Preventing ICU Subsyndromal Delirium Conversion to Delirium With Haloperidol

Delirium occurs in up to 50% of patients who are not mechanically ventilated and up to 80%
of intensive care unit (ICU) patients who are mechanically ventilated. Even after
controlling for preexisting morbidities, severity of illness, coma and use of sedatives,
patients who develop delirium in the ICU are more than 3-times as likely to be dead at 6
months compared to those patients who do not develop delirium. (1-4) Additionally, ICU
delirium is predictive of a threefold-higher reintubation rate and > 10 additional days in
the hospital. (5) Each additional day of mechanical ventilation places patients at increased
risk for life-threatening sequelae such as ventilator-associated pneumonia and barotrauma.
The sequelae of delirium are cumulative; for example, each additional day spent in delirium
is associated with a 20% increased risk of prolonged hospitalization and a 10% increased
risk of death. Given these negative outcomes, it is not surprising that delirium is
independently associated with substantially higher ICU and total hospital costs than for
patients who do not develop delirium. (6) Up to a quarter of patients who develop delirium
in the ICU develop long-term cognitive impairment that frequently manifests as dementia.
(7-10) This post-ICU long-term cognitive impairment affects memory, attention, and executive
function. It therefore compromises the ability to return to work, impairs activities of
daily living, increases the need for institutionalization, and decreases quality of life.
(11-13) More than 5,000,000 patients are admitted to an ICU in the United States each year.
Delirium may develop in up 80% of these patients. (1, 2, 14) It is therefore critical that
interventions that can prevent delirium from occurring in the ICU be discovered.

Given the negative sequelae of delirium, current practice guidelines recommend routine
delirium screening in the ICU with a validated screening tool such as the confusion
assessment method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist
(ICDSC). (15-17) The ICDSC (Appendix 1) is an 8-item checklist producing a score between 0
and 8, where each item (corresponding to a value of 1 out of 8) reflects a DSM-IV (or
alternative) diagnostic characteristic of delirium and has many advantages over the CAM-ICU.
(15, 16, 18) The data are collected in real-time during each nursing shift. An ICDSC score ≥
4 has been shown to highly correlate with a formal psychiatric diagnosis of delirium using
DSM-IV criteria (sensitivity 99%, ROC curve area = 0.901), and has excellent inter-observer
reliability between nurses and between nurses and critical care physicians.

Recent investigations, both within and outside of the ICU, have moved beyond simply
assigning patients the dichotomous outcome of either being delirious or not, and instead
focused on grading the severity of delirium. (19, 20) Patients who have some of the
characteristics of delirium, but not full clinical delirium, are deemed to have subsyndromal
delirium.[10] The ICDSC, given that its 8 different domains have each been shown to have
good item reliability towards the diagnosis of delirium, allows one to identify those ICU
patients that fall short of the threshold diagnostic criteria for overt or 'clinical
delirium' but who still may have clinically important sub-syndromal delirium (ie. an ICDSC
of 1-3). (19)

One recent ICU study compared the outcomes of patients who developed sub-syndromal delirium
(ICDSC 1 to 3) over the course of their ICU stay to those who developed delirium (ICDSC ≥ 4)
or who developed neither delirium or subsyndromal delirium (ICDSC = 0). In their study of
537 consecutive, non-comatose patients, 31.5% developed neither clinical delirium or
subsyndromal delirium, 33.3% developed subsyndromal delirium (but not clinical delirium) and
35.3% developed clinical delirium. Patients who developed subsyndromal delirium had an ICU
mortality rate that was more than 4x greater than patients who developed neither clinical
delirium or subsyndromal delirium (10.6% vs 2.4%, p=0.002). In addition, the patients who
developed subsyndromal delirium, when compared to those patients without clinical or
subsyndromal delirium, had both significantly longer ICU and hospital lengths of stays and
were more likely to be discharged to a long-term care facility than home.

