Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study

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)