shown to benefit from low-dose antipsychotic prophylaxis, particularly after cardiac surgery.8 While this suggests some benefit from antipsychotic prophylaxis, elective observation admissions to the ICU are at a much lower risk for delirium than acutely ill or traumatized patients and thus may have a different response to prophylaxis. We hypothesized that the use of scheduled, low-dose quetiapine might be effective in preventing delirium in highrisk, critically ill, trauma and surgical patients. The purpose of this study was to evaluate the efficacy and safety of quetiapine for delirium prophylaxis in critically ill, trauma and surgical patients identified as high-risk for delirium utilizing a validated prediction model.
Methods This was a prospective, open-label, single-center study conducted at an academic medical center in rural eastern Tennessee located in the United States. The study was conducted from November 2013 to June 2014 at a tertiary academic medical center with 23 surgical trauma ICU beds and a Level I trauma center designation. The Institutional Review Board (IRB) approved the study protocol prior to commencement. The IRB review deemed both study arms to be common practice and did not require advance consent. All patients
admitted to the surgical trauma ICU and their family members were informed as soon as possible and were provided with a “Notice of Research” describing the research protocols. Patients were free to refuse or withdraw from study participation at any time. The study was registered with clinicaltrials. gov under #NCT02612948. Trauma and surgical patients 18 years of age or older who were admitted to the surgical trauma ICU were screened for inclusion. Patients were excluded from the study if they met any one or more of the following criteria: a sustained Richmond Agitation Sedation Scale (RASS) score of 4 or 5 during the complete ICU admission or the presence of a condition preventing delirium assessment; an anticipated or known ICU length of stay less than 48 h; the use of antipsychotics prior to admission; a history of schizophrenia, epilepsy, parkinsonism, or levodopa treatment; an admission with a primary neurologic condition or an injury with a Glasgow Coma Scale (GCS) score consistently 9 during the first 48 h of their ICU stay; current treatment with a continuous infusion neuromuscular blocking agent; pregnancy; screened positive for delirium upon admission to the ICU; and/or enteral medication route was not available. Patients were included in the study if they were considered to be high-risk for delirium according to their PRE-DELIRIC score, in addition to the presence of other factors. For the inclusion screening purposes of this study, high-risk for delirium was defined as one or more of the following elements: a PRE-DELIRIC score 50%; a past medical history of dementia; a past medical history of alcohol misuse; and/or a past medical history of drug abuse. Detailed information, including APACHE II score, past medical history, and the necessary variables required to calculate the PRE-DELIRIC score were obtained at the time of enrollment. Randomization was stratified by unit location. The surgical trauma ICU is divided into two separate locations: Unit “A” and Unit “B”. Upon admission, patients had equal chance of being admitted to either unit. Patients were not sorted by their acuity. The care that was provided in both of the unit locations was equal since the same staff (nurses, physicians, respiratory therapists, etc.) serviced both units. During the first phase of the study, Unit “A” served as the quetiapine group and Unit “B” served as the active control group. Periodically throughout the study the group assignments for the two units were switched to more evenly distribute the number of patients between the two study groups. This was necessary because there is a difference in the size of the units: Unit “A” is a 15 bed unit and Unit “B” is an 8 bed unit. Quetiapine therapy was initiated at 12.5 mg twice daily and administered either orally or via a nasogastric/enteral tube. Tube feeds were not held prior to the administration of the quetiapine. The patient's quetiapine dose was crushed, mixed with 10 mL of water, and administered via nasogastric/enteral tube. Feeding tubes were then flushed with 30 mL of sterile water after administration of each dose of quetiapine as per hospital protocol. After the patient received the first dose of quetiapine 12.5 mg, the regimen could then be adjusted by the multidisciplinary ICU team. If the team felt that the patient may benefit from receiving a higher prophylactic dose of quetiapine, the dose could then be increased. Quetiapine was
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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discontinued if life-threatening drug-related adverse events occurredde.g. torsades de pointes or other ventricular tachycardia requiring treatment. All patients that received at least one dose of quetiapine remained in the final intention-to-treat analyses. All prescribing decisions regarding sedation, analgesia, and treatment of delirium were left to the discretion of the patient's rounding ICU team and were not mandated as part of the study. The primary end point was the incidence of delirium during ICU admission. Secondary end points included time to onset of delirium, ICU and hospital lengths of stay, ICU and hospital mortality, duration of mechanical ventilation, and adverse events. The disposition of subjects after hospital discharge was categorized into one of five groups: home, inpatient rehabilitation facility, nursing home, extended care facility, or death. To assess for delirium, the nursing staff in the ICU utilized the RASS and the CAM-ICU assessment. Patients were assessed for delirium twice daily (from 7:00 AM to 7:00 PM and from 7:00 PM to 7:00 AM), and the assessment was performed in two steps. First, level of sedation was assessed using the RASS. If the patient was deeply sedated or was unarousable (RASS -4 or 5), the assessment was not performed and the patient was reassessed at a later time. If the patient had a RASS of 3 to þ4, then the assessment was continued to the next step. Second, delirium was diagnosed using the CAMICU. The screening tool detects four features of delirium: acute onset of mental status change or a fluctuating course, inattention, disorganized thinking, and altered level of consciousness. To have delirium diagnosed, a patient displays the first two features with either the third or fourth feature. Before the study, the ICU nurses were trained to use the CAM-ICU. At the midpoint of the study, the ICU nurses received additional education regarding the CAM-ICU. Safety was assessed by monitoring electrocardiogram and adverse events. Electrocardiograms were only obtained if clinically indicated. Significant QTc prolongation was defined as QTc interval longer than 500 ms.9 Adverse events were monitored until delirium was diagnosed or quetiapine was discontinued. The incidence of delirium in a comparable population of a previous study was 67%.10 We assumed that the incidence of delirium would be 45% in the quetiapine group. This would be a one third reduction from the initial incidence. The calculated sample size that would provide 80% power to detect this difference based on a two-tailed significance level of 0.05 was 181 patients per group. Intention -to-treat analyses were performed. Continuous data were presented as means with standard deviations. Categorical data were presented using percentages and crosstabulations. Continuous variables were analyzed with either an independent samples t-test or a ManneWhitney U test. Categorical variables were analyzed with chi-square analysis or Fisher exact test. Times to onset of delirium, extubation, ICU discharge, and hospital discharge were calculated using KaplaneMeier survival analyses, and the differences between groups was assessed by log-rank test. A multivariate logistic regression model was used to determine whether the association between the intervention
3
and the primary outcome was confounded by baseline differences. Baseline variables, BMI and sedative use within the first 24 h, which differed between the two groups (p < 0.10) were entered into the model. The sample size calculation and all statistical analyses were performed on SPSS Version 19 software (Armonk, NY: IBM Corp). Statistical tests were two-sided and p < 0.05 were considered statistically significant.
