This forward-looking randomized double-masked placebo-regulated investigation was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Bengbu Medical College (Approval No. 2021KY013) and registered with the Chinese Clinical Study Registry (No. ChiCTR2100051804). The study was performed in strict compliance with the Helsinki Guidelines, the principles of the Universal Declaration on the Human Rights and guidelines established by the World Health Organization Research Ethics Review Committee. Written informed consent was obtained from the participants before surgery.

Patients undergoing CABG under CPB in the Cardiac Surgery Department of the First Affiliated Hospital of Bengbu Medical Collegewere were recruited from January 2021 to December 2022. The eligibility criteria were as follows: a) minimum age ≥ 18 years; b) evaluation level II or III of The American Society for Anesthesia classification or New York Heart Association (NYHA) stage II to III; c) sufficient kidney function, defined as an estimated glomerular filtration rate (eGFR) of >60mL/min/1.73 m2; and d) provision of agreed written agreement.

The exclusion criteria were as follows: a) individuals with insufficient liver and kidney function, characterized as a eGFR of<60mL/min/1.73 m2; b) cardiogenic shock; c) a history of surgery or infection within the previous 2 weeks; d) malignant tumors; e) use of nephrotoxic drugs before the operation or during the study; f) an inability to complete the study due to poor adherence; g) cardiac catheterization within 7 days before surgery; h) contrast-induced AKI.

The patients were randomly divided into either the Dex group or the normal saline (NS) group using an online randomization tool.20 The ratio was set to 1:1, with block sizes of 2 and 4 and a list length of 232. The list length was based on the sample size estimate and consequently 238 patients were recruited to account for possible dropouts. However, 6 patients were excluded, resulting in 232 patients for randomization. The randomly assigned results were placed in opaque envelopes and retained by special personnel. Dex and NS solutions were prepared by a designated research group member based on the randomization results. The Dex and NS solutions were prepared and drawn into 50mL syringes, which were marked only with random codes. At the end of all the tests, the code in the envelope was matched to the code on the syringe to reveal the grouping status. To avoid bias due to subjective factors relating to the participant and investigator, the participants, study operators and outcome evaluators were not informed of the grouping status or syringe contents (figure 1 and figure 2).

Figure 1.

Central illustration. Illustration of the randomization methodology and the main results of the study. Dex, Dexmedetomidine; NS, normal saline.

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Figure 2.

Flowchart of patient recruitment. Dex, dexmedetomidine; NS, normal saline.

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Prior to surgery, patients fasted for 8hours. Intravenous-inhaled general anesthesia was administered, with continuous monitoring of electrocardiography, non-invasive blood pressure, pulse oximetry saturation, and bispectral index. Peripheral venous access and radial artery catheterization under local anesthesia were established for continuous invasive blood pressure monitoring. Anesthesia induction involved midazolam (0.06mg/kg), etomidate (0.3mg/kg), sufentanil (2μg/kg), and cisatracurium (0.3mg/kg) administered intravenously in sequence. Tracheal intubation was performed, maintaining an inhalation oxygen concentration of 75% to 100%, oxygen flow at 1.0 to 1.5 L/min, tidal volume at 8 to 10mL/kg, ventilation rate at 10 to 12 cycles/min, and PetCO2 at 35 to 45mmHg. Right internal jugular vein cannulation facilitated central venous tension monitoring, blood sampling, and drug administration. Anesthesia maintenance included intermittent inhalation of sevoflurane, intravenous infusion of propofol and remifentanil, and intermittent intravenous injection of sufentanil and cisatracurium, with narcotic drug dosages adjusted to maintain the bispectral index value between 40 and 60. Cefazolin was used as the antibiotic prophylaxis for all patients unless they were allergic or resistant to this drug. Hydroxyethyl starch was used as the colloid of choice for all patients unless they were allergic to this drug or had intolerance.

