By: Zachary Moszczenski, PharmD; PGY1 Pharmacy Resident (2019-2020)
Mentor: Jackie A. Harris, PharmD, BCPS, Christian Hospital – St. Louis, MO
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The use of anti-psychotics to treat delirium has been a controversial topic in recent years, owing to the short supply of high-quality trials and a shift in guideline recommendations. However, the debate started earlier in the beginning of the millennium when we began to ask ourselves: does what we’ve simply been doing for years actually work?
Anti-psychotics certainly made logical sense, as the symptoms of delirium largely mimic psychoses and other symptoms associated with cognitive disorders such as schizophrenia, and non-controlled studies along with expert opinion supported their use. We certainly wanted and felt the obligation to do something about delirium, as it not only can cause significant distress to the patient, family, and caregivers but also is associated with detrimental outcomes, as we’ll discuss. The difference/problem of anti-psychotic use for delirium is that it’s the result of a non-cognitive cause, whether it be a disease state, medication(s), severity of illness, and other factors. Additionally, the course and resolution of the delirium is heavily related to the presence or resolution/absence of the causative factor. Delirium can also be quite subjective in its presentation and assessment (it’s not as easy to assess as blood pressure!).
Since there were not any trials that directly compared anti-psychotics to placebo, the above-mentioned question was starting to and continues to be asked: is treating these patients with anti-psychotics actually doing anything? We’ll address that question in this review of the literature, while also giving an overview of delirium.
What is Delirium?
Before we dive into the available data, it’s important to understand exactly what delirium is and how it can present differently. According to the DSM-V, delirium is a state of attentional, cognitive, and emotional disturbances with or without psychomotor hyper and/or hypo activity.1 It occurs outside of a coma/significantly reduced state of arousal, which may seem like common sense, but it is an important distinction. Disturbances cannot be evident if a patient is too sedated or comatose to show hardly any function at all. This becomes relevant if we overly sedate a patient. They’re technically no longer showing signs of delirium, but we now have another problem on our hands and most likely just not able to tell if we’ve gotten rid of the delirium. The delirious state also differs from baseline mentation/behavior, develops over hours/days, fluctuates throughout the day, and as mentioned above, is not due to another cognitive disorder. There also has to be at least some evidence of another offending medical state or substance, which is essentially never an issue with our critically-ill ICU patients. A higher severity of illness is strongly related to the incidence of delirium, but the copious amount of delirium-inducing agents (opioids, benzodiazepines, steroids, etc.) that these patients commonly receive likely play a larger role.2,3 Simply laying in a bed in the same room for days to weeks at a time certainly doesn’t help either (which is something society as a whole started to understand while on quarantine during the COVID-19 epidemic).
It is also important to distinguish the different types of delirium, as we’ll see, which are described in Table 1.
The hyperactive subtype is easier to identify, though when we screen correctly, it’s easy to see how hypoactive could be more commonly diagnosed.2 SSD is not quite considered clinical delirium and is often not distinguished in comparative trials, though it has been linked with undesirable outcomes in the literature.4
The Problem with Delirium
Depending on the estimate, which is related to how well and often an institution screens for delirium, the prevalence in the ICU can range from 16% to 80% of patients.2 The older and sicker the patient, the higher the risk of delirium, which also tends to exhibit within 48 hours of ICU admission.5 Delirium is also touted to cost the US healthcare system up to an estimated $16 billion annually,2 largely due to the complications associated with delirium listed in Table 2.
Due to these significant complications, it is important to appropriately screen for and diagnose delirium. There are currently two bedside scales recommended by the 2018 Society of Critical Care Medicine (SCCM) Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guidelines for diagnosing delirium.3 The first and most commonly used scale in the US is the Confusion Assessment Method for the ICU, or the CAM-ICU (Table 3).