Results During the study period, 751 patients admitted to the surgical trauma ICUs were screened. Of those screened, 669 were excluded, with two patients being excluded due to their refusal to participate in the study. Ultimately, 82 patients were initially randomized into the study. Eleven patients assigned to the quetiapine group failed to receive the study drug prior to the onset of delirium; therefore, they were excluded from the final analysis, resulting in a final count of 71 total patients (Table 1). The study was closed with less than the intended number of patients due to difficulty enrolling subjects and the limited study personnel available. Post hoc power analysis yielded an achieved power of 76.1%, suggesting an adequate number of patients were evaluated to detect a significant effect. Baseline statistics were similar between the two study groups (Table 1) with the exception of sedative use in the first 24 h of ICU admission. The two main sedatives used during this time were propofol and midazolam. The doses for propofol and midazolam ranged from 5 to 50 mcg/kg/min and 1e4 mg/h, respectively. These doses were titrated and adjusted frequently throughout the day to achieve a RASS goal of 0. After analyzing the baseline demographics, there were two potential confounding variables that met criteria (p < 0.10) for being entered into the logistic regression model, BMI and sedative use within 24 h. When these confounders were entered into the model predicting for delirium, along with the primary predictor variable, it was found that case participants had 78% lesser odds of delirium (95% CI 27.3%e93.4%). Neither BMI (p ¼ 0.07; AOR 0.94, 95% CI 0.88e1.01), nor sedative use within 24 h (p ¼ 0.098; AOR 3.14, 95% CI 0.81e12.14), were significantly associated with the outcome of delirium. Overall, the majority of subjects in both groups were less than 60 years of age (p ¼ 0.46), were admitted with a traumatic injury (p ¼ 0.66), and did not have significant differences in APACHE II scores [SD] (15.0 [10.0] in the control group and 15.0 [9.0] in the intervention arm; p ¼ 0.88). Risk factors for delirium were equally distributed with no statistically significant differences, including alcohol misuse (p ¼ 0.40), drug misuse (p ¼ 0.55), history of dementia (p ¼ 0.67), and PRE-DELIRIC score (p ¼ 0.44). Patients included solely due to their PREDELIRIC score had no difference in their average PREDELIRIC score (control 71.3%, prophylaxis 66.4%; p ¼ 0.44). Additionally, the control group remained at a significantly higher risk of delirium in this particular group. There were significant differences between the study groups for both the primary outcomes (Table 2) and other clinical factors (Table 3). The incidence of delirium was
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Table 1 e Baseline demographics. Control Group (n ¼ 49)
Quetiapine Group (n ¼ 22)
P Value
59 ± 18 27 (55.1) 27.5 ± 9.7 15 (7.0)
55 ± 24 16 (72.7) 23.3 ± 7.1 15 (8.0)
0.46 0.16 0.07 0.92
24 (10.2) 15.0 (10.0) 2.0 (3.0)
26 (13.1) 15.0 (9.0) 2.0 (2.0)
0.66 0.88 0.27 e
3 38 8
1 19 2
17 2 11 4 2 3 10 6 (12.2) 20 (40.8)
5 0 11 3 1 1 1 4 (18.1) 3 (13.6)
0.49 0.024
29 1 17 2 13 (26.5) 71.3 (15.8) 13 (26.5) 9 (18.4) 10 (20.4) 21 (42.9) 25 (51.0) 25 (51.0)
17 0 4 1 7 (31.8) 66.4 (15.2) 8 (36.4) 5 (9.1) 4 (18.2) 9 (40.9) 13 (59.1) 14 (63.6)
0.65 0.44 0.40 0.67 0.55 0.88 0.53 0.32
Age (years), median (IQR) Male, n (%) BMI Glasgow Coma Scale (GCS) on admission to ICU Injury Severity Score (ISS) (std dev) APACHE-II score on admission to ICU SOFA score, on admission to ICU Admission category, n Surgery Trauma Neuro/Neurosurgery Mechanism of injury, n Fall ATV MVC MCC Assault Surgical Other Infection, n (%) Sedative used in first 24 h of ICU admission, n (%) None Midazolam Propofol Combination Metabolic acidosis, n (%) PRE-DELIRIC scorea % (SD) History of alcohol misuse, n (%) History of dementia, n (%) History of drug misuse, n (%) Intracranial injury, n (%) Operation during ICU stay, n (%) Ventilated during ICU stay, n (%) a
e
For patients included in the study solely due to PRE-DELIRIC score.
