Postoperative glucocorticoids in patients with acute type A aortic dissection (GLAD): study protocol for a prospective, single-center, randomized controlled trial

Setting

This study will be an investigator-initiated, prospective, single-blind, randomized, single-center study, which will investigate the effect of postoperative GC on patients with aTAAD. The trial will be conducted in the cardiac intensive care center of Zhongshan Hospital, Fudan University.

Overview

All patients with aTAAD undergoing surgery will be screened for study eligibility. Upon enrollment, eligible patients will be randomized 1:1 to one of the two treatment arms (i.e. GC or normal treatment) (Fig. 1). Data will be collected until hospital discharge or death.

Fig. 1figure 1

Flow chart of study protocol. GC:glucocorticoids; ICD: implantable cardioverter defibrillator

Study population

Inclusion and exclusion criteria are defined for enrolled patients;

Inclusion criteria

Patients meeting all of the following criteria:

1. Age 18 years old or above;

2. Obtain informed consent from the patient's family or legal representative;

3. Confirmed diagnosis of acute type A aortic dissection and received surgical treatment.

4. Life expectancy > 3 days after surgery.

Exclusion criteria

1. Iatrogenic aortic dissection;

2. History of bacterial or fungal infections within the past 30 days;

3. History of GCs or anti-inflammatory drug use within the previous 14 days;

4. Allergy to GCs;

5. Pregnancy;

6. Cushing's syndrome or Addison's syndrome;

7. History of implantable cardioverter defibrillator or permanent pacemaker implantation;

8. Patients with malignancies undergoing chemotherapy, immunotherapy or targeted therapy;

9. Patients with severe preoperative hepatic insufficiency;

10. Patients with severe preoperative renal insufficiency;

Criteria for withdrawing from the study

1. Allergy to GC during the study.

2. Complications that require surgical treatment.

3. Withdrawal of the informed consent.

Intervention

All patients in the GC group will be given methylprednisolone (MP) intravenously for 3 days after entering the ICU postoperatively. MP will be injected every 12 h with a tapering dosage (Fig. 2).

Fig. 2figure 2

The first dose of MP will be given on the morning of postoperative day (POD) 1 at a dosage of 2 mg/kg/d, followed by another dose with the same dosage 12 h later. On POD 2 and POD 3, MP will be reduced to 1 mg/kg/d and 0.5 mg/kg/d respectively, with 12 h intervals between two injections.

All patients in the control group will receive treatments as usual without the administration of GC. Patients will be required to be supervised by medical personnel when administering the study drug, and their vital signs will be checked regularly in case of emergency.

Strategies to improve adherence to intervention and monitor adherence to procedures will be implemented. Three dedicated research fellows will screen all patients who enter the ICU after surgery. They will be responsible to check if certain candidate meets the study criteria. They will also be in charge of ensuring that intervention will be prescribed based on the protocol. In addition, two independent intensive care specialists will monitor adherence to interventions throughout the study period.

Outcomes

The primary outcome will be the difference of Sequential Organ Failure Assessment (SOFA) score on POD 4 compared to baseline (on POD1 before MP administration).

Secondary outcomes will be in-hospital mortality, days of ICU stay; days of hospital stay; duration of mechanical ventilation; tracheotomy; continuous renal replacement therapy; postoperative infection; inflammatory markers on POD 1, 2 and 3; composite endpoint (in-hospital morbidity and mortality or ICU stay over 30 days or tracheotomy).

Safety outcomes

An adverse event is an incident that occurs after a patient or clinical trial subject receives a drug, but is not necessarily causally related to the treatment. All ICU staff will be instructed to pay attention to allergic reactions such as urticaria, shock and shortness of breath. These observations will be recorded on the participating patient’s data sheet and reported to investigators. Other extraordinary or questionable side effects will also be recorded.

