PD, POCD, Postoperative Cognitive Dysfunction, Postoperative Delirium
Conditions
Keywords
Postoperative Confusion, Postoperative Delirium, PD, Postoperative Cognitive Dysfunction, POCD
Brief summary
Elderly patients who undergo anesthesia and non-cardiac surgery are subject to deterioration of brain function including the development of postoperative delirium (PD) and postoperative cognitive dysfunction (POCD). These disorders cause disability, distress for both patients and their families, are associated with other medical complications and account for significant additional health care costs. We currently use relatively primitive approaches to preventing and treating PD and POCD. Dexmedetomidine is a drug used for sedation in critically ill patients that provides some pain relief and controls the bodies response to stress. The sedation produced by dexmedetomidine appears more similar to natural sleep than any other drug used for anesthesia and postoperative sedation. Data suggesting that dexmedetomidine can prevent delirium following cardiac surgery and the developing understanding of the causes of PD and POCD suggest that dexmedetomidine will be particularly effective.
Detailed description
Postoperative Delirium or PD and Postoperative Cognitive Dysfunction or POCD are syndromes of central nervous system dysfunction that significantly complicate the recovery of a proportion of elderly patients following surgery. Delirium is typically a transient syndrome characterized by a de-novo appearance of several pathognomonic behaviors, including disorientation, decreased attention span, sensory misperceptions, a waxing-and-waning type of confusion, and disorganized thinking. PD typically occurs on postoperative days 1 to 3 and is associated with prolonged hospital stays, increased risks for morbidity and mortality and significant health care expenditures. The neuroendocrine stress response to surgery, including the immediate postoperative period, remains an important potential etiologic factor. In particular, our data suggests that stress in the immediate postoperative period is poorly controlled by all anesthetic techniques and the normal diurnal variation in cortisol is suppressed in subjects who develop POCD. Dexmedetomidine is a highly selective alpha 2A agonist currently approved for sedation in the ICU. Dexmedetomidine produces analgesia, sympatholysis, and a light sedation characterized by easy arousal. Its action converges on the endogenous substrates for natural sleep to produce their sedative action, an effect that could prove beneficial to elderly postoperative patients. We hypothesize that treatment with dexmedetomidine will diminish both PD and POCD. The essential proposition is that modulation of perioperative stress can ameliorate perioperative delirium and cognitive dysfunction. Based on both the concept of cognitive reserve as well as clinical experience, there is concern that patients with preoperative cognitive impairment are particularly vulnerable to POCD. In general, such patients have been excluded from previous studies. This study is unique in that we will assess all participants for mild cognitive impairment prior to surgery. Assessment of the impact of preexisting cognitive impairment is a secondary aim. A broad goal of this interdisciplinary project is to evaluate POCD, which is primarily an anesthesia concept, in the more general context of dementing illness as explored by geriatric psychiatry.
Interventions
0.5/ug/kg/hr Dexmedetomidine infusions will begin prior to the surgery (no loading dose), and will be maintained at 0.5 mcg/kg/hour throughout surgery and titrated postoperatively for 2 hours postoperatively.
0.5/ug/kg/hr Placebo infusions will begin prior to the surgery (no loading dose), and will be maintained at 0.5 mcg/kg/hour throughout surgery and titrated postoperatively for 2 hours postoperatively.
Sponsors
Study design
Eligibility
Inclusion criteria
* 68 and older * elective major surgery under general anesthesia(major surgery is defined by a planned 2 day hospitalization) * ASA physical status I-III * capable and willing to consent * MMSE \> 20 (to exclude dementia)
Exclusion criteria
* Cardiac surgery * Intracranial Surgery * Emergency Surgery * Patients with severe visual or auditory disorder/handicaps * Illiteracy * Patients with clinically significant Parkinson's Disease * Patients not expected to be able to complete the 3 and 6 month postoperative tests * Sick sinus syndrome without pacemaker * Hypersensitivity to drug or class * Current 2nd or 3rd degree AV block * History of clinically significant bradycardia * Contraindication to the use of an 2A-agonist * Presence of a major psychiatric condition such as bipolar disorder, major depression, schizophrenia, or dementia * ASA physical status IV or V
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delirium Battery | Day 1 | Number of Participants with occurrence of Post-Operative Delirium in Post-Anesthesia Care Unit (PACU) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological Testing | at 3 months postoperatively | Rate of change of cognitive function - data not collected because secondary analysis which was not performed |
| Intraoperative Bradycardia | day 1 | Number of participants with intraoperative bradycardia |
| Intraoperative Hypotension | day 1 | Number of participants with intraoperative hypotension |
| Intraoperative Hypertension | day 1 | Number of participants with intraoperative hypertension |
| Length of Stay | average 4 days | Length of Stay (LOS) in the hospital |
Countries
United States
Participant flow
Recruitment details
Trial was conducted at 10 sites from February 2008 to May 2014. The lead site was The Mount Sinai Hospital in New York City.
