Hyperactive Delirium, Mixed Delirium
Conditions
Keywords
Hyperactive delirium, Mixed delirium, Anti-psychotic, Haldol, Valproic Acid
Brief summary
Delirium is the most often encountered psychiatric diagnosis in the general hospital, with incidence up to 85% in the intensive care unit (ICU) setting and with significant consequences on patients' morbidity and mortality. Currently, although not FDA approved, antipsychotics are often considered the first-line pharmacological treatment. However, there can be limitations to their use, including side effects or lack of efficacy. Valproic acid (VPA) is one of the alternatives at times used in such patients which from limited case series data appears to be helpful and tolerated. VPA can provide relief from agitation that poses a threat to the safety and recovery of the patient. Moreover, mechanistically it addresses the neurochemical and cellular abnormalities inherent in delirium (it has NMDA-antagonist, anti-dopaminergic, GABAergic,anti-inflammatory, anti-apoptotic, and histone deacetylase inhibitor properties, among others). The purpose of this study is to evaluate the efficacy and tolerability of the VPA in the first known to us randomized controlled trial.
Detailed description
The investigators plan to investigate the efficacy and tolerability of scheduled VPA as compared to placebo with as needed basis (PRN) haloperidol (as a back-up in both arms) for treatment of hyperactive or mixed delirium. Patients will be randomized to scheduled VPA or placebo (normal saline) and both arms will have flexible PRN dosing of haloperidol. Thus, the investigators plan to learn the time to delirium resolution in patients treated with VPA versus placebo; percentage of patients responding to VPA versus placebo; tolerability of VPA versus placebo. If addition of scheduled VPA proves to shorten time to delirium resolution as compared to placebo, lead to less use of haloperidol, and/or have fewer side effects, it would provide a very important addition to our limited evidence-based repertoire of delirium treatment. Moreover, this pilot study would then pave the way for the bigger randomized control trial powered to detect its effect size.
Interventions
DRUGValproic Acid
1\. Start: VPA PO/NGT 500 mg BID 2\. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1000 mg PO/NGT QHS 3\. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1500 mg PO/NGT QHS 4.If need to increase in 24 or more hours: VPA 500 mg PO/NGT Q am, 2000 mg PO/NGT QHS
DRUGPlacebo
Placebo 500 mg matched to VPA BID PO/NGT
DRUGHaloperidol
Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* patients 18 years of age and older * admitted to surgical ICU * diagnosed with hyperactive or mixed delirium
Exclusion criteria
* hypoactive delirium * primary team does not think patient is appropriate to participate * no oral access (PO or NGT) * non-English speaking * contraindication to study medications * pregnant women or woman of child-bearing age not on documented contraception * QTc = or greater than 480 * hepatic dysfunction * decreased platelets or platelet dysfunction * bleeding disorder, current major bleeding * history of NMS, epilepsy, or PD * diagnosis of schizophrenia, bipolar disorder or schizoaffective disorder * on warfarin or carbapenems * delirium due to alcohol withdrawal * treated with antipsychotics for more than 48 hours prior to study enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Delirium Resolution | Up to 5 days | Delirium resolution was defined as three negative Confusion Assessment Method (CAM) assessments, performed by nurses every 12 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Use of as Needed Anti-psychotic Agent | Up to 5 days | Amount of Haldol administered. |
| Side Effects From Medications | Up to 5 days | Side effects may have included liver function test (LFT) increase, platelet decrease, bleeding, or QTc prolongation. |
| Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale | Up to 5 days | The items include the assessment of: (1) consciousness ( deep sedation/coma, agitation, normal wakefulness, or light sedation); (2) inattention; (3) disorientation; (4) hallucination, delusion, or psychosis; (5) psychomotor agitation or retardation; (6) inappropriate speech or mood; (7) sleep-wake cycle disturbances; and (8) fluctuation of symptomatology. The maximum score is eight; scores of ≥4 indicate the presence of delirium and score zero is indicate not in delirium. Each item is scored 0-8. |
| Length of ICU Stay | During expected average hospitalization (of 1 month) | — |
| Length of Hospital Stay | During expected average hospitalization (of 1 month) | Participation in the study ended once delirium was resolved and the patient was off study drug. This outcome presents the total length of hospital stay, which may have been longer than participation in the study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valproic Acid Participants received VPA and flexible haloperidol as needed. | 1 |
| Placebo Participants received VPA placebo and flexible haloperidol as needed. | 2 |
| Total | 3 |
Baseline characteristics
| Characteristic | Valproic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 0 / 1 | 1 / 2 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 |
Outcome results
Primary
Time to Delirium Resolution
Delirium resolution was defined as three negative Confusion Assessment Method (CAM) assessments, performed by nurses every 12 hours.
Time frame: Up to 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Time to Delirium Resolution | 2 days | — |
| Placebo | Time to Delirium Resolution | 1.5 days | Standard Deviation 0.7 |
Secondary
Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale
The items include the assessment of: (1) consciousness ( deep sedation/coma, agitation, normal wakefulness, or light sedation); (2) inattention; (3) disorientation; (4) hallucination, delusion, or psychosis; (5) psychomotor agitation or retardation; (6) inappropriate speech or mood; (7) sleep-wake cycle disturbances; and (8) fluctuation of symptomatology. The maximum score is eight; scores of ≥4 indicate the presence of delirium and score zero is indicate not in delirium. Each item is scored 0-8.
Time frame: Up to 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale | 5 score on a scale | — |
| Placebo | Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale | 4 score on a scale | Standard Deviation 2.7 |
Secondary
Length of Hospital Stay
Participation in the study ended once delirium was resolved and the patient was off study drug. This outcome presents the total length of hospital stay, which may have been longer than participation in the study.
Time frame: During expected average hospitalization (of 1 month)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Length of Hospital Stay | 4 days | — |
| Placebo | Length of Hospital Stay | 8 days | Standard Deviation 8.5 |
Secondary
Length of ICU Stay
Time frame: During expected average hospitalization (of 1 month)
Population: Data were not collected for this outcome
Secondary
Side Effects From Medications
Side effects may have included liver function test (LFT) increase, platelet decrease, bleeding, or QTc prolongation.
Time frame: Up to 5 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Valproic Acid | Side Effects From Medications | Bleeding | 0 Participants |
| Valproic Acid | Side Effects From Medications | LFT increase | 0 Participants |
| Valproic Acid | Side Effects From Medications | Platelet decrease | 0 Participants |
| Valproic Acid | Side Effects From Medications | QTc prolongation | 0 Participants |
| Placebo | Side Effects From Medications | QTc prolongation | 1 Participants |
| Placebo | Side Effects From Medications | Bleeding | 0 Participants |
| Placebo | Side Effects From Medications | Platelet decrease | 0 Participants |
| Placebo | Side Effects From Medications | LFT increase | 0 Participants |
Secondary
Use of as Needed Anti-psychotic Agent
Amount of Haldol administered.
Time frame: Up to 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Use of as Needed Anti-psychotic Agent | 0 mg | — |
| Placebo | Use of as Needed Anti-psychotic Agent | 1 mg | Standard Deviation 1.2 |