Postoperative delirium (PD) is a common and serious complication after cardiac surgery, contributing to extended hospital stays, increased morbidity, and reduced quality of life. Despite ongoing efforts to identify preventive strategies, the precise mechanisms behind PD remain elusive, though inflammation and blood-brain barrier (BBB) disruption have been strongly implicated.
A growing body of literature suggests that tranexamic acid (TXA), a widely used antifibrinolytic agent in cardiac surgery, may have beneficial anti-inflammatory and neuroprotective properties. These are believed to result from TXA’s inhibition of plasmin, which contributes to neuroinflammation and BBB permeability. This retrospective cohort study, conducted at the Royal Papworth Hospital in the UK, set out to determine whether different weight-adjusted doses of TXA have a dose-dependent impact on the incidence of PD in patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB).
Study Design and Methodology
The study evaluated 5,525 adult patients who underwent elective or semi-urgent cardiac surgery with CPB between May 2018 and September 2022. Patients undergoing emergency surgeries, organ transplants, or those involving deep hypothermic circulatory arrest were excluded. All patients received TXA due to UK NICE guidelines mandating its use in surgeries with moderate bleeding risk, precluding a TXA-free control group.
TXA was given as a fixed 2g bolus before heparinization, irrespective of patient weight. Based on resulting mg/kg dosing, patients were divided into three groups:
- Group A: ≤22 mg/kg (n=1780)
- Group B: 22.01–27 mg/kg (n=2130)
- Group C: ≥27.01 mg/kg (n=1615)
Postoperative delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU), with any positive entry in the first 48 hours considered indicative of PD.
Key Findings
- Overall, 18% of patients experienced at least one CAM-ICU positive episode within 48 hours postoperatively.
- PD incidence did not significantly differ between TXA dose groups: 18% in Group A, 17% in Group B, and 20% in Group C (p = 0.25).
- No statistically significant differences were found in ICU or hospital length of stay among the dose groups for CAM-ICU positive or negative patients.
- PD was more common in older patients, those with poor left ventricular function, longer CPB and aortic cross-clamp times, and patients undergoing more complex surgeries.
- Notably, there were no reported seizures across the patient cohort, suggesting TXA at these dosing levels is neurologically safe in this context.
Implications and Discussion
Although TXA has shown promise in reducing neuroinflammation in trauma and elective surgery settings, these findings suggest that it does not offer a dose-dependent protective effect against PD in cardiac surgical patients. This may be due to the multifactorial nature of PD, which involves not only neuroinflammation but also ischemic injury, baseline cognitive function, and other systemic factors that TXA does not influence.
Previous studies on TXA have reported both neurotoxic and neuroprotective outcomes. High-dose TXA has historically been associated with seizures due to its potential to inhibit GABA and glycine receptors. However, the 2g fixed bolus used in this study aligns with more contemporary dosing practices, which are considered safe and not associated with increased seizure risk.
TXA’s hypothesized neuroprotective mechanisms—such as reducing BBB permeability and neuroinflammation—remain biologically plausible. Yet, the clinical data here suggest that if these mechanisms do offer benefit, it may not be sufficient to overcome other stronger contributors to PD in this patient population.
The study’s retrospective design is a notable limitation. While it reflects real-world practice and leverages a robust electronic health record system, it cannot establish causality or eliminate potential confounding factors such as variations in hemodynamic management, transfusion practices, or pre-existing cognitive impairments.
The lack of a control group (i.e., patients not receiving TXA) further restricts interpretation, though this is due to national clinical guidelines mandating TXA use in cardiac surgery. Moreover, the fixed-dose approach, rather than weight-adjusted administration, may have introduced variability in actual systemic drug exposure.
This large, real-world retrospective study concludes that within the clinically acceptable dose ranges of TXA, there is no dose-dependent reduction in the incidence of postoperative delirium following cardiac surgery. The results underscore the complex and multifactorial nature of PD, which likely requires multi-pronged prevention strategies.
Future research should include prospective, randomized trials with variable TXA dosing and possibly even placebo controls where ethically permissible. International studies or those involving other surgical specialties (e.g., the TRIGS-D trial) may provide further insight into TXA’s neuroprotective potential across diverse populations and conditions.
