Postoperative Cognitive Dysfunction
Conditions
Keywords
postoperative analgesia, postoperative cognitive disfunction
Brief summary
The purpose of this study is to determine whether epidural levobupivacaine applied for the purpose of post-operative analgesia compared to systemic analgesia with morphine leads to better pain control, stronger suppression of the inflammatory response and the production of inflammatory mediators, faster recovery of patients and consequently less incidence of postoperative cognitive dysfunction (POCD) in elderly patients after surgical treatment of femoral fractures.
Detailed description
The research will be carried out at the Department of Surgery at Clinical Hospital Centre(CHC) Osijek after approval by the Ethics Committee of CHC Osijek and will be organized as a prospective randomized trial. Respecting the including and excluding criteria for participation in the study, the research will include 70 patients aged 65 years and over who are undergoing surgery for proximal femur fractures and will be operated with the same operating technique (osteosynthesis with nail). All participants will receive the same type of anesthesia and one of two forms of post-operative analgesia, so it will be divided into two groups (35 patients) depending on which form of post-operative analgesia receive. Randomization will be performed by drawing an envelope in which the specified one or other form of post-operative analgesia will be written. The study will be stopped in case of serious complications life-threatening (excessive sedation, respiratory insufficiency, hemodynamic instability and profound hypotension, heart rhythm disorders), which could possibly be related to the administration of drugs used for postoperative analgesia.
Interventions
DRUGmorphine
DRUGlevobupivacaine
Sponsors
Osijek University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* patients age 65 and over * fracture of the proximal femur * preoperative assessment American Society of Anesthesiologists(ASA) score I - ASA III * a written consent of the patient to participate in research
Exclusion criteria
* patient non-compliance * ASA status IV and IV above * patients younger than 65 years * dementia, Parkinson's disease, cerebrovascular accident history; simultaneous head injuries,the use of opioids and benzodiazepines longer than a month before the surgery; alcoholism; serious liver disease (class C according to Child-Pugh's classification); severe kidney disease that require dialysis * result of MMSE test (Mini-Mental State Examination) under 17 * the existence of any contraindications for the implementation of regional anesthesia and one or other form of post-operative analgesia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin-6 Concentration in Peripheral Blood. | Before, 24 and 72 hours after the surgery | Measurement will be done before and 24 and 72 hours after the surgery. |
| Changes in Cognitive Function | Before, 24,48,72,96 and 120 hours after the surgery | Assessment of cognitive function will be done using the Mini-mental state examination (MMSE) rating scales before and 24,48,72,96 and 120 hours after the surgery at the same time every morning. Mini-Mental State Examination Scale: minimum score is 0 and maximum score is 30; the severity of cognitive impairment: no cognitive impairment=25-30; mild cognitive impairment=19-24; moderate cognitive impairment=10-18; and severe cognitive impairment\<9. Higher scores mean a better and lower scores mean a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in C-reactive Protein (CRP) Levels | Before, 24,72 and 120 hours after the surgery | Measurement will be done before and 24,72 and 120 hours after the surgery. |
| Changes in Fibrinogen Concentrations in Peripheral Blood | Before, 24,72 and 120 hours after the surgery | Measurement will be done before and 24,72 and 120 hours after the surgery. |
| Changes in Pain Intensity | During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily until discharge | Assessment will be done using Numeric Rating Scale (NRS). During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily. Median of 8 time points measurements during the first 24, 48 and 72 hours after the surgery will be reported. After that, median of 3 time points will be reported from the 4. to 6. postoperative day and on the day of discharge. Minimum score 0 and maximum score 10 ( 0-No Pain; 1-3 Mild Pain; 4-6 Moderate Pain; 7-10 Severe Pain ). Higher scores mean a worse and lower scores mean a better outcome. |
| Postoperative Hospital Stay | 14 days | Duration of postoperative hospital stay in days |
Countries
Croatia
Participant flow
Recruitment details
From July 2016 to September 2017, 86 patients were included in the study in accordance with the inclusion criteria and 70 of them completed the study. The study design was a prospective, randomized, controlled trial. It was conducted at the University Hospital Osijek (Croatia).
Pre-assignment details
No patients were excluded from the study before assignment to groups.