significantly higher for the control group (77.6% [38/49]) than the quetiapine group (45.5% [10/22]; p ¼ 0.008; OR 0.24 [95% CI 0.08e0.71]). Despite the lack of statistical significance, the mean time to onset of delirium was longer when patients received quetiapine for delirium prophylaxis (2.5 days [SD ± 1.5]) than those that did not (1.4 days [SD ± 1.5]; p ¼ 0.06). Similarly, patients that received quetiapine also spent fewer hours in delirium. The statistically significant clinical outcome was decreased days of mechanical ventilation in the prophylaxis group (Table 3). Pharmacologic prophylaxis did
Table 2 e Primary outcomes. Endpoint
Incidence of delirium, n (%) Incidence of delirium if included solely for PRE-DELIRIC score, n (%)
Control Group Quetiapine P Value (n ¼ 49) Group (n ¼ 22) 38 (77.6)
10 (45.5)
0.008
19 (90.5)
3 (33.3)
0.01
not significantly impact ICU and hospital LOS, and hospital mortality did not differ between groups (Table 3). No ventricular arrhythmia or other significant adverse effects were reported during the study period. The number of patients with documented QTc prolongation was determined by reviewing ordered EKGs for a QTc > 500 msec. Twelve patients in the quetiapine group and 32 patients in the control group had EKGs ordered. Of those patients with ordered EKGs, 41.7% (5/12) of patients in the quetiapine group had a QTc > 500 msec, whereas only 9.4% (3/32) of patients in the control group had a prolonged QTc. Patients receiving quetiapine for prophylaxis received it for an average of 4.25 days. The prophylaxis was discontinued when the patient was deemed to be clinically improving and not at risk for delirium anymore or when discharged from the ICU. Four quetiapine arm patients had their dose adjusteddtwo had their dose decreased and two had their dose increased. One patient's dose was increased after developing delirium; one was titrated up over several days; and one ultimately was stopped before discharge. One patient developed delirium while on the baseline dose, but this resolved without a dose increase. Later in the hospital stay, when the patient did not receive prophylaxis the delirium re-occurred. The
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Table 3 e Other clinical outcomes. Endpoint
Length of stay in ICU, mean (95% CI) days Length of stay in hospital, mean (95% CI) days Time to onset of delirium, mean (95% CI) days Duration of delirium, mean (95% CI) days Duration of mechanical ventilation, days (95% CI) ICU mortality, n (%) Hospital mortality, n (%) Discharge status Death Home Inpatient rehabilitation Extended care facility Nursing home
Control Group (n ¼ 49)
Quetiapine Group (n ¼ 22)
P Value
7.7 (7.1)
4.3 (2.7)
0.10
15.3 (14.2)
10.1 (8.2)
0.114
1.41 (1.46)
2.53 (1.52)
0.06
2.3 (3.3)
1.0 (0.8)
0.52
8.2 (7.3)
1.5 (1.7)
0.002
3 (6.1) 5 (10.2)
3 (13.6) 3 (13.6)
0.37 0.70
5 18 10
3 13 3
11
1
5
2
e
quetiapine was re-administered, and the dose was then increased.
Discussion Surgical trauma ICU delirium is a significant clinical problem affecting between 61 and 73% of patients and is associated with worse clinical outcomes and higher resource utilization.10,11 A recent study conducted by Al-Qadheeb et al. found an incidence of delirium of 23.5%12 with placebo within a population of mainly medical patients. Our study found a much higher incidence of delirium of 77.6% in exclusively trauma and surgery patients receiving no prophylaxis. This suggests the presence of a different risk and potential for prophylaxis efficacy in the trauma and surgery population that should be considered by future studies to account for population differences. Previously, haloperidol has been shown to reduce delirium by approximately 25%, but its use is limited by its side effects.7 In 2013, the Society of Critical Care Medicine published guidelines regarding the monitoring of delirium; however, a study that was not referenced in the guidelines evaluated the use of haloperidol for the prophylaxis of delirium in critically ill elderly patients primarily following non-cardiac surgery, including mostly gastrointestinal surgery.5 The study showed a significant decrease in the incidence of postoperative delirium in patients receiving haloperidol. The incidence of delirium was 15.3% in the haloperidol group as compared to 23.3% in the control group (p ¼ 0.031)5. Despite the study supporting the use of haloperidol, its use is often limited due
5
to adverse events, including QTc prolongation, hypotension, and extrapyramidal symptoms.6 In addition, the study evaluated a continuous infusion dosing strategy that may be problematic in the ICU when intravenous access may be limited. However, Al-Qadheeb et al. found that the use of IV haloperidol to prevent development of delirium was ineffective versus placebo.12 Furthermore, 20% of the haloperidol study population had to stop receiving the intervention due to adverse side effects.12 This study showed that in a similar population of trauma and surgical ICU patients at high-risk for delirium, prophylactic low-dose quetiapine is effective for decreasing the incidence of delirium. Patients receiving delirium prophylaxis with quetiapine were less likely to develop delirium, and in this study, there was an equal or larger size of effect compared to haloperidol with the advantage of no clinically significant adverse side effects reported. The use of prophylactic quetiapine may also have a secondary benefit of decreasing utilization of ICU resources. There was a clinically significant difference in the number of patients still requiring sedatives at 48 h after admission. This could be due to a difference in the population characteristics, but it more likely represents a secondary benefit of quetiapine use. Furthermore, patients not showing signs of delirium and not sedated, would be more likely to be weaned from the ventilator if they could consistently follow commands appropriately. This is supported by the finding that the duration of mechanical ventilation was drastically lower for patients receiving quetiapine and averaged less than 48 h. The lower length of time on ventilator support would also likely contribute to a significantly decreased ICU length of stay. Although the results of this study did not show a significant difference in ICU length of stay, statistical analysis suggests a Type II Error; therefore, a larger study may show a difference. While the results of our study encourage the use of quetiapine for prophylaxis, there were limitations that could be addressed in future research. First, our study population was small and more significant effect sizes may be demonstrated by a larger study. A larger study population would also allow subgroup analysis. In addition, there was variability noted between individual nurses' application of the RASS and CAMICU scores. The nursing evaluation improved with education efforts, but it may have affected whether patients were excluded when they could have received prophylaxis. Finally, a study is needed with rigorous randomization and blinding. With no blinding, all members of the ICU team, as well as the patients’ and their families, knew if a patient received pharmacologic prophylaxis. Since the primary evaluators for delirium were the nurses administering the medications, observer bias could have also affected the outcomes. Quetiapine and haloperidol are the main atypical antipsychotics that have been studied for delirium prophylaxis; however, quetiapine can have administration limitations. Six patients were excluded from the study because they could not receive oral quetiapine. An additional 11 patients scheduled to receive prophylaxis developed delirium before receiving it and some of the delay was due to the lack of enteric access for medications. Olanzapine, ziprasidone, and haloperidol can all be administered to patients that are unable to take oral medications and represent alternative forms of prophylaxis for cases where quetiapine is not a viable treatment option.