The patients assigned to the Dex group were administered an initial dose of Dex (0.5μg/kg, intravenously delivered for 10minutes), followed by a constant drip at a rate of 0.4μg/kg/h until the end of surgery. The patients assigned to the NS group received NS treatment instead of Dex, with the same administration as for Dex. During the operation, blood pressure and heart rate (HR) were maintained by intravenous administration of vasoactive drugs (dopamine, ephedrine, norepinephrine, epinephrine, nitroglycerin, etc), HR-regulating drugs (atropine, isoproterenol, esmolol, etc), and dilatation. Severe bradycardia was defined as HR <40 beats per minute, and the number of patients who experienced severe bradycardia and the number of times they received HR-regulating drugs were recorded.

We recorded age, sex, body mass index, American Society of Anesthesiologists and New York Heart Association grade, European cardiovascular surgery risk factor score, left ventricular ejection fraction and the complications of hypertension, hyperlipidemia and diabetes in the 2 groups. Presurgical treatments, such as angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and nonsteroidal anti-inflammatory agents, were also documented.

Postoperative: operating time, CPB time, ascending aorta occlusion time, relapse of the cardiac condition, fluid (crystal, colloidal and allogeneic red blood cell) infusion volume, urine volume, blood loss (total blood loss minus autologous blood transfusion) and dopamine and nitroglycerin dosages were recorded. Postoperative: The number of cases of CSA-AKI, AKI stage, 24-hour postoperative urine volume, postoperative ventilatory support, length of stay in the intensive care unit, and length of postoperative hospitalization were recorded.

Mean arterial pressure, central venous pressure, HR and hemoglobin values were recorded before the induction of anesthesia (T0), at the end of the operation (T1), 12hours after the operation (T2), 24hours after the operation (T3), 48hours after the operation (T4), 72hours after the operation (T5) and 96hours after the operation (T6). CPB flow and perfusion parameters, such as pump flow, mean perfusion pressure and hematocrit, were also recorded during the operation. Minimal mean arterial pressure was defined as the lowest value of mean arterial pressure during the operation.

Arterial blood, venous blood and urine specimens were gathered at intervals T0–T6. Levels of fasting plasma glucose, lactic acid and hemoglobin in arterial blood were measured using a blood gas analyzer (Radiometer, United States). Free fatty acid, serum creatinine (SCr), blood urea nitrogen, urinary kidney damage molecule-1, urinary cystatin C concentration and superoxide dismutase activity were detected using a biochemical analyzer (Beckman Coulter, United States). eGFR was calculated using Yimai Tong medical software based on an improved simplified method from 2006 by Yimai Tong medical computing software (Beijing Medlive Technology Co, China).21 The formula estimates the glomerular filtration rate using factors such as SCr concentration, age, and sex.

Levels of serum malondialdehyde were determined using the thiobarbituric acid method, and the serum total antioxidant capacity (Nanjing Jiancheng, China) was determined by colorimetry. Serum reactive oxygen species (Shanghai Jianglai, China) and urinary neutrophil gelatinase-associated lipocalcin (Nanjing Jiancheng, China) were determined by enzyme-linked immunosorbent testing. All samples were prepared, stored and tested in strict accordance with the manufacturer's operating instructions.

Currently, AKI diagnosis and staging criteria mainly include those found in the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, the RIFLE (Risk of Renal Dysfunction, Injury to Kidney, Failure or Loss of Kidney Function), and End-stage kidney disease diagnosis and staging criteria and the Acute Kidney Injury Network staging criteria. Among them, the most commonly used are the KDIGO diagnosis and staging criteria for AKI (2012), and the diagnosis and staging criteria for CSA-AKI in this study refer to these standards.22

