Dexamethasone, Flurbiprofen Axetil and Delirium After Lung Cancer Surgery

Study Overview
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Brief Summary
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Delirium is a common complication in elderly patients after surgery. And its occurrence is associated with worse outcomes. The causes of delirium are multifactorial but may include pain, stress response and inflammation. Dexamethasone is commonly used to prevent the occurrence of postoperative nausea and vomiting. In a randomized controlled trial, small-dose dexamethasone (8 mg) administered before anesthesia induction improved the quality of recovery in patients after cardiac surgery. Flurbiprofen axetil is commonly used to improve postoperative analgesia while decreasing the requirement of opioids. In a randomized trial of the investigators, combined use of flurbiprofen axetil with sufentanil for postoperative analgesia reduced delirium in elderly patients after orthopedic surgery. The purpose of this 2 plus 2 factorial randomized controlled trial is to test the hypothesis that combined use of dexamethasone and flurbiprofen axetil may reduce delirium in elderly patients after lung cancer surgery.

Detailed Description
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Delirium is an acutely occurred, transient and fluctuating central nervous system dysfunction which is characterized by cognitive dysfunction, decreased level of consciousness, decentralized attention, and/or disturbed perception. It is a common complication in elderly patients after surgery. Systematic reviews showed that 5% to 54.4% of patients developed delirium after noncardiac surgery, and the incidences increase with age. The development of postoperative delirium is associated with worse outcomes. For example, patients with delirium had increased postoperative complications, prolonged hospital stay, and increased in-hospital mortality; they also had worse long-term outcomes, including declined cognitive function, decreased quality of life, and increased post-hospital mortality. The causes of delirium are multifactorial and may include pain, stress response and inflammation. Studies showed that postoperative pain is an important risk factor of delirium, whereas good postoperative analgesia reduces the incidence of delirium. Furthermore, the studies found that surgery related inflammatory response also plays an important role in the development of delirium. However, measures that can effectively prevent the occurrence of postoperative delirium are still lacking. Dexamethasone is commonly used to prevent the occurrence of postoperative nausea and vomiting. In a randomized controlled trial, small-dose dexamethasone (8 mg) administered before anesthesia induction improved the quality of recovery in patients after cardiac surgery. Flurbiprofen axetil is commonly used to improve postoperative analgesia while decreasing the requirement of opioids. In a randomized trial of the investigators, combined use of flurbiprofen axetil with sufentanil for postoperative analgesia reduced delirium in elderly patients after orthopedic surgery. The purpose of this 2 plus 2 factorial randomized controlled trial is to test the hypothesis that combined use of dexamethasone and flurbiprofen axetil may reduce delirium in elderly patients after lung cancer surgery.

Official Title
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Impact of Perioperative Dexamethasone and Flurbiprofen Axetil on Delirium After Surgery for Non-small Cell Lung Cancer: A 2x2 Factorial Randomized Controlled Trial

Conditions
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Carcinoma, Non-Small-Cell Lung, Surgery--Complications, Dexamethasone, Flubiprofen Axetil, Delirium

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Normal saline
* Drug: Flurbiprofen axetil
* Drug: Lipid microsphere


