Preventing ICU Subsyndromal Delirium Conversion to Delirium With Haloperidol
Condition: Subsyndromal Delirium
MeSH terms: Delirium
Study type: Interventional
Phase: Phase 4

Summary: 
      About one-third of the patients who develop mild, acute confusion (i.e., subsyndromal
      delirium) will go on to develop a severe acute confusional state (i.e. delirium). Delirium
      refers to a temporary change in the way a person thinks about things. Delirium occurs in
      patients admitted to the hospital particularly those patients that are very sick, who are
      given a number of medications, and who are not able to sleep normally. It affects their
      behavior, their understanding of the people and things around them, and their ability to make
      decisions. While ICU doctors do everything possible to eliminate the factors that may cause
      delirium, delirium may cause a person to become very agitated which if not controlled is
      dangerous to their safety as well as the safety of those around them. As well, if delirium
      develops in patients in the ICU, it may increase the risk for death, keep patients in both
      the ICU and hospital for longer and send patients to a long term care facility rather than
      home after they are discharged from the hospital. A recent medical report found that patients
      in the ICU who develop subsyndromal delirium have a mortality rate, a length of stay in both
      the ICU and the hospital, and a transfer rate to a long term care facility that is nearly as
      great as patients with delirium and greater than patients who develop neither subsyndromal
      delirium or delirium. Recent studies in non-ICU patients suggest that if a patient who is at
      high risk for developing delirium receives a medication called an antipsychotic (e.g.
      haloperidol) they may not be as likely to develop delirium or if they do develop delirium it
      will not last as long. No studies have evaluated the effect of administering an antipsychotic
      in patients in the ICU who have subsyndromal delirium. Another study completed in the ICUs at
      Tufts Medical Center found that there may be an association between the development of
      delirium in patients with subsyndromal delirium and the use of haloperidol. However, this
      small study had many limitations and thus it is not currently known whether using haloperidol
      in patients with subsyndromal delirium will actually cause fewer of these patients to develop
      delirium. Haloperidol makes a person sleepy and helps control behavior like agitation.
      Haloperidol is the drug that is used most often to help control delirium in the ICU. This
      prospective, double-blind, randomized controlled study will determine if haloperidol
      administered through the vein four times daily (1mg IV q6h) to patients who have subsyndromal
      delirium, and who are on a breathing machine and being cared for by the Medical ICU service
      at Tufts Medical Center, will help prevent patients from developing delirium. A total of 68
      participants will be enrolled. Exclusion criteria are extensive and include conditions that
      could affect the ability to determine if delirium is present or increase the risk for side
      effects related to the administration of haloperidol. Patients older than 80 will be excluded
      from the study. Study medication (i.e. haloperidol) will be administered until one the
      following occurs: 1) delirium develops (that is confirmed by a staff psychiatrist or his
      designate, 2) the patient is discharged from the ICU at Tufts Medical Center, 3) the patient
      has received haloperidol or placebo for 10 days or 4) an adverse event potentially
      attributable to the study drug is experienced by a patient that is deemed, in the opinion of
      a pulmonologist member of the investigative team to warrant discontinuation of therapy.
      Haloperidol may cause unwanted side effects such as low blood pressure, twitching, and an
      unsafe abnormal heart rhythm. Patients with chronic confusion (e.g., a dementia such as
      Alzheimer's Disease) should not receive haloperidol and will not be included in this study.
      Patients will be carefully monitored for side effects that are potentially related to
      haloperidol. Patients who become confusion-free in the ICU before they leave the ICU (i.e.,
      have no subsyndromal delirium) will be asked to provide consent for all research activities
      that occured in the ICU. If patients where cognition is regained (ie. no subsyndromal
      delirium or delirium) are not willing to provide consent then any study data collected from
      them while they were in the ICU will be destroyed and they will not be approached to
      participate in the post-ICU component of the study. This study also seeks to understand how
      the use of haloperidol in the ICU in patients with subsyndromal delirium may have affect
      memory, emotional status, happiness, ability to function, and quality of sleep in patients
      after they leave the ICU. Patients (that do not have delirium based on CAM screening at the
      time the 3-10 day and 6 month assessments are attempted) will be approached to participate in
      this post-ICU component of the study.
    

Detailed description: 
      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.
    

Intervention name(s): Haloperidol decanoate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): IV q6h.
Study drug will be continued until one of the following study withdrawal/termination criteria is met:
Delirium (ICDSC ≥ 4) develops. The diagnosis of delirium will be confirmed in all instances by the Psychiatric Consultation Service, Division of Psychiatry, Tufts Medical Center using DSM-IV criteria.
The patient is discharged from the ICU at Tufts MC.
10 days of study drug administration occurs.
The subject experiences an adverse event potentially attributable to the study drug that is deemed, in the opinion of one of the physicians on the study team or the MICU team, to warrant discontinuation of therapy.; D5W 0.2mL IV q6h
Study drug will be continued until one of the following study withdrawal/termination criteria is met:
Delirium (ICDSC ≥ 4) develops. The diagnosis of delirium will be confirmed in all instances by the Psychiatric Consultation Service, Division of Psychiatry, Tufts Medical Center using DSM-IV criteria.
The patient is discharged from the ICU at Tufts MC.
10 days of study drug administration occurs.
The subject experiences an adverse event potentially attributable to the study drug that is deemed, in the opinion of one of the physicians on the study team or the MICU team, to warrant discontinuation of therapy.
Other intervention name(s): Haldol
Intervention MeSH terms: Haloperidol; Haloperidol decanoate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: subsyndromal delirium; delirium; haloperidol; antipsychotic; randomized controlled trial; placebo-controlled; intensive care unit; critical care; subsyndromal delirium in the intensive care unit