Antipsychotic initiation in mechanically ventilated patients in a medical intensive care unit

INTRODUCTION

Mechanically ventilated patients in the intensive care unit (ICU) often require sedative medications to reduce anxiety, decrease stress, and facilitate care. However, many studies have demonstrated the adverse effects of deep levels of sedation in ICUs, such as longer ventilator time, prolonged ICU length of stay (LOS), increased risk of delirium, slower cognitive and physical recovery, and higher rates of mortality.^[1-3] Society of Critical Care Medicine’s Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in adult patients in the ICU promote the use of light sedation, rather than deep sedation, to improve patient outcomes.^[2] Further, the PADIS guideline recommends against routine use of antipsychotics (APs) to prevent or treat delirium. Delirium is a frequently encountered diagnosis occurring in up to 80% of critically ill adult patients.^[4,5] Delirium, like deep sedation, may result in longer duration of mechanical ventilation, increased ICU LOS, slower cognitive recovery, and increased mortality.^[4,6] Delirium in the ICU also increases the likelihood of being discharged to a post-acute care facility, may increase cost of care, and is a major risk factor for the development of post-intensive care syndrome.^[7,8] The use of APs in the management of ICU delirium is a known practice, and the risks of ICU delirium must be balanced with the risk of the use of APs. Our institution’s adaptation of the PADIS guideline recommends a short course of AP therapy in patients who are delirious and agitated, defined as Confusion Assessment Method for the ICU (CAM-ICU) positive with Richmond Agitation Sedation Scale (RASS) score ≥ +2 [Figure 1].^[9] The adapted recommendations also suggest short courses of continuous infusion sedatives as management for agitation and inadequate sedation. The use of APs as adjunct sedation has emerged as an area of interest that has only minimally been discussed. A recent study assessed whether adjunctive use of quetiapine reduced sedative dosage requirements among 57 mechanically ventilated medical ICU (MICU) adults without delirium.^[10] Ultimately, Ohman et al. concluded that the use of quetiapine at a median dose of 25 mg every 12 h did not result in a significant reduction in sedative requirements 24- or 48-h following initiation.^[10] In addition to the recent interest in the effects of APs on sedation, the coronavirus disease (COVID-19) pandemic has changed sedation management and AP use in the ICU. Recommendations were provided early in the pandemic to discontinue therapeutically potent sedatives as soon as possible or replace them with agents that do not suppress the respiratory drive, such as APs or alpha-2 agonists.^[11] Although these recommendations were likely affected by medication shortages and other constraints caused by the pandemic, it is possible they influenced general ICU practice or that providers were using similar approaches in patients without COVID-19 despite the lack of evidence to support transitioning from potent sedatives to alternative agents.^[12] Overall, there are many factors, as described, contributing to decision-making on the use of APs in critically ill patients and the purpose of our analysis was to further explore this area of drug utilization in our ICU. The aim of this study was to describe the use of AP therapy in critically ill, mechanically ventilated adults in the MICU of a tertiary academic medical center by assessing adherence to an institution-specific guideline for delirium management and the effects of APs on continuous infusion sedative and analgesic agents.

Close

Figure 1:

Baystate Medical Center’s PADIS adaptation.

Export to PPT

MATERIALS AND METHODS

RESULTS

Patient demographics

From June 2020 to June 2021, a total of 388 patients had an AP order associated with the MICU location. Of these 388 patients, 38 (9.8%) met eligibility criteria and were included in the study cohort [Figure 2]. Baseline characteristics are shown in Table 1. Patients had a median age of 64 years and average weight of 79.9 kg. Females constituted 57.9% of the population and reasons for admission included respiratory illness (50.0%), infection (34.2%), and neurologic illness (28.9%). Thirty-seven patients (97.4%) received quetiapine and one patient (2.6%) received olanzapine as their primary APs, respectively. The median (IQR) dose of quetiapine patients received in the 24 h following initiation was 50 (37.5–75) mg. The patient who received olanzapine was administered 10 mg in the 24 h following initiation.

Close

Figure 2:

Patient selection CONSORT diagram.

Export to PPT

Table 1: Baseline characteristics¹.