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 18 to 85 years old; Diagnose as non-small-cell lung cancer (stage IA-IIIA); Plan to undergo surgical resection; Provide written informed consents. Exclusion Criteria: Clinical evidences suggest remote metastasis of the primary cancer; have received radiotherapy, chemotherapy or targeted therapy before surgery; have received previous surgery for lung cancer; diagnosed with other cancer (other than lung cancer) currently or previously; History of therapy with glucocorticoids or immunosuppressants within 1 year, or therapy with non-steroidal anti-inflammatory drugs (NSAIDs) within 1 month; Allergy to glucocorticoids or NSAIDs; Contraindications to dexamethasone or flurbiprofen axetil, such as asthma or hives urticaria induced by aspirin or other NSAIDs; active digestive tract ulcer or bleeding, or history of repeated digestive tract ulcer or bleeding; coagulopathy (platelet count < 50*10^9/L, International Normalized Ratio > 1.4, or activated partial thromboplastin time > 4 seconds above upper limit); current therapy with lomefloxacin, norfloxacin, or enoxacin; severe cardiac dysfunction (New York heart association class 3 or above, or Left Ventricular Ejection Fraction less than 30%) or myocardial infarction within 3 months; liver injury (transaminase higher than 2 times of upper limit); kidney injury (creatinine higher than 1.5 times of upper limit); uncontrolled severe hypertension before surgery (> 180/120 mmHg); American Society of Anesthesiologists (ASA) physical status class IV or higher; Refuse to use patient-controlled analgesia pump after surgery; Other conditions that are considered unsuitable for study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone and flurbiprofen axetil<br>Dexamethasone 10 mg is administered before anesthesia induction. Flurbiprofen axetil 50 mg is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 2 mg/ml flurbiprofen axetil, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h. | Drug: Dexamethasone<br>* Dexamethasone 10 mg is administered before anesthesia induction.<br>* Other names: Dexamethasone sodium phosphate injection;Drug: Flurbiprofen axetil<br>* Flurbiprofen axetil 50 mg is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 2 mg/ml flurbiprofen axetil, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h.<br>* Other names: Flurbiprofen axetil injection;|
| Experimental: Dexamethasone and lipid microsphere<br>Dexamethasone 10 mg is administered before anesthesia induction. Lipid microsphere 5 ml is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 20 ml lipid microsphere, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h. | Drug: Dexamethasone<br>* Dexamethasone 10 mg is administered before anesthesia induction.<br>* Other names: Dexamethasone sodium phosphate injection;Drug: Lipid microsphere<br>* Lipid microsphere 5 ml is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 20 ml lipid microsphere, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h.<br>* Other names: Lipid microsphere injection;|
| Experimental: Normal saline and flurbiprofen axetil<br>Normal saline 2 ml is administered before anesthesia induction. Flurbiprofen axetil 50 mg is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 2 mg/ml flurbiprofen axetil, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h. | Drug: Normal saline<br>* Normal saline 2 ml is administered before anesthesia induction.<br>Drug: Flurbiprofen axetil<br>* Flurbiprofen axetil 50 mg is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 2 mg/ml flurbiprofen axetil, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h.<br>* Other names: Flurbiprofen axetil injection;|
| Experimental: Normal saline and lipid microsphere<br>Normal saline 2 ml is administered before anesthesia induction. Lipid microsphere 5 ml is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg sufentanil and 20 ml lipid microsphere, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h. | Drug: Normal saline<br>* Normal saline 2 ml is administered before anesthesia induction.<br>Drug: Lipid microsphere<br>* Lipid microsphere 5 ml is administered before the start of surgery. Postoperative analgesia is provided with a patient-controlled analgesia pump, which is established with 100 ml of 1.25 μg/ml sufentanil and 20 ml lipid microsphere, programmed to deliver a 2 ml bolus with a lockout interval of 6-8 min and a background infusion of 1 ml/h.<br>* Other names: Lipid microsphere injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delirium during the first five postoperative days. | Delirium is assessed twice daily with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). | From postoperative day 1 to postoperative day 5. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily prevalence of delirium during the first five days after surgery. | Delirium is assessed twice daily with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). | From postoperative day 1 to postoperative day 5. | 
| Length of stay in hospital after surgery. | Length of stay in hospital after surgery. | From end of surgery until hospital discharge or 30 days after surgery. | 
| Incidence of postoperative complications within 30 days after surgery. | Incidence of postoperative complications within 30 days after surgery. | From end of surgery until 30 days after surgery. | 
| All-cause mortality within 30 days after surgery. | All-cause mortality within 30 days after surgery. | From end of surgery until 30 days after surgery. | 
| Cognitive function at 30 days after surgery. | Cognitive function is assessed with Telephone Interview for Cognitive Status-Modified (TICS-m) | At 30 days after surgery. | 
| Quality of life at 30 days after surgery. | Quality of life is assessed with the World Health Organization Quality of Life-short version (WHOQOL-Bref). | At 30 days after surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Non-Small-Cell Lung, Surgery, Dexamethasone, Flubiprofen Axetil, Delirium