This is cousin to the Intensive Care Delirium Screening Checklist, or ICDSC, which is relatively more popular in Canada and other countries. The presence of 4 or more of the symptoms listed in Table 4 will get you a positive diagnosis of delirium.7
Note the differences. The CAM-ICU is potentially more convenient, while the ICDSC is perhaps more useful in distinguishing between hyperactive and hypoactive delirium on its own. Both scales rely on the Richmond Agitation and Sedation Scale (RASS) to measure level of consciousness, ranging from -5 (unresponsive) to +4 (combative). The RASS can be combined with the CAM-ICU to differentiate hyper and hypoactive delirium. It is important to note that both only screen for the presence of delirium, as a higher score does not indicate severity or worse prognosis. Once again, both are recommended for use, with neither one preferred over the other.3
First, we start with our non-pharm methods for managing delirium, which have shown the most positive data and are subsequently the only interventions recommended for the treatment of delirium by the PADIS guidelines.3 These methods are also recommended for the prevention of delirium, though the focus of this review is on treatment only. “ABCDE” is the acronym describing the non-pharm bundle of strategies used in the guidelines, and the components are listed in Table 5. There are various methods used to meet this bundle of interventions, such as sedation vacations, proper sleep hygiene, cognitive stimulation, music, using hearing aids and glasses, etc., but the goal is to address all of them if possible.3
Aside from anti-psychotics, many other agents and classes of agents have been trialed for the treatment of delirium, such as statins, acetylcholinesterase-inhibitors, and ketamine due to their mechanisms of action and theorized pathophysiology of delirium, but none have had great success or are recommended.3 The possible exception is dexmedetomidine, which can be useful for delirium when trying to wean sedation, and it actually is recommended by the PADIS guidelines specifically for agitation preventing extubation (not for routine/general use for delirium).3 The focus then shifts back to anti-psychotics where the main controversy lies, as no agent is FDA-approved for the treatment of delirium. As stated earlier, this controversy was ramped-up by a change in the SCCM guidelines in 2018 not recommending their routine use, which is summarized in Figure 1.
There is an important caveat that is often overlooked, as the 2018 edition also states that “patients who experience significant distress secondary to symptoms of a delirium such as anxiety, fearfulness, hallucinations, or delusions, or who are agitated and may be physically harmful to themselves or others, may benefit from a short-term course of haloperidol or an atypical anti-psychotic”.3 That description paints a picture of hyperactive delirium, and so that is why it is important to distinguish the subtype when determining whether or not a patient would potentially benefit from therapy.
The reasoning behind the recommendation in Figure 1 is that the lack of proven benefit is out-weighed by the potential risk of harm/side effects. So then, the first question is one of efficacy, which can only properly be answered by looking at the available randomized controlled trials (not trials of other anti-psychotics vs. haloperidol). The PADIS guidelines cite four such trials behind their reasoning, and so we’ll combine those (with the one exception of a trial comparing olanzapine to haloperidol from 2004)9 with other available controlled trials to evaluate the efficacy of anti-psychotics for the treatment of delirium.
Randomized Controlled Trials for Anti-Psychotics
The first controlled trial was in 2010, and it is known as the MIND-ICU study.10 It was primarily designed to test the feasibility of a placebo-controlled trial answering this question, which in fairness, is not so easy given the population, setting, ethical considerations, and the subjective nature of delirium. It also set out to see if anti-psychotics, haloperidol or ziprasidone, had a positive effect on days alive without delirium or coma in mechanically ventilated surgical and medical ICU patients. Patients received either haloperidol 5 mg (n=35), ziprasidone 40 mg (n=30), or placebo (n=36) every 6 hours for up to 14 days. Patients were also allowed as needed haloperidol based on provider discretion. No significant differences were found across the above primary outcome (p=0.66) or secondary outcomes, including mortality, ventilator-free days, length of stay, and others. Thus, this is chalked-up as a study against anti-psychotic use, though the trial had notable limitations, with one being an issue of power/actual sample size. Less than half of the patients had an actual diagnosis of delirium based on the CAM-ICU (delirium diagnosis was not required for inclusion). Non-pharm strategies discussed above were not documented as well.