Participants by arm
| Arm | Count |
|---|---|
| Precedex Precedex (Dexmedetomidine) 0.5/ug/kg/hr | 189 |
| Placebo Placebo - normal saline 0.5/ug/kg/hr | 201 |
| Total | 390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | anesthesia provider refusal | 1 | 0 |
| Overall Study | surgery cancelled | 1 | 1 |
| Overall Study | surgery rescheduled to different site | 2 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Precedex | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 74.0 years | 74.0 years | 74.0 years |
| Anesthesia Time | 252.0 minutes | 254.0 minutes | 253.0 minutes |
| ASA Status 1 or 2 | 73 Participants | 63 Participants | 136 Participants |
| ASA Status 3 | 108 Participants | 133 Participants | 241 Participants |
| ASA Status 4 | 8 Participants | 5 Participants | 13 Participants |
| Body Mass Index (BMI) | 28.1 kg/m^2 | 27.7 kg/m^2 | 28.0 kg/m^2 |
| Cancer (CA) | 81 Participants | 77 Participants | 158 Participants |
| Congestive Heart Failure (CHF) | 0 Participants | 1 Participants | 1 Participants |
| Coronary Artery Disease (CAD) | 14 Participants | 18 Participants | 32 Participants |
| Diabetes (DM) | 39 Participants | 40 Participants | 79 Participants |
| Dosage of Fentanyl used prior to this study | 250.0 µg/h | 250.0 µg/h | 250.0 µg/h |
| Education | 16.0 years | 15.0 years | 16.0 years |
| Hypertension (HTN) | 124 Participants | 116 Participants | 240 Participants |
| Mild Cognitive Impairment (MCI) | 124 Participants | 122 Participants | 246 Participants |
| Propofol | 170.0 mg/kg | 160.0 mg/kg | 165.0 mg/kg |
| Sex: Female, Male Female | 97 Participants | 103 Participants | 200 Participants |
| Sex: Female, Male Male | 92 Participants | 98 Participants | 190 Participants |
| Surgical Procedure General | 40 Participants | 53 Participants | 93 Participants |
| Surgical Procedure Orthopedic | 54 Participants | 36 Participants | 90 Participants |
| Surgical Procedure Spine | 70 Participants | 77 Participants | 147 Participants |
| Surgical Procedure Thoracic | 5 Participants | 6 Participants | 11 Participants |
| Surgical Procedure Urologic | 20 Participants | 29 Participants | 49 Participants |
| Surgical Time | 174.0 minutes | 180.0 minutes | 177.0 minutes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 189 | 3 / 201 |
| other Total, other adverse events | 0 / 189 | 0 / 201 |
| serious Total, serious adverse events | 12 / 189 | 9 / 201 |
Outcome results
Delirium Battery
Number of Participants with occurrence of Post-Operative Delirium in Post-Anesthesia Care Unit (PACU)
Time frame: Day 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precedex | Delirium Battery | Postoperative Delirium | 23 Participants |
| Precedex | Delirium Battery | PACU Delirium | 6 Participants |
| Precedex | Delirium Battery | Both | 5 Participants |
| Precedex | Delirium Battery | None | 155 Participants |
| Placebo | Delirium Battery | None | 166 Participants |
| Placebo | Delirium Battery | Postoperative Delirium | 23 Participants |
| Placebo | Delirium Battery | Both | 4 Participants |
| Placebo | Delirium Battery | PACU Delirium | 8 Participants |
Intraoperative Bradycardia
Number of participants with intraoperative bradycardia
Time frame: day 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precedex | Intraoperative Bradycardia | Requiring treatment | 35 Participants |
| Precedex | Intraoperative Bradycardia | Requiring interruption of the drug | 2 Participants |
| Precedex | Intraoperative Bradycardia | Resolved spontaneously | 45 Participants |
| Precedex | Intraoperative Bradycardia | Did not occur | 107 Participants |
| Placebo | Intraoperative Bradycardia | Did not occur | 137 Participants |
| Placebo | Intraoperative Bradycardia | Requiring treatment | 20 Participants |
| Placebo | Intraoperative Bradycardia | Resolved spontaneously | 42 Participants |
| Placebo | Intraoperative Bradycardia | Requiring interruption of the drug | 2 Participants |
Intraoperative Hypertension
Number of participants with intraoperative hypertension
Time frame: day 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precedex | Intraoperative Hypertension | Requiring treatment | 26 Participants |
| Precedex | Intraoperative Hypertension | Requiring interruption of the drug | 0 Participants |
| Precedex | Intraoperative Hypertension | Resolved spontaneoulsy | 17 Participants |
| Precedex | Intraoperative Hypertension | Did not occur | 146 Participants |
| Placebo | Intraoperative Hypertension | Did not occur | 134 Participants |
| Placebo | Intraoperative Hypertension | Requiring treatment | 36 Participants |
| Placebo | Intraoperative Hypertension | Resolved spontaneoulsy | 30 Participants |
| Placebo | Intraoperative Hypertension | Requiring interruption of the drug | 1 Participants |
Intraoperative Hypotension
Number of participants with intraoperative hypotension
Time frame: day 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precedex | Intraoperative Hypotension | Requiring Treatment | 81 Participants |
| Precedex | Intraoperative Hypotension | Requiring interruption of the drug | 3 Participants |
| Precedex | Intraoperative Hypotension | Resolved Spontaneously | 18 Participants |
| Precedex | Intraoperative Hypotension | Did not occur | 87 Participants |
| Placebo | Intraoperative Hypotension | Did not occur | 106 Participants |
| Placebo | Intraoperative Hypotension | Requiring Treatment | 69 Participants |
| Placebo | Intraoperative Hypotension | Resolved Spontaneously | 21 Participants |
| Placebo | Intraoperative Hypotension | Requiring interruption of the drug | 5 Participants |
Length of Stay
Length of Stay (LOS) in the hospital
Time frame: average 4 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Precedex | Length of Stay | 4.0 days |
| Placebo | Length of Stay | 4.0 days |
Neuropsychological Testing
Rate of change of cognitive function - data not collected because secondary analysis which was not performed
Time frame: at 3 months postoperatively