The primary outcome measure was the incidence of CSA-AKI, defined as the occurrence of AKI within 96hours after surgery. Secondary outcomes were the levels of SCr, blood urea nitrogen, free fatty acid, fasting plasma glucose and lactic acid; eGFR values and 24-hour urine volume after surgery, malondialdehyde, reactive oxygen species, total antioxidant capacity, urinary kidney damage molecule-1, urinary neutrophil gelatinase-associated lipocalcin and urinary cystatin C levels, superoxide dismutase activity and postoperative mechanical ventilation time, postoperative intensive care unit stay, number of postoperative hospitalization days, perioperative HR, and other observational indicators. eGFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula, which is predicated on SCr, age, and sex. The formula is as follows:

eGFR=141×least (SCr / κ, 1) α×greatest (SCr / κ, 1)-1.209×0.993Age×1.018 (if woman), where SCr is SCr (mg/dL), κ is 0.7 for women and 0.9 for men, α is -0.329 for women and -0.411 for men, least signifies the least value of SCr/κ or 1, and greatest signifies the greatest value of SCr/κ or 1.

A total of 238 patients scheduled to receive CABG under CPB were recruited for eligibility screening based on the sample size estimate. Six patients were excluded due to insufficient renal function or chronic kidney disease before surgery (n=4) or refusal to participate (n=2). Thus, a total of 232 patients were eligible for inclusion. The Dex cohort (n=116) and the NS cohort (n=116) were randomly divided using a computerized numerical method. Of these 232 patients, 3 were excluded due to withdrawal requests (n=1) or death due to severe postoperative infection and low cardiac output (n=2). Finally, a total of 229 patients were enrolled and analyzed, including 115 patients in the Dex cohort and 114 in the NS cohort (figure 2).

Baseline data indicated there were no substantial differences in age, sex, body mass index, American Society of Anesthesiologists grade, New York Heart Association grade, European cardiovascular surgery risk factor score, left ventricular ejection fraction, or complications due to hypertension, hyperlipidemia and diabetes among the 2 cohorts (P>.05). The use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs was also comparable between the 2 cohorts (P>.05) (table 1).

Among the 229 patients, 58 (25.33%) showed different degrees of CSA-AKI, of which 36 (15.72%) were identified as having AKI stage 1, 11 (6.55%) as AKI stage 2, and 7 (3.06%) as AKI stage 3. Within the Dex cohort, 21 patients (18.26%) developed CSA-AKI, of which 13 (11.30%) had AKI stage 1, 6 (5.22%) had AKI stage 2, and 2 (1.74%) had AKI stage 3. In the NS cohort, 37 patients (32.46%) developed CSA-AKI, including 23 (20.18%) with AKI stage 1, 9 (7.89%) with AKI stage 2, and 5 (4.39%) with AKI stage 3. The incidence of CSA-AKI was significantly lower in the Dex group than in the NS group (18.26% vs 32.46%, P=.014) (table 2).

There were no marked differences in operating time, CPB time, occlusion time of the ascending aorta, automatic heart relapse rate, intraoperative fluid (crystal, colloid and allogeneic blood cell) infusion volume, intraoperative urine volume, intraoperative blood loss (total blood loss minus autotransfusion) and intraoperative dosages of dopamine and nitroglycerin between the 2 groups (P>.05). Compared with the value in the NS group, the volume of urine produced 24hours postsurgery in the Dex group was significantly elevated, the length of postoperative mechanical ventilation and intensive care unit residency was notably shorter, and the number of postoperative hospitalization days was statistically lower (P<.05). There was no marked variance between the 2 groups in the number of patients with severe bradycardia (P>.05). However, the frequency at which the patients in the Dex group were administered HR-modulating drugs was substantially higher than that of the patients in the NS group (P<.01). This implies that Dex can cause bradycardia, especially when an initial dose is administered, and that HR-modulating drugs may be necessary to prevent or treat this adverse effect. There was no appreciable difference in the mean arterial pressure between the 2 groups (P>.05) (table 2).

