Propofol and Dexmedetomidin vs Midazolam Intraoperative Sedation and POCD

Postoperative Cognitive Dysfunction Clinical Trial

— ProDex-POCD  

Official title:

The Effect of Intraoperative Administration of Dexmedetomidine, Propofol and Midazolam on Postoperative Levels of Inflammatory Markers and Development of Postoperative Cognitive Dysfunction After Pertrochanteric Fracture Surgery.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05398757
• Other study ID #: OsijekPOCD
• Status: Recruiting
• Phase: N/A
• Start date: July 1, 2022
• Est. completion date: March 1, 2024

Study information

• Verified date: July 2023
• Source: Osijek University Hospital
• Contact: Nenad Neskovic, PhD
• Phone: +385996787250
• Email: nneskov[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will examine the effect of intraoperative sedation with midazolam, propofol and dexemdetomidine on the occurrence of postoperative cognitive impairment in patients undergoing surgical treatment of pertrochanteric fracture of the femur.

Description:

Patients undergoing surgical treatment of pertrochanteric femoral fracture by intramedullary fixation will be included in the study. Patients will be older than 65 years and will belong to class I to III anesthesia risk according to the ASA classification. All patients included in the study will sign informed consent. Patients with dementia, mental illness, psychoorganically altered patients, and patients with a contraindication to dexmedetomidine, propofol, midazolam or with a contraindication to spinal anesthesia will be excluded from the study. All patients included in the study will have their blood taken for laboratory analysis of red blood cells, leukocytes, CRP, PCT, ChE and IL-6. Analyzes will be performed before the procedure, on the 1st, 3rd and 5th postoperative day. All patients will be tested for Mini mental state exame (MMSE) score before surgery to rule out pre-existing cognitive impairment, and those patients who have an MMSE value <17 prior to surgery will be excluded from the study. In premedication, patients will be randomized using three envelopes selected by the blind researcher for the contents of each envelope. According to envelope patients will be divided into three groups: dexmedetomidine group (DS), propofol group (PS) and midazolam group (MS). Neuroaxial spinal block with intrathecal administration of 12.5 - 15 mg 0.5% levobupivacaine in the intervertebral space L3 / L4 or L4 / L5 will be the technique of anesthesia. After spinal block, patients in the DS group will receive a continuous infusion of dexmedetomidine at a dose of 0.5 mcg / kg / h, patients in the PS group will receive a continuous infusion of propofol at a dose of 25-75 mcg / kg / min, while patients in the MS group will receive 0.05-0.07 mg / kg bolus i.v. midazolam. The total dose administered and the duration of surgery will be recorded. The volume of intraoperatively administered crystalloids or blood products will be recorded in all patients included in the study. In the postoperative period, pain will be measured with a numerical rating scale (NRS) 4, 8, 12 and 24 hours after surgery. All patients will receive the usual postoperative analgesia with metamizole and tramadol according to the protocol of the Department. On the 1st, 3rd and 5th postoperative days in the morning between 8.00 and 10.00, all patients will be tested for MMSE and Digit Symbol Substitution Test (DSST) score. A researcher who will evaluate MMSE and DSST values in the postoperative period will be blind to the drug that patients received intraoperatively.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: March 1, 2024
• Est. primary completion date: March 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

• Pertrochanteric fracture surgery

• Informed consent signed

Exclusion Criteria:

• MMSE before surgery < 17

• Allergy on midazolam, propofol or dexemdetomidine

• Contraindication for neuroaxial anesthesia

Related Conditions & MeSH terms

• Acute Pain
• Cognitive Dysfunction
• Fractures, Bone
• Pain, Postoperative
• Pertrochanteric Fracture
• Postoperative Cognitive Complications
• Postoperative Cognitive Dysfunction

Intervention

Behavioral:
• Mini mental state exame (MMSE)
Before the operation, and on the 1st, 3rd and 5th day after the operation, the Mini mental state exam (MMSE) score will be measured
• Digit Symbol Substitution Test (DSST)
Before the operation, and on the 1st, 3rd and 5th day after the operation, the Digit Symbol Substitution Test (DSST) score will be measured

Diagnostic Test:
• Numeric rating Scale (NRS)
4h, 8h, 12h and 24h after surgery, pain in all patients will be assessed by the NRS scale.
• Postoperative inflammation
All patients included in the study will have their blood taken for laboratory analysis of red blood cells, leukocytes, CRP, PCT, ChE and IL-6. Analyzes will be performed before the procedure, on the 1st, 3rd and 5th postoperative day.

Drug:
• Midazolam
For sedation during surgery, patients in midazolam group will receive i.v. midazolam in dose 0.05 - 0.07 mg/kg after spinal anesthesia.
• Propofol
For sedation during surgery, patients in propofol group will receive i.v. propofol in dose 25-27 mcg/kg/min.
• Dexmedetomidin
For sedation during surgery, patients in dexmedetomidin gropu will receive i.v. dexmedetomidin in dose 0.5 mcg/kg/h

Locations

Country	Name	City	State
Croatia	University Hospital Osijek	Osijek

Sponsors (2)

Lead Sponsor	Collaborator
Osijek University Hospital	Josip Juraj Strossmayer University of Osijek

Country where clinical trial is conducted

Croatia, 

References & Publications (12)

Chen RM, Chen TG, Chen TL, Lin LL, Chang CC, Chang HC, Wu CH. Anti-inflammatory and antioxidative effects of propofol on lipopolysaccharide-activated macrophages. Ann N Y Acad Sci. 2005 May;1042:262-71. doi: 10.1196/annals.1338.030. — View Citation