When correction of the potential causative factors for delirium fails to reverse delirium,
clinicians frequently turn to antipsychotic therapy. (21) Haloperidol remains the first-line
pharmacologic therapy for the treatment of delirium by critical care clinicians and is
advocated for use in this population by practice guidelines. (14, 22) One large
retrospective cohort analysis, where potential confounding variables were addressed, found
that use of haloperidol within 2 days of mechanical ventilation reduced death. (23)

Two recent studies demonstrate the benefit of antipsychotic therapy in non-ICU patients at
high risk for developing delirium. (23, 24) In one randomized study of elderly patients
undergoing hip surgery, a population at high risk for developing delirium, administration of
oral haloperidol 0.5mg q8h decreased the average Delirium Rating Scale (DRS) Score (14.4 ±
3.4 vs 18.4 ± 4.3, p < 0.001), the duration of delirium (5.4 vs 11.8 days, p < 0.001) and
the mean number of days in the hospital (17.1± 11.1 vs 22.6 ± 16.7, p < 0.001). No
haloperidol-related side effects were noted. (23) A more recent placebo-controlled study
demonstrated that the post-operative administration of a single dose of risperidone in
patients undergoing coronary artery bypass surgery decreased the incidence of delirium from
31.7% to 11.1% (p= 0.009). (24) It should be noted that neither of these studies enrolled
ICU patients and the incidence of subsyndromal delirium at baseline was not measured.

The safety and efficacy of treating ICU patients with delirium symptoms with antipsychotic
therapy has not been evaluated. Recent data highlights the deleterious sequelae of
subsyndromal delirium in the ICU. In addition, the results of two studies demonstrate the
benefits of administering low-dose antipsychotic therapy in patients at high risk for
delirium. We therefore hypothesize that treatment of subsyndromal delirium in the critically
ill with haloperidol will prevent progression to clinical delirium. This should be
associated with decreased agitation, a shorter duration of mechanical ventilation, and
improved cognitive function after ICU discharge. Given the documented safety of low-dose
haloperidol therapy in clinical practice, we anticipate the potential risk-benefit ratio for
this intervention to be low - particularly in an ICU environment where patients receive
continuous cardio- respiratory monitoring.

Critically ill patients with subsyndromal delirium (ICDSC 1-3) are also at risk for
substantial morbidity and mortality and are at high risk for developing delirium (ICDSC ≥
4). Recent studies suggest that the administration of low-dose antipsychotic therapy to
non-ICU patients at risk for delirium prevents transition to delirium, reduces delirium
severity and shortens length of hospital stay without causing adverse effects. Given that up
1.5 million Americans may develop subsyndromal delirium each year, an intervention that is
found to be safe and effective, particularly if it is of low cost, will have a profound
impact on the U.S. healthcare system.

A subsyndromal risk factor study evaluated ICSDC nursing assessment data for 100 consecutive
mechanically ventilated patients admitted to the ICU at Tufts MC for ≥ 24 hours without a
neurologic reason for admission (e.g., acute stroke) or having acute alcohol withdrawal. Of
the 100 patients, 72 developed subsyndromal delirium (ICDSC 1 to 3). Of these 72 patients,
26 (36%) went on to develop delirium (ICDSC ≥ 4) during their ICU admission. The remaining
28 patients developed neither subsyndromal delirium or delirium over the course of their ICU
stay. For the 26 patients who developed delirium, we found that only 2 of the patients
received ≥ 1 dose of haloperidol therapy in the period prior to when delirium was first
identified. In contrast, for the 46 patients with subsyndromal delirium who did not progress
to delirium, 14 of these patients received ≥ 1 dose of haloperidol during their ICU stay.
Therefore, there was a weak association for a lower incidence of delirium in those patients
with subsyndromal delirium who received ≥ 1 dose of haloperidol at any time during their ICU
admission than patients who did not receive haloperidol [2/16 (12.5%) vs 24/56 (43%), p <
0.0001]. This retrospective, observational data suggests that patients with subsyndromal
delirium who are exposed to haloperidol may remain in subsyndromal delirium and not progress
to delirium. However, there are many methodological limitations with this pilot study thus
it remains unknown if administering low-dose haloperidol to ICU patients with subsyndromal
delirium will prevent the development of delirium.