There was no appreciable difference in mean arterial pressure, central venous pressure and hemoglobin between the 2 cohorts at each time point (P>.05). Compared with the baseline value in the control group, HR at the initial time point in the Dex group was significantly reduced (P<.01). The data showed that although HR (83.47±8.41 times/min vs 77.34±6.46 times/min) was significantly lower at the end of surgery in the Dex group, it was still within the normal and safe range. However, in patients with coronary heart disease, this HR was more conducive to maintaining the balance of myocardial oxygen supply and demand, reducing myocardial energy consumption, alleviating myocardial injury and promoting myocardial protection than the HR of the patients in the NS group at this time point. This difference in HR can be attributed to the sedative and sympatholytic effects of Dex, which can lower the HR and reduce myocardial oxygen demand (figure 3).

Figure 3.

Comparison of hemodynamic changes at each time between the 2 groups. A, mean arterial pressure (MAP) values; B, heart rate (HR) values; C, central venous pressure (CVP) values; and D, hemoglobin (Hb) values. Compared with the NS group, *P<.01. Dex, dexmedetomidine; NS, normal saline.

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There were no significant differences in urinary cystatin C levels between the 2 cohorts at any time point (P>.05). Compared with the NS group, at T4–T6, the SCr concentration in the Dex group was substantially decreased, and the approximate rate of glomerular filtration was notably enhanced, with the eGFR value considerably increased (P<.05); at T3–T6, the blood urea nitrogen concentration in the Dex group was notably reduced (P<.01); at T3–T5, the urinary kidney damage molecule-1 protein concentration in the Dex group was markedly decreased (P<.01). At T2–T5, the concentration of urinary neutrophil gelatinase-associated lipocalcin in the Dex group was substantially lower (P<.05). These outcomes indicated that Dex significantly improved renal function in patients with CABG under CPB (figure 4).

Figure 4.

Comparison of renal function between the 2 patient groups. A, serum creatinine (SCr) levels; B, serum blood urea nitrogen (BUN) levels; C, estimated glomerular filtration rate (eGFR) values; D, urine kidney injury molecule-1 (uKIM-1) levels; E, urine neutrophil gelatinase-associated lipocalin (NGAL) levels; and F, urine cystatin C (uCys-C) levels. Compared with the NS group, aP<.01; bP<.05. Dex, dexmedetomidine; NS, normal saline.

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In contrast to the level in the NS group, the free fatty acid concentration in the Dex group was substantially decreased at T2–T3 (P<.01). At T1–T2, fasting plasma glucose status in the Dex group was notably lower (P<.01). At T3–T4, the lactate status in the Dex group was notably reduced (P<.01). These outcomes suggested that Dex maintained the balance of fatty acid and glucose metabolism and reduced lactic acid generation (figure 5).

Figure 5.

Comparison of energy metabolism levels between the 2 groups. A, free fatty acid (FFA) levels; B, fasting plasma glucose (FPG) levels; and C, Lactic acid (Lac) levels. Compared with the NS group; *P<.01. Dex, dexmedetomidine; NS, normal saline.

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In contrast to the measurements in the NS group, the reactive oxygen species status was significantly reduced in the Dex group, and superoxide dismutase activity was notably increased in the Dex group at T1–T5 (P<.01). At T2–T5, the malondialdehyde level in the Dex group was markedly reduced (P<.01). At T3–T5, the total antioxidant capacity status in the Dex group was significantly elevated (P<.01). The above results confirmed that Dex significantly reduced the oxidative stress reaction caused by surgery (figure 6).

Figure 6.

Comparison of oxidative stress levels between the 2 groups. A, reactive oxygen species (ROS) levels; B, malondialdehyde (MDA) levels; C, superoxide dismutase (SOD) activity; and D, total antioxidant capacity (T-AOC) levels. Compared with the NS group, *P<.01. Dex, dexmedetomidine; NS, normal saline.

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Nevertheless, the present study has inherent limitations, including its single-center design and its limited sample size. Prolonged follow-up is crucial for a comprehensive understanding of the therapeutic implications of Dex. Future research should include more extensive study areas and populations with longer-term follow-ups to investigate in depth the mechanism through which Dex mitigates CSA-AKI in patients undergoing CABG with extracorporeal circulation.