Hohener D, Blumenthal S, Borgeat A. Sedation and regional anaesthesia in the adult patient. Br J Anaesth. 2008 Jan;100(1):8-16. doi: 10.1093/bja/aem342. — View Citation

Kochiyama T, Li X, Nakayama H, Kage M, Yamane Y, Takamori K, Iwabuchi K, Inada E. Effect of Propofol on the Production of Inflammatory Cytokines by Human Polarized Macrophages. Mediators Inflamm. 2019 Mar 17;2019:1919538. doi: 10.1155/2019/1919538. eCollection 2019. — View Citation

Mei B, Li J, Zuo Z. Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central alpha2A adrenoceptor. Brain Behav Immun. 2021 Jan;91:296-314. doi: 10.1016/j.bbi.2020.10.008. Epub 2020 Oct 8. — View Citation

Monk TG, Price CC. Postoperative cognitive disorders. Curr Opin Crit Care. 2011 Aug;17(4):376-81. doi: 10.1097/MCC.0b013e328348bece. — View Citation

Rasmussen LS, Larsen K, Houx P, Skovgaard LT, Hanning CD, Moller JT; ISPOCD group. The International Study of Postoperative Cognitive Dysfunction. The assessment of postoperative cognitive function. Acta Anaesthesiol Scand. 2001 Mar;45(3):275-89. doi: 10.1034/j.1399-6576.2001.045003275.x. — View Citation

Tobias JD, Leder M. Procedural sedation: A review of sedative agents, monitoring, and management of complications. Saudi J Anaesth. 2011 Oct;5(4):395-410. doi: 10.4103/1658-354X.87270. — View Citation

Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc. 1992 Sep;40(9):922-35. doi: 10.1111/j.1532-5415.1992.tb01992.x. — View Citation

Urits I, Orhurhu V, Jones M, Hoyt D, Seats A, Viswanath O. Current Perspectives on Postoperative Cognitive Dysfunction in the Ageing Population. Turk J Anaesthesiol Reanim. 2019 Dec;47(6):439-447. doi: 10.5152/TJAR.2019.75299. Epub 2019 Sep 2. — View Citation

van Sinderen K, Schwarte LA, Schober P. Diagnostic Criteria of Postoperative Cognitive Dysfunction: A Focused Systematic Review. Anesthesiol Res Pract. 2020 Nov 16;2020:7384394. doi: 10.1155/2020/7384394. eCollection 2020. — View Citation

Wang K, Wu M, Xu J, Wu C, Zhang B, Wang G, Ma D. Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth. 2019 Dec;123(6):777-794. doi: 10.1016/j.bja.2019.07.027. Epub 2019 Oct 24. — View Citation

Xiao QX, Liu Q, Deng R, Gao ZW, Zhang Y. Postoperative cognitive dysfunction in elderly patients undergoing hip arthroplasty. Psychogeriatrics. 2020 Jul;20(4):501-509. doi: 10.1111/psyg.12516. Epub 2020 Jan 24. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of postoperative cognitive dysfunction (POCD) measured by MMSE	The incidence of POCD with respect to intraoperative sedation in the postoperative period will be measured by MMSE test on the first, third and fifth postoperative day. An absolute z-score greater than 1.96 in postoperative testing or a decrease in the postoperative MMSE value by more than 20% relative to the preoperative value will be considered the occurrence of POCD in the postoperative period.	5 days
Primary	Occurrence of postoperative cognitive dysfunction (POCD) measured by DSST	The incidence of POCD with respect to intraoperative sedation in the postoperative period will be measured by DSST on the first, third and fifth postoperative day. An absolute z-score greater than 1.96 in postoperative testing or a decrease in the postoperative DSST value by more than 20% relative to the preoperative value will be considered the occurrence of POCD in the postoperative period.	5 days
Primary	Postoperative inflammation measured by serum CRP levels	Postoperative inflammation with respect to intraoperative sedation will be assessed by serum levels of CRP at postoperative day 1, 3 and 5. CRP > 50 mg/L and rising dynamic of CRP in postoperative serial measurements will be considered as systemic inflammation state.	5 days
Primary	Postoperative inflammation measured by white blood cells count	Postoperative inflammation with respect to intraoperative sedation will be assessed by serum levels of white blood cells. Leukocytes > 12.000/mm3 or < 4.000/mm3 in postoperative serial measurements will be considered as systemic inflammation state.	5 days
Primary	Postoperative inflammation measured by serum IL-6 levels	Postoperative inflammation with respect to intraoperative sedation will be assessed by serum levels IL-6 at postoperative day 1, 3 and 5. Continuous increase of IL-6 in postoperative serial measurements will be considered as systemic inflammation state.	5 days
Primary	Postoperative inflammation measured by serum cholinesterase activity	Postoperative inflammation with respect to intraoperative sedation will be assessed by serum cholinesterase activity at postoperative day 1, 3 and 5. Cholinesterase activity < 4000 U/L in postoperative serial measurements will be considered as systemic inflammation state.	5 days
Primary	Postoperative inflammation measured by serum PCT levels	Postoperative inflammation with respect to intraoperative sedation will be assessed by serum levels of PCT at postoperative day 1, 3 and 5. PCT > 0.5 ng/ml and continuous increase in postoperative serial measurements will be considered as systemic inflammation state.	5 days
Secondary	Postoperative pain	Postoperative pain with respect to intraoperative sedation will be examined by Numeric rating scale (NRS) 4, 8, 12 and 24 hours after surgery. NRS is a scale from 0 to 10, where 0 means no pain and 10 means the strongest pain. NRS above or equal to 4 will be considered inadequate postoperative analgesia.	24 hours