Over the past 3 years, our delirium research group, a joint collaboration between
Northeastern University and Tufts Medical Center has conducted a number of studies
surrounding the identification and treatment of delirium in the ICU environment. (18, 26-29)
A three-hospital evaluation lead by our group found that an educational intervention
consisting of both patient cases using script concordance theory and a didactic presentation
improved the ability of the bedside nurse to use the ICDSC correctly and to recognize
delirium when compared to a judge. (26) Another study our group conducted found physician
use of the ICDSC improves their ability to recognize delirium compared to a validated judge.
(27) A large regional survey focusing on critical care nurse preferences and practices
regarding delirium assessment compared delirium assessment practices to those for sedation
assessment. (28) Finally, our group concluded a 36 patient double-blind randomized
controlled trial evaluating the use of quetiapine for the delirium treatment in the ICU that
was recently published in Critical Care Med. (29) The track record of our research group is
important given the many challenges of implementing an ICU delirium-focused investigation
such as the one that we have proposed. We therefore feel that we are qualified to conduct
the study we have proposed to evaluate the safety and efficacy of haloperidol therapy in
critically ill patients with subsyndromal delirium.

This prior data and our experience conducting delirium research demonstrate:

1. That progression to delirium may be lower in patients with subsyndromal delirium who
receive haloperidol.

2. Our ability to conduct high quality research in the field of ICU delirium.

3. A multidisciplinary ICU delirium research group that includes a psychiatrist.

4. An academic environment where delirium assessment with the ICDSC has become a standard
of care.

Delirium occurs in up to 80% of mechanically ventilated patients admitted to the intensive
care unit (ICU). (1-4) Patients who develop delirium are more likely to die, stay in the ICU
longer and cost the healthcare system more. (1-6) Moreover, delirium may cause cognitive
dysfunction that persist long after recovery and impact long-term functional ability and
quality of life. (7-10) Given that more than 5 million patients are admitted each year to an
ICU in the United States, delirium in the critically ill is a major health care issue.
Patients who meet some but not all of the Diagnostic and Statistical Manual of Mental
Disorders (DSM) IV criteria for delirium are deemed to have subsyndromal delirium. (19)
Patients who develop subsyndromal delirium are also more likely to die in the ICU and
require a higher level of care after ICU discharge. (19) Current practice guidelines
recommend routine delirium screening in the ICU using a validated tool such as the Intensive
Care Delirium Screening Checklist (ICDSC). (14, 22) Delirium often persists despite the
reversal of causative factors thereby necessitating the use of pharmacologic therapy.
Haloperidol remains the pharmacologic treatment of choice for delirium in the ICU and its
use has been associated with lower ICU mortality. (23) However, its potential role in
preventing the conversion of subsyndromal delirium to delirium is unknown. In this study we
plan to determine whether the treatment of subsyndromal delirium in the critically ill with
haloperidol prevents progression to delirium without causing adverse effects.

Accomplishing these aims will determine if a pharmacologic intervention, haloperidol, can be
routinely used in critical care practice to prevent patients with subsyndromal delirium from
developing clinical delirium. If haloperidol is found to be safe and effective in the
proposed study, larger studies will be needed to determine the effect of haloperidol therapy
on patient mortality and evaluate predictors for drug response. Information from the
proposed study is greatly needed to determine if there is a safe and effective
pharmacological intervention for the estimated 1.5 million Americans each year who develop
subsyndromal delirium in the ICU.

Survivors of critical illness who develop delirium may experience prolonged cognitive
impairment and decline, decreased functionality and may suffer significant anxiety and
depression. Sleep disturbance is a common factor in patients with delirium and is known to
contribute to impaired function. Hence, a strategy that aims to reduce the incidence of
delirium in the ICU may improve both short and long-term outcomes.