The next trial is also from 2010 and evaluated quetiapine for the treatment of delirium in the ICU.11 The primary outcome was time to first resolution of delirium, and secondary outcomes included time spent in delirium along with the secondary outcomes listed above for the MIND-ICU trial that are common in all of the trials mentioned here. Patients received quetiapine (n=18) 50 mg every 12 hours, titrated to a max of 200 mg per dose per provider discretion, or placebo (n=18) for a max of 10 days. Patients were also allowed to receive open-label as needed anti-psychotics (an order for as needed haloperidol was an inclusion criterion). The treatment group did exhibit a significantly shorter time to resolution compared to placebo (1 vs. 4.5 days, p=0.001) and patients spent less total and percentage of time spent in delirium (36 vs 120 hrs, p=0.006; 53% vs. 69%, p=0.02). This, as we’ll see, is a rare positive result, though the use of as needed haloperidol, the same lack of documentation of non-pharm strategies, and the very small sample size limit the conclusions we could draw about quetiapine.
The HOPE-ICU trial in 2013 was the next hopeful study to try its luck at this question.12 It’s objective was to see if haloperidol had an effect on delirium and coma-free days alive in the first 14 days of ICU admission. Patients were included if they were mechanically ventilated within the first 72 hours, but as with the MIND-ICU trial, baseline diagnosis of delirium was not required. Thus, this borders on evaluating prevention rather than treatment, but it is one of the studies cited by the PADIS guidelines against treatment. Our purely treatment population is likely somewhere within the total study population as well. Patients received IV haloperidol (n=71) 2.5 mg or placebo (n=70) every 8 hours for a max of 14 days, with doses being decreased (but not increased) per provider discretion. Once again, open-label haloperidol was allowed. There was not a significant difference in the primary outcome (p=0.53), though fewer patients in the haloperidol group exhibited agitation (13% vs. 18%, p=0.0075). Also, more patients in the placebo group received open-label haloperidol (8 vs. 18, 95% CI: 0.20-0.94). This was another strike against anti-psychotics with a larger sample size relative to its predecessors, though it was not without its limitations including the afore-mentioned question of prevention vs. treatment, the potential under-dosing of haloperidol, and the common limitations of the previous trials.
Flowing further through time brings us a study in 2015 by Michaud et al. looking at quetiapine again and its effect on the duration of hypoactive delirium in ICU patients.13 This is the one study included that was retrospective; patients were matched with a historical control. Hypoactive delirium was defined as a positive CAM-ICU and a RASS score of 0 to-3. 52 patients that received quetiapine during their ICU stay were matched with 61 patients without any pharmacologic treatment for delirium. The dosing regimen was not provided. The mean duration of delirium was found to be significantly shorter in the quetiapine group (1.5 vs. 2.0 days, p=0.04). Additionally, in the treatment group, if quetiapine was administered within 24 hours of delirium diagnosis, patients spent less time in delirium (1 vs. 3.5 days, p<0.001) and exhibited less time to extubation (1.5 vs. 5 days, p=0.003). This is a potential positive finding for the real population in question (hypoactive), and patients were excluded if they received any other pharmacologic treatment for delirium (no as needed haloperidol). However, the retrospective nature, small-sample size, and lack of a dosing protocol make this more hypothesis generating rather than definitive evidence for the efficacy of quetiapine.
The last and most recent randomized trial is the MIND-USA trial from 2018.14 This highly anticipated study was published after the 2018 update to the PADIS guidelines, and so we can use it to supplement their recommendations. Similar to the MIND-ICU study, it also evaluated the effect of haloperidol and ziprasidone on delirium and coma-free days alive. Patients received either IV haloperidol 2.5 mg (n=192), IV ziprasidone 5 mg (n=190), or placebo (n=184) every 12 hours for a max of 14 days. Doses were titrated per provider discretion up to 20 mg daily for haloperidol and 40 mg daily for ziprasidone, while patients greater than 70 years old received half of the initial and max dose. In keeping with the other trials for haloperidol, no significant differences were seen for any of the primary (p=0.26) or secondary outcomes. Regarding study design, this likely the strongest trial available, due to its larger sample size, standardization and documentation of ABCDE non-pharm interventions, and more practical dose titration strategies. It is not without limitations, though. Open-label as needed anti-psychotics were also allowed, and if you’re scratching your head at IV ziprasidone, you’re not alone (approved for PO and IM use). The investigators needed IND approval from the FDA for this route of administration, and the determination that IV Ziprasidone is half as potent as IV haloperidol is certainly debatable.