Baseline characteristic	n=38
Age (years)	64 (53.5–73.8)
Gender (female)	22 (57.9)
Weight (kg)	79.9 (60.9–92.2)
Admission diagnosis/reason for admission
Neurologic illness	11 (28.9)
Respiratory illness	19 (50)
Cardiac illness	4 (10.5)
Digestive or urologic illness	1 (2.6)
Hepatic disease	1 (2.6)
Renal disease	1 (2.6)
Infection	13 (34.2)
Hematologic/oncologic illness	2 (5.3)
Hemodynamic compromise	3 (7.9)
Other	1 (2.6)
On vasopressors at time of AP2initiation	8 (21.1)
QTc (ms, Bazett)	446 (424–475)

1Baseline characteristics of included patients. Data are presented as median (interquartile range) or n(%), ²AP: Antipsychotic

Guideline adherence

Of the 38 patients who received APs, only five (13.2%) patients were CAM-ICU positive with RASS ≥ +2 at time of AP initiation. CAM-ICU and RASS scores at 24 ± 8 h before initiation, time of initiation (± 8 h), and 24 ± 8 h following initiation are shown in Figure 3. Patients were primarily CAM-ICU positive at all three assessment times. RASS scores ranged from −4 to +3, with patients primarily RASS +1 at 24 h prior, RASS −2 at time of initiation, and RASS −1 at 24 h after AP initiation.

Close

Figure 3:

Confusion assessment method for the intensive care unit and Richmond Agitation Sedation Scale scores.

Export to PPT

Sedative and opioid utilization

The most common sedative agents used in the study cohort were propofol and dexmedetomidine with 23 and 21 patients receiving each agent, respectively. There were three patients each on midazolam and ketamine infusions. The most common continuous analgesic agent was fentanyl, with 19 patients receiving continuous infusions. Only three patients received continuous infusion hydromorphone. Changes in continuous infusion sedative and analgesic rates are shown in Figure 4. In patients who received propofol, the average (±SD) rate before AP initiation was 16.8 ± 15.8 mcg/ kg/min while the average rate following initiation was 16.7 ± 14.5 mcg/kg/min. In patients who received dexmedetomidine, the average (±SD) rates in the 24 h before and following AP initiation were the same at 0.7 ± 0.5 mcg/kg/h. For midazolam, patients received an average (±SD) of 1.3 ± 0.6 mg/h in the 24 h before initiation compared to 0.4 ± 0.2 mg/h in the 24 h following. Finally, in the patients who received ketamine, the average (±SD) rates before and after were 0.9 ± 0.6 mg/kg/h and 0.5 ± 0.5 mg/kg/h, respectively. Rates (±SD) of fentanyl before and after initiation were 81.1 ± 40.6 mcg/h and 76.0 ± 52.0 mcg/h and rates (±SD) of hydromorphone were 4.4 ± 3.4 mg/h and 3.8 ± 2.7 mg/h, respectively. Overall, there was no clinically significant difference in rates of continuous infusion sedatives or analgesics in the 24 h before and after AP initiation. Despite minimal changes in continuous infusion analgesics, patients’ CPOT scores decreased over the study period. Most patients (63.1%) had CPOT scores <2 at 24 h before AP initiation. At time of initiation, 73.7% were documented as CPOT <2 and at 24 h following initiation, 86.9% had CPOT scores <2. Total daily dose of opioids, collected and reported as MMEs, decreased by an average of 2.5% in the overall cohort. Further description of patients’ RASS and CAM scores is provided in Figure 3.

Close

Figure 4:

Change in continuous infusion sedative and analgesic medications.

Export to PPT

DISCUSSION

In this study, we found adherence to institution-specific recommendations for the use of APs in mechanically ventilated adults with hyperactive delirium to be low with many patients being initiated on APs who were not CAMICU positive with RASS ≥ ±2. Most patients who received APs were CAM-ICU positive with RASS -2 to +1 at time of initiation [Figure 3]. In addition to our main finding, we also found that APs did not appear to have a clinically significant effect on rates of continuous infusion sedatives or analgesics in the 24 h following initiation. Changes in depth of sedation and level of pain also did not appear to be largely different, though fewer patients seemed to be agitated based on RASS scores 24 h after the first dose of APs. Finally, we found that many patients were continued on APs at time of ICU and hospital discharge. A prior review conducted at BMC indicated that 16.3% of patients were continued on APs at time of hospital discharge. While the present study indicates progress in AP discontinuation with only 10.5% of patients discharged from the hospital on new start APs, there is still room for improvement. Our findings indicate that APs were being used in patients without agitated delirium, suggesting potential alternate prescribing indications such as adjunct sedation. The initiation of APs should be done with some precautions, and further description of the potential benefits and risks as described in this study will help providers in discerning appropriate use of APs.

