Background:

The inflammatory response following cardiac surgery is known to contribute significantly to morbidity and mortality. Neutrophils and inflammatory mediators play a critical role in the pathogenesis of postoperative complications. The aim of this study was to evaluate the effect of intraoperative ketamine administration on the inflammatory response in patients undergoing cardiac surgery using routinely employed immuno-inflammatory parameters in clinical practice.

Methods:

After randomization, patients were divided into two groups: the ketamine group and the control group. Following admission to the operating room, standard monitoring and anesthesia induction were performed. In addition to the control group, patients in the ketamine group received 1 mg/kg ketamine during induction and a continuous intravenous infusion of 2.4 mg/kg/h ketamine for maintenance.

Immuno-inflammatory parameters were assessed using routine blood tests obtained preoperatively and on postoperative day 1. These parameters included leukocyte, neutrophil, lymphocyte, and platelet counts; neutrophil-to-lymphocyte ratio (NLR); platelet-to-lymphocyte ratio (PLR); NLR index; delta NLR; ΔPLR; PLR index; systemic inflammatory response index (SIRI); systemic immune-inflammation index (SII); and C-reactive protein (CRP), ΔCRP, and CRP index. In addition, patients' pain scores within the first 24 hours following postoperative extubation, as well as hospital mortality and morbidity rates, were evaluated.

Participants and Study Design We conducted a single-center, randomized, controlled, single-blind clinical study including patients scheduled for cardiac surgery. Patients aged 18-80 years who were able to provide informed consent and reliably communicate their symptoms to the research team, and who were scheduled for elective cardiac surgery, were included in the study.

Patients were excluded if they had contraindications to anesthesia; cognitive impairment or communication barriers; end-stage renal failure (receiving routine hemodialysis); pregnancy or lactation; a known history of ketamine allergy; ejection fraction (EF) <35%; planned emergency or reoperation; arrhythmia; morbid obesity; psychiatric disorders; hepatic failure; use of anti-inflammatory medications; preoperative white blood cell count (leukocyte) ≥15 × 10³/µL; C-reactive protein (CRP) ≥30 mg/L; or refusal to participate in the study.

A total of 177 patients scheduled for cardiac surgery at Necmettin Erbakan University Meram Faculty of Medicine Hospital were enrolled between October 30, 2022, and March 30, 2023. Eleven patients were excluded due to surgical cancellation and data loss. Six patients who died intraoperatively or within the first 24 hours postoperatively were excluded from biomarker analyses due to unavailable postoperative measurements; however, these patients were included in the mortality analysis. A total of 160 patients with complete postoperative data were included in the primary biomarker analysis. Patients were randomly assigned to either the ketamine group or the control group, with 80 patients in each group.

Randomization Patients were randomized using the closed opaque envelope method by a researcher who was not involved in study coordination or data collection.

Anesthesia Protocol In the operating room, patients received intravenous (IV) premedication with 1 mg midazolam and 50 µg fentanyl. Standard noninvasive monitoring (electrocardiogram and peripheral oxygen saturation) was applied to all patients. Under local anesthesia, the radial artery was cannulated with a 20 G catheter, and invasive arterial blood pressure monitoring was initiated. Hemodynamic data were recorded using invasive measurements. Drug doses were calculated based on adjusted body weight.

For anesthesia induction, all patients received 0.1 mg/kg midazolam, 3 µg/kg fentanyl, and 0.6 mg/kg rocuronium IV. In addition, patients in the ketamine group received ketamine at a dose of 1 mg/kg during induction and a continuous infusion of 2.4 mg/kg/h. After achieving adequate muscle relaxation and anesthetic depth, endotracheal intubation was performed. Following intubation, a central venous catheter was placed via the right internal jugular vein.

Analgesia management was guided by hemodynamic parameters and Surgical Pleth Index (SPI) monitoring, an objective nociceptive monitoring method based on photoplethysmographic signals. Baseline hemodynamic parameters [heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP)] were recorded before induction (after sedation). Hemodynamic parameters were recorded immediately before intubation, every minute during the first 5 minutes, and then every 10 minutes throughout the operation.