Participants by arm
| Arm | Count |
|---|---|
| Morphine The patient-controlled intravenous analgesia with morphine (basal flow of 0.5-2 mg / h, bolus dose of 0.5 mg, lockout interval of 20 minutes, hour limit of 3 doses), which will be carried out 72 hours after the surgery
morphine | 35 |
| Levobupivacaine Upon completion of the operation for a period of 72 hours will be implemented continuous epidural local anesthetic through the Patient Controlled Analgesia (PCA) pump (Levobupivacaine 0.125%, basal flow of 6 ml / hour, a bolus dose of 2 ml, lockout interval of 20 minutes, hour limit of 3 doses).
levobupivacaine | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 7 | 9 |
Baseline characteristics
| Characteristic | Total | Levobupivacaine | Morphine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 70 Participants | 35 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| ASA (American Society of Anesthesiologist physical status) ASA II | 6 Participants | 3 Participants | 3 Participants |
| ASA (American Society of Anesthesiologist physical status) ASA III | 64 Participants | 32 Participants | 32 Participants |
| BMI | 24.4 kg/m^2 | 23.9 kg/m^2 | 24.8 kg/m^2 |
| Duration of surgery | 52 minutes | 52 minutes | 49 minutes |
| Education High school | 8 Participants | 5 Participants | 3 Participants |
| Education Less than high school | 60 Participants | 29 Participants | 31 Participants |
| Education No school | 2 Participants | 1 Participants | 1 Participants |
| Perioperative transfusion | 2 Units of PRBC (packed red blood cells) | 2 Units of PRBC (packed red blood cells) | 2 Units of PRBC (packed red blood cells) |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Sex: Female, Male Female | 66 Participants | 32 Participants | 34 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 5 / 35 | 2 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 |
Outcome results
Primary
Changes in Cognitive Function
Assessment of cognitive function will be done using the Mini-mental state examination (MMSE) rating scales before and 24,48,72,96 and 120 hours after the surgery at the same time every morning. Mini-Mental State Examination Scale: minimum score is 0 and maximum score is 30; the severity of cognitive impairment: no cognitive impairment=25-30; mild cognitive impairment=19-24; moderate cognitive impairment=10-18; and severe cognitive impairment\<9. Higher scores mean a better and lower scores mean a worse outcome.
Time frame: Before, 24,48,72,96 and 120 hours after the surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine | Changes in Cognitive Function | 72 h after surgery | 20 score on a scale |
| Morphine | Changes in Cognitive Function | Before surgery | 21 score on a scale |
| Morphine | Changes in Cognitive Function | 96 h after surgery | 20 score on a scale |
| Morphine | Changes in Cognitive Function | 24 h after surgery | 20 score on a scale |
| Morphine | Changes in Cognitive Function | 120 h after surgery | 20 score on a scale |
| Morphine | Changes in Cognitive Function | 48 h after surgery | 20 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | 120 h after surgery | 22 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | 24 h after surgery | 22 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | 48 h after surgery | 21 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | 72 h after surgery | 21 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | 96 h after surgery | 21 score on a scale |
| Levobupivacaine | Changes in Cognitive Function | Before surgery | 22 score on a scale |
Primary
Interleukin-6 Concentration in Peripheral Blood.
Measurement will be done before and 24 and 72 hours after the surgery.
Time frame: Before, 24 and 72 hours after the surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine | Interleukin-6 Concentration in Peripheral Blood. | Before surgery | 27.2 pg/ml |
| Morphine | Interleukin-6 Concentration in Peripheral Blood. | 72h after surgery | 50 pg/ml |
| Morphine | Interleukin-6 Concentration in Peripheral Blood. | 24h after surgery | 104 pg/ml |
| Levobupivacaine | Interleukin-6 Concentration in Peripheral Blood. | 72h after surgery | 30.5 pg/ml |
| Levobupivacaine | Interleukin-6 Concentration in Peripheral Blood. | Before surgery | 26.6 pg/ml |
| Levobupivacaine | Interleukin-6 Concentration in Peripheral Blood. | 24h after surgery | 97.7 pg/ml |
Secondary
Changes in C-reactive Protein (CRP) Levels
Measurement will be done before and 24,72 and 120 hours after the surgery.
