Postoperative delirium (POD) is a frequent and serious complication following cardiac surgery with cardiopulmonary bypass (CPB), associated with prolonged hospitalization, impaired rehabilitation, increased healthcare costs, and higher mortality. Despite decades of recognition, effective preventive strategies for POD remain limited. Increasing evidence suggests that neuroinflammation triggered by CPB-related systemic inflammatory responses plays a central role in the pathogenesis of delirium and early postoperative cognitive disturbances. Against this background, Lan and colleagues conducted a randomized controlled trial to evaluate whether zero-balance ultrafiltration (Z-BUF), when added to conventional ultrafiltration, could reduce delirium and improve postoperative cognitive outcomes in adult cardiac surgery patients.
This prospective, single-blinded randomized trial enrolled adults aged 18 years or older undergoing cardiac surgery requiring CPB. Patients were randomly assigned in a 1:1 ratio to either conventional ultrafiltration alone or conventional ultrafiltration combined with Z-BUF. Importantly, the study design incorporated rigorous masking: patients, outcome assessors, follow-up personnel, and statisticians were blinded to group allocation, minimizing assessment bias. The trial was ethically approved and registered with the Chinese Clinical Trial Registry, and it followed CONSORT reporting standards.
Ultrafiltration strategies differed primarily in timing and intent. Conventional ultrafiltration was performed during the rewarming phase of CPB and focused mainly on fluid removal and hemoconcentration. In contrast, Z-BUF was initiated earlier, after aortic cross-clamping, and emphasized continuous removal of inflammatory mediators through a “filter-and-replace” mechanism that maintained intravascular volume stability. A standardized Z-BUF dose of 35 mL/kg was selected to maximize inflammatory mediator clearance while avoiding electrolyte imbalance or hemolysis.
The primary outcome was the incidence of POD within the first seven postoperative days, assessed twice daily using validated tools—the Confusion Assessment Method (CAM) and CAM-ICU. Delirium subtypes (hyperactive, hypoactive, and mixed) were also recorded. Secondary outcomes included postoperative cognitive dysfunction (POCD) assessed by the Mini-Mental State Examination (MMSE) at 1 and 3 months, as well as postoperative complications, duration of mechanical ventilation, ICU stay, and total hospital length of stay.
Of 183 patients screened, 116 were randomized, and 106 were ultimately included in the final analysis. Baseline demographic and clinical characteristics were well balanced between groups, including age, sex, comorbidities, baseline cognitive function, surgical type, and CPB duration. This balance strengthens the internal validity of the findings and supports the interpretation that observed differences were attributable to the ultrafiltration strategy.
The results demonstrated a clinically and statistically significant reduction in postoperative delirium among patients receiving Z-BUF. Within the first seven postoperative days, delirium occurred in 22.6% of patients in the Z-BUF group compared with 50.9% in the conventional ultrafiltration group, corresponding to a relative risk reduction of 55% and a number needed to treat of approximately four. Importantly, reductions were observed across delirium subtypes, with fewer hyperactive episodes and fewer patients experiencing multiple delirium episodes in the Z-BUF group.
In contrast, longer-term cognitive outcomes did not differ significantly between groups. MMSE scores at 1 and 3 months postoperatively were similar, and the incidence of MMSE-defined cognitive impairment was numerically lower but not statistically different in the Z-BUF group. These findings suggest that while Z-BUF effectively mitigates acute delirium, its influence on longer-term cognitive recovery may be limited or may require larger studies with more sensitive neuropsychological testing to detect differences.
Postoperative complications—including pneumonia, pleural effusion, and acute kidney injury—were comparable between groups, as were ICU and hospital lengths of stay. These findings indicate that the addition of Z-BUF did not increase perioperative risk and was safe within the studied protocol.
Mechanistically, the authors propose that Z-BUF reduces POD primarily through attenuation of the systemic inflammatory response associated with CPB. By continuously clearing small-molecule inflammatory mediators and stabilizing endothelial function, Z-BUF may reduce blood–brain barrier disruption and subsequent neuroinflammation. Improved volume control and cerebral perfusion during CPB may also contribute to its protective effect. These hypotheses are supported by prior pediatric and experimental studies demonstrating the anti-inflammatory potential of Z-BUF, though adult data have historically been sparse.
The study has several limitations. It was conducted at a single center, potentially limiting generalizability. The sample size was powered for delirium outcomes rather than long-term cognition, which may explain the lack of statistically significant differences in POCD. Cognitive assessment relied on the MMSE, a global screening tool that may not detect subtle deficits in specific cognitive domains. Additionally, subgroup analyses were exploratory and not prespecified, warranting cautious interpretation.
Despite these limitations, this trial provides important high-quality evidence that perfusion-based strategies can meaningfully reduce postoperative delirium after cardiac surgery. The findings highlight Z-BUF as a practical intraoperative intervention that targets inflammation at its source, rather than relying solely on pharmacologic or postoperative measures. Larger, multicenter trials with longer follow-up and more comprehensive neurocognitive testing are now needed to confirm these results and clarify the long-term cognitive implications.