Anesthesia maintenance was achieved with remifentanil IV infusion (0.1-0.3 µg/kg/min) and 0.5-1 minimum alveolar concentration (MAC) sevoflurane inhalation. Nociceptive and/or hemodynamic management was guided by SPI (target range: 40-60), HR, and SAP, with a 20-30% deviation from baseline values considered significant. Hypotension was treated with ephedrine or norepinephrine, while hypertension was managed by adjusting remifentanil and sevoflurane doses.

For postoperative pain management, 0.1 mg/kg morphine was administered as a slow IV bolus one hour before the end of surgery, and 10-15 mg/kg IV paracetamol was administered three times daily (every 8 hours) in the postoperative period. After surgery, all patients were transferred to the intensive care unit (ICU) while intubated and received sedoanalgesia with remifentanil (0.05-0.1 µg/kg/min) and dexmedetomidine (0.5-1 µg/kg/h) infusions until extubation criteria were met.

Based on blood gas analysis and clinical parameters, patients were weaned from mechanical ventilation once hemodynamic stability and normothermia were achieved. After meeting weaning criteria, patients were extubated. Post-extubation rescue analgesia consisted of tramadol (1 mg/kg, 50-100 mg). Pain severity during the first 24 hours after extubation was assessed, and routine laboratory (hemogram) tests were performed.

Routine blood tests obtained preoperatively and on postoperative day 1 were analyzed to determine leukocyte, neutrophil, lymphocyte, and platelet counts; neutrophil-to-lymphocyte ratio (NLR); NLR index; delta NLR; platelet-to-lymphocyte ratio (PLR); PLR index; delta PLR; C-reactive protein (CRP); CRP index; delta CRP; systemic inflammatory response index (SIRI); and systemic immune-inflammation index (SII). Additionally, cardiopulmonary bypass (CPB) parameters and vasoactive inotropic score (VIS) mean and end-of-operation values were recorded.

The vasoactive inotropic score (VIS) was calculated as follows:

Index values were defined as the ratio of postoperative to preoperative measurements.

Delta values were calculated by subtracting preoperative measurements from postoperative measurements.

SIRI was calculated using the formula: neutrophil count × monocyte count / lymphocyte count.

SII was calculated using the formula: platelet count × neutrophil count / lymphocyte count.

Additionally, extubation times, additional analgesic requirements within the first 24 hours after extubation, Numeric Rating Scale (NRS) scores and Prince Henry Hospital Pain Score (PHHPS), ICU and hospital length of stay, and 28-day mortality rates were recorded in detail.

Sample Size Calculation A pilot study was conducted with 10 patients in each group to determine the sample size. Based on the analysis of the pilot data, a total of 144 patients (at least 72 patients per group) was calculated to be sufficient to compare the two groups, with a statistical power of 95%, a type I error rate of 5%, and an effect size of 0.55.

Statistical Analysis The data obtained in this study were analyzed using the IBM SPSS 23.0 (IBM Corp., Armonk, New York, USA) statistical software package. The level of statistical significance was set at p < 0.05. Initially, the normality of data distribution was assessed using the Shapiro-Wilk tests. Based on the results (p > 0.05), the data were considered to be normally distributed, and the use of parametric tests was deemed appropriate. For comparisons between groups based on continuous variables, the independent samples t-test was used. For comparisons of categorical variables, the chi-square test was applied.

Inclusion Criteria

• Patients aged 18-80 years.
• Scheduled to undergo elective cardiac surgery.
• Able to provide informed consent.
• Able to reliably communicate symptoms to the research team. Exclusion Criteria
• Contraindications to anesthesia.
• Cognitive impairment or communication barriers.
• End-stage renal failure (receiving routine hemodialysis).
• Pregnancy or breastfeeding.
• Known allergy to ketamine.
• Ejection fraction (EF) <35%.
• Emergency or repeat surgery.
• Arrhythmia.
• Morbid obesity.
• Psychiatric disorders.
• Hepatic failure.
• Use of anti-inflammatory medications.
• Preoperative white blood cell count (leukocyte) ≥15 × 10³/µL.
• C-reactive protein (CRP) ≥30 mg/L.
• Declined to participate in the study

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Starting March 2026 and available upon reasonable request

De-identified individual participant data will be available upon reasonable request from the corresponding author (turgayatay@gmail.com). Requests will be evaluated based on scientific merit and ethical considerations. Data will be shared after approval of a research proposal and signing of a data use agreement.