A table summarizing the findings of the above trials is located in the Appendix for your reference. Based on these results, coupled with the guideline recommendations, it would appear quality evidence is lacking that supports the use of anti-psychotics. Regarding haloperidol, this notion is further supported by a meta-analysis in 2019 which showed no benefit for any our adverse clinical outcomes.15 Use of quetiapine remains quite popular due to the 2013 PADIS guideline recommendation for atypicals based on the above positive data for quetiapine. Any time spent in delirium can be more than a hindrance to all involved, and so the possibility of reducing delirium even by just half a day can be attractive. Its use for delirium refractory to non-pharm interventions may be reasonable based on the above studies, especially if dosed at night time if the patient is having sleep/wake cycle disturbances, though the available evidence just isn’t quite strong enough to fully recommend the routine use of quetiapine.
The Problem with Anti-Psychotics
We’ve answered (or at least addressed) the question of efficacy, and so the question of safety or potential harm remains. Anti-psychotics are by no means benign, and some common adverse effects are listed in Table 6. This list is by no means exhaustive, and some agents are associated with greater frequencies or cause more serious adverse effects than others.
Some of these effects are more associated with long-term use, and so we typically wouldn’t be concerned with short-term treatment for delirium. However, one institution estimated that nearly half of their anti-psychotic naïve ICU patients received anti-psychotics, and 24% of them were prescribed at discharge.17 These results are similar in other studies,18 and while inappropriate continuation can and should be addressed by more systematic interventions, long-term effects could still be considered when initiating therapy.
QTc prolongation can happen in the short-term and is a common concern, especially in our critically-ill cardiac patients. What’s interesting is that in all of the trials discussed above, no differences in QTc prolongation, or any adverse effects for that matter, were seen compared to placebo. A retrospective chart review in 2018 replicated these results with quetiapine, showing a mean baseline increase of just 2 msec in patients that received quetiapine for delirium.19 So, while it is certainly possible, QTc prolongation may not be as much of a concern as previously thought, especially for quetiapine. However, another previously non-associated adverse event may exist for quetiapine use in ICU patients. Recently, the concern for pulmonary complications has arisen for short-term use, with one retrospective review showing an increase in these complications for critically injured trauma patients that received quetiapine for delirium, which included respiratory failure and aspiration, bacterial and ventilator-associated pneumonia.20
Conclusions and Future Directions
The incidence of delirium in critically-ill patients is associated with significant morbidity and mortality. What is not always focused-on is the serious short and long-term psychological toll this disease state can have on patients, families, and caregivers, and so we should and have taken measures to combat this issue. Patients in the ICU should be routinely screened using guideline-recommended tools, especially if they are at higher risk, such as the elderly, more severely-ill, and patients receiving medications associated with the induction of delirium.3 We can use proven and recommended non-pharm interventions (the ABCDE bundle) to prevent and treat delirium, though when this fails, we often turn to anti-psychotics to mitigate the above complications. However, as we’ve seen, there is an absence of quality data supporting the efficacy of anti-psychotics for delirium, while the actual risks of short-term use are not as evident as once thought and are still under debate.
There may still be hope for the future, though. Haloperidol has failed to show any benefit, but does that mean all anti-psychotics won’t? Unlike other classes of medications, these agents can vary widely in their receptor profiles in affinity and activity, and so the failure of one does not necessarily rule-out the efficacy of another. Two controlled trials discussed above have shown a potential benefit with quetiapine, and while the results may not be strong enough to recommend the routine use of quetiapine, they are certainly promising. As it so happens, a clinical trial, aptly named the HALOQUET trial, evaluating quetiapine or haloperidol against placebo is ongoing in Canada (NCT01811459, ClinicalTrials.gov), and so this study and further research can help us better evaluate this agent. Other agents could potentially be evaluated as well. For example, cariprazine is a newer anti-psychotic that has shown benefit for the treatment of negative symptoms of schizophrenia (cognition, disorganized thoughts, blunted affect, etc.), which largely mimic symptoms of hypoactive delirium.21 While investigation of this agent for delirium is currently unlikely due to cariprazine still being brand name (VraylarÒ) and therefore expensive, it’s possible this and similar agents could be evaluated or developed in the future. Once again, the main issue is the lack of large controlled trials, and so further quality research will be the only remedy to the practitioner’s own delirium regarding this debate.