The impact of APs on sedative and analgesic requirements has only been explicitly evaluated in one study.^[10] In the retrospective intrapatient comparator analysis by Ohman et al., the authors found that the use of quetiapine as an adjunct sedative was not associated with reduced dosage requirements of dexmedetomidine, propofol, or midazolam at 24- and 48-h following AP initiation.^[10] There was also no statistically significant difference in the absolute dose of opioids.^[10] While the use of quetiapine as adjunct sedation and analgesia has only been discussed in one study, to our knowledge, the effects have been described in prior studies evaluating the use of APs for delirium and delirium prophylaxis. Results from these prior studies have been mixed, with smaller prospective studies describing fewer sedative and opioid days and larger, randomized trials failing to find significant effects of APs on sedation.^[13-16] There is significant heterogeneity among these studies and despite some studies having similar AP dosing and titration protocols, there is a lack of agreeance regarding the effects of various APs on benzodiazepine, opioid, propofol, and dexmedetomidine exposure.^[13-16] Assessment of the effects of APs on analgesia is confounded by the fact that CPOT assessment involves many components that are affected by delirium. Patients may have a CPOT score of two or higher from actions such as fighting the ventilator or body movements including attempting to sit up, pulling at tubes, and thrashing limbs.^[17] There is significant overlap between the presentations of delirium and pain in mechanically ventilated, sedated patients. Given the conflicting evidence and clinician desire to reduce the amounts of sedatives and opioids patients receive, it is possible that APs were being initiated in this cohort as adjunct sedation. We hypothesize that the indication for APs was often for adjunct sedative therapy as demonstrated by the low rates of initiation for agitated delirium described in our study. The prevalence of this clinical practice is relevant, and the use of APs as adjunct sedation should be further investigated at our institution and beyond.

While it is difficult to quantify the effects of the COVID-19 pandemic on ICU management of non-COVID patients, we suspect that the adjusted management of PADIS in patients with COVID-19 has affected our management of patients without the viral infection. The question of what effects the pandemic has had on critically ill patients without COVID-19 has yet to be elucidated but is an area that would help further explain the findings of our study. The increased use of APs has been described in other populations since the pandemic began, raising the possibility that COVID-19 has led to increased prescribing rates of APs in the critically ill population, too.^[18,19] We suspect that AP utilization as adjunct sedation has increased in attempts to wean patients with acute respiratory distress syndrome from COVID-19 from the high amounts of sedatives and opioids they require; we question if this practice has potentially affected the nonCOVID critically ill population.

Although we find the results from our study to be clinically relevant, we acknowledge that there are many limitations. This is a single-center descriptive study with a small sample size that was not powered to show statistical significance and, therefore, external validity may be limited. All data were collected retrospectively which may have led to incomplete or inaccurate information. Only 10% of patients screened met inclusion criteria; extensive exclusion criteria were applied to try and account for potential confounding factors that would have affected patients’ level of sedation, odds of developing ICU delirium, and opioid requirements. We acknowledge that it is impossible to account for all potential confounding variables. Finally, patient condition changes frequently in the ICU and we recognize that retrospective data fails to account for all measures taken into consideration when managing patients’ sedation, agitation, and delirium. Patients who may have been agitated and delirious at time of AP ordering could have received interventions not accounted for in our data collection, thus making them appear to have lower RASS scores at time of AP administration. Although some patients may have been appropriate for APs at time of physician ordering and pharmacist verification, this may not have been captured in our data collection. Furthermore, while a goal-directed, nursing-driven approach to sedation was utilized in our MICU during the study period, adherence to sedation goals was assumed and compliance was not assessed. Sedation management was not standardized during the study period and frequent sedative titration, tapering, and transitions occurred, which is reflective of current clinical practice in the management of critically ill adults but could not be accounted for in this study. Finally, the frequency and timing of ECG assessment were not standardized nor were patients assessed for concomitant QT prolonging agents, thus affecting the accuracy and description of QTc prolongation in our study population. Strengths of this study include its pragmatic design, the exclusion of patients with important confounders, and assessment of both disease-oriented and patient-oriented outcomes. This novel study also shed light on the topic of APs as adjunct sedatives, which has only previously been discussed in one publication. The findings of this study have been shared with practitioners within our MICU, but we feel that this information should also be shared broadly to encourage others to assess indications for AP use in their critically ill patient populations.

CONCLUSION

Overall, these findings are an important contribution to practice at our institution as it relates to AP use and to the limited literature available describing the off-label use of APs as adjunct sedatives. The use of APs did not result in a clinically significant change in continuous infusion sedative and opioid requirements in the 24 h following initiation in mechanically ventilated adults with or without delirium. Clinicians in the ICU should reassess the indication and utility of APs in their patients frequently and should consider discontinuation if the AP is being used for an indication outside of ICU delirium. Future studies that examine the effects of APs on sedation prospectively using a standardized sedation approach would be useful as would studies assessing the changes in PADIS management of patients before and after the COVID-19 pandemic.