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Regarding safety, there is increased risk of QTc prolongation with all atypical antipsychotics, including quetiapine, although the risk of significant arrhythmias such as torsades de pointes is extremely low.13e15 While all patients were monitored with single lead continuous EKG monitoring, not all patients received a full 12 lead EKG since these were not obtained unless clinically indicated. Nonetheless, drug recipients were four times as likely to have QTc prolongation. None of the patients had lethal arrhythmias or clinically significant rhythm changes and none were withdrawn from the intervention arm due to arrhythmia; therefore, the clinical significance of QTc prolongation is likely minimal. Further research could also explore using other atypical antipsychotics or head-to-head comparison of different drugs for prophylaxis. Finally, the PRE-DELIRIC score takes into consideration issues such as reasons for admission and severity of illness. The PRE-DELIRIC model is a validated prediction model for delirium in the ICU (Fig. 1).4 The model was shown to be significantly more effective at predicting the risk of delirium (0.87, 95% confidence interval 0.81 to 0.93) than both nurses (0.59, 95% CI 0.49 to 0.70) and physicians (0.59, 95% CI 0.49 to 0.70).4 The PRE-DELIRIC model can, on the basis of ten readily available risk factors obtained within 24 h of ICU admission, predict the development of delirium for the patient's complete stay in the ICU4 (Fig. 1). Patients can then be stratified as either high-risk or low-risk for the development of delirium based on their PRE-DELIRIC score. High-risk patients are those with a PRE-DELIRIC score of 50%.4 The model excludes patients with a past medical history of alcohol misuse and dementia since these patient
populations are considered to be at high-risk for developing delirium regardless of the presence of other risk factors. Future studies may elucidate if there are particular risk factors grouped into this score that predict more of a response to delirium prophylaxis. It is possible that patients may respond differently based on their mechanism of injury or illness. This study was not able to differentiate between patients with or without neurologic injury or those with respiratory failure compared to those with sepsis or multiorgan failure. Medical comorbidities may also contribute to the efficacy of quetiapine as well.
Conclusion Our study showed evidence that scheduled, low-dose quetiapine is effective in preventing delirium in high-risk, critically ill, trauma and surgical patients. Prophylaxis also reduced ventilator duration. Although not statistically significant, for those that did experience delirium, quetiapine delayed the onset of symptoms and reduced the hours spent in delirium. Overall, quetiapine appears to be a safe and effective medication for delirium prophylaxis in the high-risk, critically ill, trauma and surgical population.
Acknowledgments We would like to thank the staff of the Surgical Trauma ICU at the medical center for their continual commitment to quality patient care. We would like to also acknowledge Benjamin Ainley for his work on the critical review, editing and formatting of the manuscript.
references
Fig. 1 e PRE-DELIRIC model.
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12. Al-Qadheeb NS, Skrobik Y, Schumaker G, Pacheco MN, Roberts RJ, Ruthazer RR, et al. Preventing ICU subsyndromal delirium conversion to delirium with low-dose IV haloperidol: a double-blind, placebo-controlled pilot study. Crit Care Med 2016 Mar;44(3):583e91. 13. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics Jan-Feb 2013;54(1):1e13. 14. Lee S, Morris A, Kim S, Li F, Baumgartner L. Impact of quetiapine therapy on QTc prolongation in critically ill patients. Ann Pharmacother Jul 2019;53(7):705e10. 15. Dube KM, DeGrado J, Hohlfelder B, Szumita PM. Evaluation of the effects of quetiapine on QTc prolongation in critically ill patients. J Pharm Pract Jun 2018;31(3):292e7.
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
Quetiapine for delirium prophylaxis in high-risk critically ill patients Matthew P. Abraham a, Melisande Hinds b, Isson Tayidi a, David R. Jeffcoach a, James M. Corder c, Leslie A. Hamilton b, Christie M. Lawson c, Reagan W. Bollig c, R. Eric Heidel a, Brian J. Daley c, Jessica E. Taylor c,*, James C. McMillen b a
1924 Alcoa Highway, The University of Tennessee Graduate School of Medicine, Knoxville, TN, 37920, USA 1924 Alcoa Highway, Box 41, Department of Pharmacy, The University of Tennessee Medical Center, Knoxville, TN, 37920, USA c 1924 Alcoa Highway, Box U-11, Department of Surgery, Division of Trauma & Critical Care Surgery, The University of Tennessee Medical Center, Knoxville, TN, 37920, USA b
article info
abstract
Article history:
Background: Delirium is common in patients admitted to the surgical trauma intensive care
Received 24 October 2019
unit (ICU), and the risk factors for these patients differ from medical patients. Given the
Received in revised form
morbidity and mortality associated with delirium, efforts to prevent it may improve patient
26 January 2020
outcomes, but previous efforts pharmacologically have been limited by side effects and
Accepted 21 February 2020
insignificant results. We hypothesized that scheduled quetiapine could reduce the inci-
Available online xxx
dence of delirium in this population. Methods: The study included 71 adult patients who were at high-risk for the development of
Keywords:
delirium (PRE-DELIRIC Score 50%, history of dementia, alcohol misuse, or drug abuse).