Vital signs will be continually monitored and recorded in the ICU. The vital parameters include blood pressure, pulse, SpO2, temperature and respiratory rate. Blood counts, tests for infection, clinical chemistry biomarkers, and serum glucose will also be monitored. Prophylactic antibiotics will be used in all patients. If sepsis is suspected in the period when GC is given, treatment will follow the latest sepsis guidelines [13]. Electrolyte imbalance and hyperglycemia will also be corrected.

Randomization and blinding

Block randomization will be conducted using a computer-generated random sequence, in blocks of size 4. Eligible patients will be assigned to one of the two study arms. A unique patient identification code will be generated to every screened patient without possible inference to patient identity.

Patients and researchers involved in data collection and analysis will be blinded. Doctors and nurses who will give the GC will not be blinded for allocations. These staff members will not be involved either in outcome evaluation or data analysis.

Data to be collected (Table 1)Table 1 Data to be collected

Assessment of organ dysfunction: SOFA score.

Investigational medication: methylprednisolone.

Patient's inflammatory indicators (high sensitivity C-reactive protein, Procalcitonin, Tumor Necrosis Factor α, IL-6, IL-10).

Blood count: hemoglobin, white blood cell, neutrophil count, lymphocyte count, platelet count.

Blood biochemistry: alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, serum creatinine, plasma brain natriuretic peptide precursor, serum troponin T.

Blood gas analysis: PH, partial pressure of oxygen, partial pressure of carbon dioxide, electrolytes (potassium ion, sodium ion), blood glucose.

Concomitant medications: β-blockers, calcium channel blockers, anticoagulants, antiplatelet agents, antihypertensive agents, cardiotonic agents, proton pump inhibitors or H2-blockers, antibiotics used within the previous 7 days.

Adverse events: occurrence of infections, gastrointestinal bleeding or perforation, etc.

Vital signs: including blood pressure, pulse rate, respiratory rate, body temperature.

Data collection and storage

Blinded trial investigators will enter the baseline characteristics, process variables, and outcome data from the patient files into web-based case report forms (Electronic Data Capture System) from POD 1 to POD 4, and follow up at discharge from hospital. Calculation of the SOFA score will be done by the on-duty physician. Personal information about potential and enrolled participants will be collected and maintained. The initial of patient’s full name will be used instead of the real name to identify certain patients. In addition, during the study period, a unique identification number will be used as the dominant way to follow certain patients to protect confidentiality. If necessary, information stored in the electronic patient record will be used for follow-up and patients or their surrogates will be contacted directly if additional data is needed. Data will be stored in a third-party system and the trial investigators have full access to it.

Clinical definitionsInclusion criteria Acute type A aortic dissection

Referring to patients with clinical manifestations such as chest pain, abnormal electrocardiogram or blood pressure, and confirmed by computerized tomography angiography.

Exclusion criteria Iatrogenic aortic dissection

Referring to aortic dissection occurs in cardiac surgery intraoperatively or postoperatively with definite evidence.

Bacterial or fungal infections

Presence of clinical manifestations of systemic or local inflammatory response such as fever and elevated inflammatory indicators, and with or without support of bacterial or fungal pathogenic tests.

Cushing's syndrome

Referring to patients meeting the diagnostic criteria in clinical practice guideline of Cushing’s Syndrome 2021 [14].

Addison's syndrome

Referring to patients meeting the diagnostic criteria of Addison's syndrome [15].

Severe preoperative hepatic insufficiency

Referring to patients obtained 10–15 points in the Child-Turcotte-Pugh score.

Severe preoperative renal insufficiency

Referring to patients having acute or chronic kidney injury before surgery and meeting the indications for renal replacement therapy.

Outcomes Postoperative infection

Referring to infection after cardiac surgery, including deep incisional surgical site infection occurring at the primary chest incision, deep incisional surgical site infection occurring at a secondary incision site, mediastinitis, infectious myocarditis or pericarditis, endocarditis, cardiac device infection, pneumonia, empyema, Clostridium difficile colitis, and bloodstream infection, with or without support of pathogenic evidence [16].

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