Neurocognitive deficits persist in up to 75% of ICU patients 6-12 months after ICU discharge
and presumably may be higher in ICU patients who develop delirium (30). Cognitive deficits
are global (31-33), including deficits in processing speed, memory, and attention. (31)
Hopkins concludes that the most consistent deficit across studies is decreased memory. (30)
This pattern of deficits, as well as the consistent findings of impaired social and
occupational functioning in ICU survivors (32, 34) suggests impaired executive function.
Executive function refers to the capacity to plan, initiate, organize, inhibit, and monitor
thought and behavior. It is a pattern of impairment which is thought to represent diffuse
frontal lobe damage. Executive function is typically poorly assessed in medically ill
patients and yet has potentially substantial impact on overall functioning. Functional
incapacity includes everyday issues such as difficulty buying groceries, keeping
appointments or adhering to medication regimens. (34, 35) For geriatric patients treated in
the ICU, only 3% have normal post-ICU functional capacity. (36) It remains unclear if there
is a change in anxiety and depressive symptoms among patients who develop delirium and those
that do not.

Delirium will worsen functional ability and it is suspected that it will also worsen
emotional well being, although it is not well established whether this is the case. Given
the deleterious effects that delirium may have on functional status, it is therefore
important to measure physical status, social functioning, mental health and general health
perception between between patients exposed to an intervention that may decrease the
incidence of delirium. Sleep disturbance is a risk factor for neurocognitive impairment and
is a prominent component of delirium. (37) Thus disturbed sleep is understood as both a
potential cause and a consequence of ICU-related psychological and cognitive morbidity.
Since psychological morbidity often persists after ICU discharge, it is likely that
disturbed sleep is frequent during post-ICU hospitalization. An intervention focused on
reducing delirium incidence will affect post-ICU sleep quality.

Inclusion Criteria:

- Age 18-84 years old

- Subsyndromal delirium (ICDSC of 1-3)

- Mechanically ventilated

- No objection from the MICU, CCU, or SICU service attending MD for enrollment

- Admitted to the MICU, CCU, or SICU service at Tufts Medical Center

- Patients is expected by their ICU attending physician to require admission to the ICU
for ≥ 24 hours

Exclusion Criteria:

- Pregnancy

- Delirium (ICDSC ≥ 4)

- History of severe dementia or an Informant Questionnaire on Cognitive Decline in the
Elderly (IQCODE)) score ≥ 4

- IQCODE is not able to be completed.

- Current treatment with donepezil (aricept), tacrine (cognex), rivastigmine (exelon),
or memantine (namenda)

- Admitted with a neurologic diagnosis (e.g., CVA)

- Past diagnosis of schizophrenia or a formal thought disorder as defined by DSM IV
criteria.

- Treatment with an antipsychotic agent in the 30 days prior to ICU admission

- Current treatment with a neuromuscular blocker or dexmedetomidine

- A patient requiring a level of sedation equivalent to a sedation-agitation scale
(SAS) score ≤ 2

- Inability to conduct valid ICDSC assessment (e.g., coma, deaf)

- Acute alcohol or drug withdrawal

- Acute drug overdose

- Severe encephalopathy

- History of end stage liver failure (based on presence of ≥ 1 or more of the
following: AST/ALT ≥ 2 times ULN, INR ≥ 2, total bilirubin ≥ 1.5

- Patients with a baseline QTc interval >/= 500 msec or an elevation >/= 60mmHg above
baseline

- Current drug therapy with a class Ia, Ic or III antiarrhythmic other than amiodarone.

- History of haloperidol allergy

- History of neuroleptic malignant syndrome.

- Patients expected to die within 24 hours

- Inability to obtain informed consent

- Current participation in another research study.

- Lack of permission of the patient's primary MICU service attending physician for
participation in the study.

- Current employment at Tufts Medical Center.

- Age ≥ 85 years.