Delirium
Patients were randomized to receive quetiapine 12.5 mg every 12 h for delirium or no
Quetiapine
pharmacologic prophylaxis within 48 h of admission to the ICU. The primary end point was
Surgery
the incidence of delirium during admission to the ICU. Secondary end points included time
Intensive care unit
to onset of delirium, ICU and hospital length of stay (LOS), ICU and hospital mortality, duration of mechanical ventilation, and adverse events. Results: The incidence of delirium during admission to the ICU was 45.5% (10/22) in the quetiapine group and 77.6% (38/49) in the group that did not receive pharmacological prophylaxis. The mean time to onset of delirium was 1.4 days for those who did not receive prophylaxis versus 2.5 days for those who did (p ¼ 0.06). The quetiapine group significantly reduced ventilator duration from 8.2 days to 1.5 days (p ¼ 0.002). Conclusions: The findings suggested that scheduled, low-dose quetiapine is effective in preventing delirium in high-risk, surgical trauma ICU patients. © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Delirium is an acute onset of fluctuations in mental status characterized by changes in levels of consciousness and
inattentiveness that result from physiological stress.1,2 Poor outcomes have been associated with the presence of delirium, including increased morbidity, higher mortality, a nonfavorable discharge status, increased intensive care unit (ICU) and hospital lengths of stay, and costlier
* Corresponding author. E-mail addresses: [email protected] (M.P. Abraham), [email protected] (M. Hinds), [email protected] (I. Tayidi), [email protected] (D.R. Jeffcoach), [email protected] (J.M. Corder), [email protected] (L.A. Hamilton), cmlawson78@gmail. com (C.M. Lawson), [email protected] (R.W. Bollig), [email protected] (R.E. Heidel), [email protected] (B.J. Daley), jtaylor4@utmck. edu (J.E. Taylor), [email protected] (J.C. McMillen). https://doi.org/10.1016/j.surge.2020.02.002 1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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hospitalizations.3,4 Understanding risk factors related to the development of delirium can aid clinicians in identifying patients who are at high-risk for the deleterious outcomes associated with the development of delirium. Early prediction of the development of delirium in critically ill patients can facilitate the use of preventative measures aimed at reducing incidence of ICU delirium among patients who are categorized as high-risk. More recently, atypical antipsychotics are beginning to replace the neuroleptic agents such as haloperidol for the treatment of psychiatric conditions as a result of their more favorable safety profile.5 In 2018 the Society of Critical Care Medicine (SCCM) published Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU, known as the PADIS Guidelines. Based on the guidelines, the SCCM suggests not to use haloperidol, atypical antipsychotics, dexmedetomidine, statins or ketamine for prevention of delirium. Although the guidelines suggest not use the above mentioned pharmacologic interventions, the quality of evidence is low.6 Scheduled quetiapine was compared to placebo in a pilot analysis for the treatment of delirium in critically ill patients requiring as needed haloperidol.7 The study showed that quetiapine was associated with a shorter time to resolution of delirium, a reduced duration of delirium, and a more favorable disposition at hospital discharge.7 Despite the prevalence of delirium in injured patients admitted to the trauma ICU,1 the majority of the literature reviewing delirium focuses on elderly hospitalized medical and surgical patients. In comparison, there is little literature that focuses on delirium in the trauma population, which typically consists of a relatively young subgroup of patients. Additionally, surgical populations have been shown to benefit from low-dose antipsychotic prophylaxis, particularly after cardiac surgery.8 While this suggests some benefit from antipsychotic prophylaxis, elective observation admissions to the ICU are at a much lower risk for delirium than acutely ill or traumatized patients and thus may have a different response to prophylaxis. We hypothesized that the use of scheduled, low-dose quetiapine might be effective in preventing delirium in highrisk, critically ill, trauma and surgical patients. The purpose of this study was to evaluate the efficacy and safety of quetiapine for delirium prophylaxis in critically ill, trauma and surgical patients identified as high-risk for delirium utilizing a validated prediction model.
Methods This was a prospective, open-label, single-center study conducted at an academic medical center in rural eastern Tennessee located in the United States. The study was conducted from November 2013 to June 2014 at a tertiary academic medical center with 23 surgical trauma ICU beds and a Level I trauma center designation. The Institutional Review Board (IRB) approved the study protocol prior to commencement. The IRB review deemed both study arms to be common practice and did not require advance consent. All patients
admitted to the surgical trauma ICU and their family members were informed as soon as possible and were provided with a “Notice of Research” describing the research protocols. Patients were free to refuse or withdraw from study participation at any time. The study was registered with clinicaltrials. gov under #NCT02612948. Trauma and surgical patients 18 years of age or older who were admitted to the surgical trauma ICU were screened for inclusion. Patients were excluded from the study if they met any one or more of the following criteria: a sustained Richmond Agitation Sedation Scale (RASS) score of 4 or 5 during the complete ICU admission or the presence of a condition preventing delirium assessment; an anticipated or known ICU length of stay less than 48 h; the use of antipsychotics prior to admission; a history of schizophrenia, epilepsy, parkinsonism, or levodopa treatment; an admission with a primary neurologic condition or an injury with a Glasgow Coma Scale (GCS) score consistently 9 during the first 48 h of their ICU stay; current treatment with a continuous infusion neuromuscular blocking agent; pregnancy; screened positive for delirium upon admission to the ICU; and/or enteral medication route was not available. Patients were included in the study if they were considered to be high-risk for delirium according to their