Delirium Recognition: In accordance with national guidelines , the study will identify delirium by using the RASS and the CAM-ICU on all patients who are admitted directly from the emergency room or transferred from other services to the ICU. Such assessment will be performed after 24 hours of ICU admission and twice daily until discharge from the hospital. As an initial step in conducting the CAM-ICU, the interviewer must assess the patient's sedation status to assure a valid CAM-ICU result. The CAM-ICU was validated using the RASS, and therefore this will be the sedation scale utilized for our study evaluation. RASS has excellent inter-rater reliability among adult medical and surgical ICU patients and has excellent validity when compared to a visual analogue scale and other selected sedation scales . The RASS requires 30-60 seconds to perform with minimal training and has been used by our local ICU team. The RASS is a 10-point scale that reflects the patient level of sedation as determined by their responses to verbal versus physical stimulation. A RASS score of -5 indicates a comatose state with lack of response to verbal or physical stimuli, a score of 0 represents alert and calm, and a score of +4 indicates a state of combative, violent behavior with immediate danger to staff, self, or others. A patient with a RASS score of -3 to +4 will be considered eligible to be assessed by the CAM-ICU to determine the presence of delirium .
The CAM-ICU will detect delirium among patients receiving ICU care at both the time of ICU admission and during their ICU stay. The CAM-ICU was chosen because of its practical use in the ICU wards, its acceptable psychometric properties, and based on the recommendation of national guidelines [4, 35]. The CAM-ICU score is determined by examining the patient for (a) acute and fluctuating changes in mental status, (b) inattention, (c) disorganized or incoherent thinking, and (d) altered level of consciousness. A CAM-ICU score is considered to be positive if the patient displays both a and b, plus c and/or d. The CAM-ICU diagnosis of delirium was validated against the DSM-III-R delirium criteria determined by a psychiatrist and found to have a sensitivity of 97% and a specificity of 92% . The CAM-ICU has been developed, validated and applied into ICU settings and multiple investigators have used the same method to identify patients with delirium [36–38].
Delirium Severity: Since the CAM-ICU does not evaluate delirium severity, we selected the Delirium Rating Scale revised-1998 (DRS-R-98) [39, 40] developed by Dr. Paula Trzepacz and colleagues. The DRS-R-98 was designed to evaluate the breadth of delirium symptoms for phenomenological studies in addition to measuring symptom severity with high sensitivity and specificity. It has been used in treatment, phenomenological and pathophysiological studies and has been translated into 12 languages. Characteristic symptoms include impairments of attention, short and long-term memory, visuospatial ability and orientation, perceptual and sleep-wake cycle disturbances, abnormalities of language and thought process and content, motor agitation and retardation, and mood lability. The DRS-R-98 is a 16-item clinician-rated scale with anchored items descriptions corresponding to both symptoms and temporal aspects of delirium. The severity scale has 13 items each rated from 0 to 3 where the sum has a maximum of 39 points, with higher scores indicating greater severity of delirium. Three additional items (rated from 0 to either 2 or 3) capture temporal course and attribution to an underlying etiology and when added to the sum of the 13 symptom items produce the DRS-R-98 total score that ranges from 0 to 46. The DRS-R-98 has excellent inter-rater reliability (intra-class correlation 0.97) and internal consistency (Cronbach's alpha 0.94) [39, 40].
The study will collect demographic and baseline functional information from the patient's legally authorized representative and/or caregivers. Cognitive function status will be obtained by interviewing the patient's legally authorized representative using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). IQCODE is a questionnaire that can be completed by a relative or other caregiver to determine whether that person has declined in cognitive functioning. The IQCODE lists 26 everyday situations where a person has to use their memory or intelligence. Each situation is rated by the informant for amount of change over the previous 10 years, using a Likert scale ranging from 1-much improved to 5-much worse. The IQCODE has a sensitivity between 69% to 100% and specificity of 80% to 96% for dementia .
Utilizing the electronic medical record system (RMRS), we will collect several data points of interest at baseline and throughout the study period. First, RMRS will allow us to collect reason for admission, severity of illness (APACHE II) , and the number of comorbid conditions (Charlson Comobidity Index)  for each patient enrolled in the study. We will also collect length of stay (both ICU and total hospital stay), mortality rate, and hospital-related consequences. We have previously defined hospital-related consequences to include: the number of patients with documented falls, use of physical restraints, injuries such as pulling out IV lines or urinary catheters, any ordered or observed re-intubation, and pressure ulcers. These will be assessed using the RMRS, direct daily observation, and retrospective review of the electronic medical record. This definition of delirium-related hospital complications has been previously used and published [44, 45].
Use of all medications, including focused intervention-related medications (anticholinergics, benzodiazepines, and haloperidol) will be monitored through the GOPHER computerized order entry system, as well as the McKesson medication administration system. The McKesson system is used at the patient's bedside and collects the administration of each medication. Additionally, McKesson is able to monitor medications administered as continuous infusions by documenting start times, stop times, and drip rates throughout the administration period.
In our study an adverse event will be defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. Adverse events will be collected after the subject has provided consent and enrolled in the study. If a subject experiences an adverse event after the informed consent document is signed (entry) but the subject has not started to receive study intervention, the event will be reported as not related to study drug. All adverse events occurring after entry into the study and until hospital discharge will be recorded. An adverse event that meets the criteria for a serious adverse event (SAE) between study enrollment and hospital discharge will be reported to the local IRB as an SAE. If haloperidol is discontinued as a result of an adverse event, study personnel will document the circumstances and data leading to discontinuation of treatment. A serious adverse event for this study is any untoward medical occurrence that is believed by the investigators to be causally related to study-drug and results in any of the following: Life-threatening condition (that is, immediate risk of death); severe or permanent disability, prolonged hospitalization, or a significant hazard as determined by the Data Safety Monitoring Board. Serious adverse events occurring after a subject is discontinued from the study will NOT be reported unless the investigators feels that the event may have been caused by the study drug or a protocol procedure. Investigators will determine relatedness of an event to study drug based on a temporal relationship to the study drug, as well as whether the event is unexpected or unexplained given the subject's clinical course, previous medical conditions, and concomitant medications.
Although haloperidol is widely used in treatment of delirium, it is not approved by the FDA for such use, and its efficacy in such treatment is not clear. Although our study employs a low dose (1.5 mg per day) of haloperidol for a short period of time (seven days), its potential adverse effects of QT prolongation and extrapyramidal symptoms (EPS) will be monitored during the study. The study will monitor for the following movement-related adverse effects daily through patient examination and chart review: dystonia, akathisia, pseudoparkinsonism, akinesia, and neuroleptic malignant syndrome. Study personnel will use the Simpson-Angus  and Barnes Akathisia  scales to monitor movement-related effects.