Time frame: Before, 24,72 and 120 hours after the surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine | Changes in C-reactive Protein (CRP) Levels | Before surgery | 57.2 mg/L |
| Morphine | Changes in C-reactive Protein (CRP) Levels | 24 h after surgery | 106.2 mg/L |
| Morphine | Changes in C-reactive Protein (CRP) Levels | 72 h after surgery | 118.5 mg/L |
| Morphine | Changes in C-reactive Protein (CRP) Levels | 120 h after surgery | 66.9 mg/L |
| Levobupivacaine | Changes in C-reactive Protein (CRP) Levels | 120 h after surgery | 54.6 mg/L |
| Levobupivacaine | Changes in C-reactive Protein (CRP) Levels | Before surgery | 57.8 mg/L |
| Levobupivacaine | Changes in C-reactive Protein (CRP) Levels | 72 h after surgery | 95 mg/L |
| Levobupivacaine | Changes in C-reactive Protein (CRP) Levels | 24 h after surgery | 98.1 mg/L |
Secondary
Changes in Fibrinogen Concentrations in Peripheral Blood
Measurement will be done before and 24,72 and 120 hours after the surgery.
Time frame: Before, 24,72 and 120 hours after the surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine | Changes in Fibrinogen Concentrations in Peripheral Blood | 72 h after surgery | 5.7 g/L |
| Morphine | Changes in Fibrinogen Concentrations in Peripheral Blood | Before surgery | 5.5 g/L |
| Morphine | Changes in Fibrinogen Concentrations in Peripheral Blood | 24 h after surgery | 5.3 g/L |
| Morphine | Changes in Fibrinogen Concentrations in Peripheral Blood | 120 h after surgery | 5.4 g/L |
| Levobupivacaine | Changes in Fibrinogen Concentrations in Peripheral Blood | 120 h after surgery | 5 g/L |
| Levobupivacaine | Changes in Fibrinogen Concentrations in Peripheral Blood | 72 h after surgery | 5.2 g/L |
| Levobupivacaine | Changes in Fibrinogen Concentrations in Peripheral Blood | 24 h after surgery | 4.7 g/L |
| Levobupivacaine | Changes in Fibrinogen Concentrations in Peripheral Blood | Before surgery | 4.5 g/L |
Secondary
Changes in Pain Intensity
Assessment will be done using Numeric Rating Scale (NRS). During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily. Median of 8 time points measurements during the first 24, 48 and 72 hours after the surgery will be reported. After that, median of 3 time points will be reported from the 4. to 6. postoperative day and on the day of discharge. Minimum score 0 and maximum score 10 ( 0-No Pain; 1-3 Mild Pain; 4-6 Moderate Pain; 7-10 Severe Pain ). Higher scores mean a worse and lower scores mean a better outcome.
Time frame: During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily until discharge
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Morphine | Changes in Pain Intensity | 51,54,57,60,63,66,69 and 72h after surgery | 1.4 score on a scale |
| Morphine | Changes in Pain Intensity | 5. postoperative day (every 8 hours) | 1.4 score on a scale |
| Morphine | Changes in Pain Intensity | 27,30,33,36,39,42,45 and 48h after surgery | 1.5 score on a scale |
| Morphine | Changes in Pain Intensity | 6. postoperative day (every 8 hours) | 1.3 score on a scale |
| Morphine | Changes in Pain Intensity | 4. postoperative day (every 8 hours) | 1.4 score on a scale |
| Morphine | Changes in Pain Intensity | Day of discharge | 1 score on a scale |
| Morphine | Changes in Pain Intensity | 3,6,9,12,15,18,21 and 24h after surgery | 1.4 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | Day of discharge | 0 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 3,6,9,12,15,18,21 and 24h after surgery | 0.6 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 27,30,33,36,39,42,45 and 48h after surgery | 0.5 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 51,54,57,60,63,66,69 and 72h after surgery | 0.5 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 4. postoperative day (every 8 hours) | 0.3 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 5. postoperative day (every 8 hours) | 0 score on a scale |
| Levobupivacaine | Changes in Pain Intensity | 6. postoperative day (every 8 hours) | 0 score on a scale |
Secondary
Postoperative Hospital Stay
Duration of postoperative hospital stay in days
Time frame: 14 days
Population: The reasons for exclusion of 16 patients were: inability to perform combined spinal-epidural anaesthesia (5 patients), technical problems with PCA pump (4 patients), withdrawal of epidural catheter (2 patients), postoperative delirium and use of antipsychotics (3 patients) and fever and use of antipyretics (2 patients).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Morphine | Postoperative Hospital Stay | 7 days |
| Levobupivacaine | Postoperative Hospital Stay | 7 days |