PRE-DELIRIC score, in addition to the presence of other factors. For the inclusion screening purposes of this study, high-risk for delirium was defined as one or more of the following elements: a PRE-DELIRIC score 50%; a past medical history of dementia; a past medical history of alcohol misuse; and/or a past medical history of drug abuse. Detailed information, including APACHE II score, past medical history, and the necessary variables required to calculate the PRE-DELIRIC score were obtained at the time of enrollment. Randomization was stratified by unit location. The surgical trauma ICU is divided into two separate locations: Unit “A” and Unit “B”. Upon admission, patients had equal chance of being admitted to either unit. Patients were not sorted by their acuity. The care that was provided in both of the unit locations was equal since the same staff (nurses, physicians, respiratory therapists, etc.) serviced both units. During the first phase of the study, Unit “A” served as the quetiapine group and Unit “B” served as the active control group. Periodically throughout the study the group assignments for the two units were switched to more evenly distribute the number of patients between the two study groups. This was necessary because there is a difference in the size of the units: Unit “A” is a 15 bed unit and Unit “B” is an 8 bed unit. Quetiapine therapy was initiated at 12.5 mg twice daily and administered either orally or via a nasogastric/enteral tube. Tube feeds were not held prior to the administration of the quetiapine. The patient's quetiapine dose was crushed, mixed with 10 mL of water, and administered via nasogastric/enteral tube. Feeding tubes were then flushed with 30 mL of sterile water after administration of each dose of quetiapine as per hospital protocol. After the patient received the first dose of quetiapine 12.5 mg, the regimen could then be adjusted by the multidisciplinary ICU team. If the team felt that the patient may benefit from receiving a higher prophylactic dose of quetiapine, the dose could then be increased. Quetiapine was
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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discontinued if life-threatening drug-related adverse events occurredde.g. torsades de pointes or other ventricular tachycardia requiring treatment. All patients that received at least one dose of quetiapine remained in the final intention-to-treat analyses. All prescribing decisions regarding sedation, analgesia, and treatment of delirium were left to the discretion of the patient's rounding ICU team and were not mandated as part of the study. The primary end point was the incidence of delirium during ICU admission. Secondary end points included time to onset of delirium, ICU and hospital lengths of stay, ICU and hospital mortality, duration of mechanical ventilation, and adverse events. The disposition of subjects after hospital discharge was categorized into one of five groups: home, inpatient rehabilitation facility, nursing home, extended care facility, or death. To assess for delirium, the nursing staff in the ICU utilized the RASS and the CAM-ICU assessment. Patients were assessed for delirium twice daily (from 7:00 AM to 7:00 PM and from 7:00 PM to 7:00 AM), and the assessment was performed in two steps. First, level of sedation was assessed using the RASS. If the patient was deeply sedated or was unarousable (RASS -4 or 5), the assessment was not performed and the patient was reassessed at a later time. If the patient had a RASS of 3 to þ4, then the assessment was continued to the next step. Second, delirium was diagnosed using the CAMICU. The screening tool detects four features of delirium: acute onset of mental status change or a fluctuating course, inattention, disorganized thinking, and altered level of consciousness. To have delirium diagnosed, a patient displays the first two features with either the third or fourth feature. Before the study, the ICU nurses were trained to use the CAM-ICU. At the midpoint of the study, the ICU nurses received additional education regarding the CAM-ICU. Safety was assessed by monitoring electrocardiogram and adverse events. Electrocardiograms were only obtained if clinically indicated. Significant QTc prolongation was defined as QTc interval longer than 500 ms.9 Adverse events were monitored until delirium was diagnosed or quetiapine was discontinued. The incidence of delirium in a comparable population of a previous study was 67%.10 We assumed that the incidence of delirium would be 45% in the quetiapine group. This would be a one third reduction from the initial incidence. The calculated sample size that would provide 80% power to detect this difference based on a two-tailed significance level of 0.05 was 181 patients per group. Intention -to-treat analyses were performed. Continuous data were presented as means with standard deviations. Categorical data were presented using percentages and crosstabulations. Continuous variables were analyzed with either an independent samples t-test or a ManneWhitney U test. Categorical variables were analyzed with chi-square analysis or Fisher exact test. Times to onset of delirium, extubation, ICU discharge, and hospital discharge were calculated using KaplaneMeier survival analyses, and the differences between groups was assessed by log-rank test. A multivariate logistic regression model was used to determine whether the association between the intervention
3
and the primary outcome was confounded by baseline differences. Baseline variables, BMI and sedative use within the first 24 h, which differed between the two groups (p < 0.10) were entered into the model. The sample size calculation and all statistical analyses were performed on SPSS Version 19 software (Armonk, NY: IBM Corp). Statistical tests were two-sided and p < 0.05 were considered statistically significant.
Results During the study period, 751 patients admitted to the surgical trauma ICUs were screened. Of those screened, 669 were excluded, with two patients being excluded due to their refusal to participate in the study. Ultimately, 82 patients were initially randomized into the study. Eleven patients assigned to the quetiapine group failed to receive the study drug prior to the onset of delirium; therefore, they were excluded from the final analysis, resulting in a final count of 71 total patients (Table 1). The study was closed with less than the intended number of patients due to difficulty enrolling subjects and the limited study personnel available. Post hoc power analysis yielded an achieved power of 76.1%, suggesting an adequate number of patients were evaluated to detect a significant effect. Baseline statistics were similar between the two study groups (Table 1) with the exception of sedative use in the first 24 h of ICU admission. The two main sedatives used during this time were propofol and midazolam. The doses for propofol and midazolam ranged from 5 to 50 mcg/kg/min and 1e4 mg/h, respectively. These doses were titrated and adjusted frequently throughout the day to achieve a RASS goal of 0. After analyzing the baseline demographics, there were two potential confounding variables that met criteria (p < 0.10) for being entered into the logistic regression model, BMI and sedative use within 24 h. When these confounders were entered into the model predicting for delirium, along with the primary predictor variable, it was found that case participants had 78% lesser odds of delirium (95% CI 27.3%e93.4%). Neither BMI (p ¼ 0.07; AOR 0.94, 95% CI 0.88e1.01), nor sedative use within 24 h (p ¼ 0.098; AOR 3.14, 95% CI 0.81e12.14), were significantly associated with the outcome of delirium. Overall, the majority of subjects in both groups were less than 60 years of age (p ¼ 0.46), were admitted with a traumatic injury (p ¼ 0.66), and did not have significant differences in APACHE II scores [SD] (15.0 [10.0] in the control group and 15.0 [9.0] in the intervention arm; p ¼ 0.88). Risk factors for delirium were equally distributed with no statistically significant differences, including alcohol misuse (p ¼ 0.40), drug misuse (p ¼ 0.55), history of dementia (p ¼ 0.67), and PRE-DELIRIC score (p ¼ 0.44). Patients included solely due to their PREDELIRIC score had no difference in their average PREDELIRIC score (control 71.3%, prophylaxis 66.4%; p ¼ 0.44). Additionally, the control group remained at a significantly higher risk of delirium in this particular group. There were significant differences between the study groups for both the primary outcomes (Table 2) and other clinical factors (Table 3). The incidence of delirium was
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Table 1 e Baseline demographics. Control Group (n ¼ 49)
Quetiapine Group (n ¼ 22)
P Value
59 ± 18 27 (55.1) 27.5 ± 9.7 15 (7.0)
55 ± 24 16 (72.7) 23.3 ± 7.1 15 (8.0)
0.46 0.16 0.07 0.92
24 (10.2) 15.0 (10.0) 2.0 (3.0)
26 (13.1) 15.0 (9.0) 2.0 (2.0)
0.66 0.88 0.27 e
3 38 8
1 19 2
17 2 11 4 2 3 10 6 (12.2) 20 (40.8)
5 0 11 3 1 1 1 4 (18.1) 3 (13.6)
0.49 0.024
29 1 17 2 13 (26.5) 71.3 (15.8) 13 (26.5) 9 (18.4) 10 (20.4) 21 (42.9) 25 (51.0) 25 (51.0)
17 0 4 1 7 (31.8) 66.4 (15.2) 8 (36.4) 5 (9.1) 4 (18.2) 9 (40.9) 13 (59.1) 14 (63.6)
0.65 0.44 0.40 0.67 0.55 0.88 0.53 0.32
Age (years), median (IQR) Male, n (%) BMI Glasgow Coma Scale (GCS) on admission to ICU Injury Severity Score (ISS) (std dev) APACHE-II score on admission to ICU SOFA score, on admission to ICU Admission category, n Surgery Trauma Neuro/Neurosurgery Mechanism of injury, n Fall ATV MVC MCC Assault Surgical Other Infection, n (%) Sedative used in first 24 h of ICU admission, n (%) None Midazolam Propofol Combination Metabolic acidosis, n (%) PRE-DELIRIC scorea % (SD) History of alcohol misuse, n (%) History of dementia, n (%) History of drug misuse, n (%) Intracranial injury, n (%) Operation during ICU stay, n (%) Ventilated during ICU stay, n (%) a
e
For patients included in the study solely due to PRE-DELIRIC score.
significantly higher for the control group (77.6% [38/49]) than the quetiapine group (45.5% [10/22]; p ¼ 0.008; OR 0.24 [95% CI 0.08e0.71]). Despite the lack of statistical significance, the mean time to onset of delirium was longer when patients received quetiapine for delirium prophylaxis (2.5 days [SD ± 1.5]) than those that did not (1.4 days [SD ± 1.5]; p ¼ 0.06). Similarly, patients that received quetiapine also spent fewer hours in delirium. The statistically significant clinical outcome was decreased days of mechanical ventilation in the prophylaxis group (Table 3). Pharmacologic prophylaxis did
Table 2 e Primary outcomes. Endpoint
Incidence of delirium, n (%) Incidence of delirium if included solely for PRE-DELIRIC score, n (%)
Control Group Quetiapine P Value (n ¼ 49) Group (n ¼ 22) 38 (77.6)
10 (45.5)
0.008
19 (90.5)
3 (33.3)
0.01
not significantly impact ICU and hospital LOS, and hospital mortality did not differ between groups (Table 3). No ventricular arrhythmia or other significant adverse effects were reported during the study period. The number of patients with documented QTc prolongation was determined by reviewing ordered EKGs for a QTc > 500 msec. Twelve patients in the quetiapine group and 32 patients in the control group had EKGs ordered. Of those patients with ordered EKGs, 41.7% (5/12) of patients in the quetiapine group had a QTc > 500 msec, whereas only 9.4% (3/32) of patients in the control group had a prolonged QTc. Patients receiving quetiapine for prophylaxis received it for an average of 4.25 days. The prophylaxis was discontinued when the patient was deemed to be clinically improving and not at risk for delirium anymore or when discharged from the ICU. Four quetiapine arm patients had their dose adjusteddtwo had their dose decreased and two had their dose increased. One patient's dose was increased after developing delirium; one was titrated up over several days; and one ultimately was stopped before discharge. One patient developed delirium while on the baseline dose, but this resolved without a dose increase. Later in the hospital stay, when the patient did not receive prophylaxis the delirium re-occurred. The
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Table 3 e Other clinical outcomes. Endpoint
Length of stay in ICU, mean (95% CI) days Length of stay in hospital, mean (95% CI) days Time to onset of delirium, mean (95% CI) days Duration of delirium, mean (95% CI) days Duration of mechanical ventilation, days (95% CI) ICU mortality, n (%) Hospital mortality, n (%) Discharge status Death Home Inpatient rehabilitation Extended care facility Nursing home
Control Group (n ¼ 49)
Quetiapine Group (n ¼ 22)
P Value
7.7 (7.1)
4.3 (2.7)
0.10
15.3 (14.2)
10.1 (8.2)
0.114
1.41 (1.46)
2.53 (1.52)
0.06
2.3 (3.3)
1.0 (0.8)
0.52
8.2 (7.3)
1.5 (1.7)
0.002
3 (6.1) 5 (10.2)
3 (13.6) 3 (13.6)
0.37 0.70
5 18 10
3 13 3
11
1
5
2
e
quetiapine was re-administered, and the dose was then increased.
Discussion Surgical trauma ICU delirium is a significant clinical problem affecting between 61 and 73% of patients and is associated with worse clinical outcomes and higher resource utilization.10,11 A recent study conducted by Al-Qadheeb et al. found an incidence of delirium of 23.5%12 with placebo within a population of mainly medical patients. Our study found a much higher incidence of delirium of 77.6% in exclusively trauma and surgery patients receiving no prophylaxis. This suggests the presence of a different risk and potential for prophylaxis efficacy in the trauma and surgery population that should be considered by future studies to account for population differences. Previously, haloperidol has been shown to reduce delirium by approximately 25%, but its use is limited by its side effects.7 In 2013, the Society of Critical Care Medicine published guidelines regarding the monitoring of delirium; however, a study that was not referenced in the guidelines evaluated the use of haloperidol for the prophylaxis of delirium in critically ill elderly patients primarily following non-cardiac surgery, including mostly gastrointestinal surgery.5 The study showed a significant decrease in the incidence of postoperative delirium in patients receiving haloperidol. The incidence of delirium was 15.3% in the haloperidol group as compared to 23.3% in the control group (p ¼ 0.031)5. Despite the study supporting the use of haloperidol, its use is often limited due
5
to adverse events, including QTc prolongation, hypotension, and extrapyramidal symptoms.6 In addition, the study evaluated a continuous infusion dosing strategy that may be problematic in the ICU when intravenous access may be limited. However, Al-Qadheeb et al. found that the use of IV haloperidol to prevent development of delirium was ineffective versus placebo.12 Furthermore, 20% of the haloperidol study population had to stop receiving the intervention due to adverse side effects.12 This study showed that in a similar population of trauma and surgical ICU patients at high-risk for delirium, prophylactic low-dose quetiapine is effective for decreasing the incidence of delirium. Patients receiving delirium prophylaxis with quetiapine were less likely to develop delirium, and in this study, there was an equal or larger size of effect compared to haloperidol with the advantage of no clinically significant adverse side effects reported. The use of prophylactic quetiapine may also have a secondary benefit of decreasing utilization of ICU resources. There was a clinically significant difference in the number of patients still requiring sedatives at 48 h after admission. This could be due to a difference in the population characteristics, but it more likely represents a secondary benefit of quetiapine use. Furthermore, patients not showing signs of delirium and not sedated, would be more likely to be weaned from the ventilator if they could consistently follow commands appropriately. This is supported by the finding that the duration of mechanical ventilation was drastically lower for patients receiving quetiapine and averaged less than 48 h. The lower length of time on ventilator support would also likely contribute to a significantly decreased ICU length of stay. Although the results of this study did not show a significant difference in ICU length of stay, statistical analysis suggests a Type II Error; therefore, a larger study may show a difference. While the results of our study encourage the use of quetiapine for prophylaxis, there were limitations that could be addressed in future research. First, our study population was small and more significant effect sizes may be demonstrated by a larger study. A larger study population would also allow subgroup analysis. In addition, there was variability noted between individual nurses' application of the RASS and CAMICU scores. The nursing evaluation improved with education efforts, but it may have affected whether patients were excluded when they could have received prophylaxis. Finally, a study is needed with rigorous randomization and blinding. With no blinding, all members of the ICU team, as well as the patients’ and their families, knew if a patient received pharmacologic prophylaxis. Since the primary evaluators for delirium were the nurses administering the medications, observer bias could have also affected the outcomes. Quetiapine and haloperidol are the main atypical antipsychotics that have been studied for delirium prophylaxis; however, quetiapine can have administration limitations. Six patients were excluded from the study because they could not receive oral quetiapine. An additional 11 patients scheduled to receive prophylaxis developed delirium before receiving it and some of the delay was due to the lack of enteric access for medications. Olanzapine, ziprasidone, and haloperidol can all be administered to patients that are unable to take oral medications and represent alternative forms of prophylaxis for cases where quetiapine is not a viable treatment option.
Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002
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Regarding safety, there is increased risk of QTc prolongation with all atypical antipsychotics, including quetiapine, although the risk of significant arrhythmias such as torsades de pointes is extremely low.13e15 While all patients were monitored with single lead continuous EKG monitoring, not all patients received a full 12 lead EKG since these were not obtained unless clinically indicated. Nonetheless, drug recipients were four times as likely to have QTc prolongation. None of the patients had lethal arrhythmias or clinically significant rhythm changes and none were withdrawn from the intervention arm due to arrhythmia; therefore, the clinical significance of QTc prolongation is likely minimal. Further research could also explore using other atypical antipsychotics or head-to-head comparison of different drugs for prophylaxis. Finally, the PRE-DELIRIC score takes into consideration issues such as reasons for admission and severity of illness. The PRE-DELIRIC model is a validated prediction model for delirium in the ICU (Fig. 1).4 The model was shown to be significantly more effective at predicting the risk of delirium (0.87, 95% confidence interval 0.81 to 0.93) than both nurses (0.59, 95% CI 0.49 to 0.70) and physicians (0.59, 95% CI 0.49 to 0.70).4 The PRE-DELIRIC model can, on the basis of ten readily available risk factors obtained within 24 h of ICU admission, predict the development of delirium for the patient's complete stay in the ICU4 (Fig. 1). Patients can then be stratified as either high-risk or low-risk for the development of delirium based on their PRE-DELIRIC score. High-risk patients are those with a PRE-DELIRIC score of 50%.4 The model excludes patients with a past medical history of alcohol misuse and dementia since these patient
populations are considered to be at high-risk for developing delirium regardless of the presence of other risk factors. Future studies may elucidate if there are particular risk factors grouped into this score that predict more of a response to delirium prophylaxis. It is possible that patients may respond differently based on their mechanism of injury or illness. This study was not able to differentiate between patients with or without neurologic injury or those with respiratory failure compared to those with sepsis or multiorgan failure. Medical comorbidities may also contribute to the efficacy of quetiapine as well.
Conclusion Our study showed evidence that scheduled, low-dose quetiapine is effective in preventing delirium in high-risk, critically ill, trauma and surgical patients. Prophylaxis also reduced ventilator duration. Although not statistically significant, for those that did experience delirium, quetiapine delayed the onset of symptoms and reduced the hours spent in delirium. Overall, quetiapine appears to be a safe and effective medication for delirium prophylaxis in the high-risk, critically ill, trauma and surgical population.
Acknowledgments We would like to thank the staff of the Surgical Trauma ICU at the medical center for their continual commitment to quality patient care. We would like to also acknowledge Benjamin Ainley for his work on the critical review, editing and formatting of the manuscript.
references
Fig. 1 e PRE-DELIRIC model.
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Please cite this article as: Abraham MP et al., Quetiapine for delirium prophylaxis in high-risk critically ill patients, The Surgeon, https:// doi.org/10.1016/j.surge.2020.02.002