Major head and neck cancer surgery requiring free-flap reconstruction is typically prolonged and combines extensive oncologic resection and microvascular reconstruction with complex airway management and intensive postoperative flap surveillance.5<\/a> Perioperative tissue injury, hemodynamic fluctuation, postoperative pain, sleep disruption, inflammatory activation, tracheal intubation or tracheostomy, and communication difficulties may further predispose these patients to postoperative delirium. Previous studies have identified several risk factors for delirium after head and neck or oral cancer surgery, including advanced age, prolonged operative time, tracheotomy, blood transfusion, flap reconstruction, and postoperative complications.6\u20139<\/a> In this setting, delirium may not only delay general recovery but also interfere with airway safety, wound care, flap monitoring, early mobilization, and nutritional rehabilitation.<\/p>\n Dexmedetomidine, a highly selective \u03b12-adrenoceptor agonist, has sedative, anxiolytic, analgesic, sympatholytic, and opioid-sparing properties. Its cooperative and arousable sedative profile may be advantageous during perioperative recovery. Dexmedetomidine may also target several modifiable pathways related to delirium, including sleep disruption, pain and opioid exposure, sympathetic activation, and perioperative inflammation.10\u201313<\/a> These effects are clinically relevant for patients undergoing major head and neck reconstruction, in whom sleep disturbance, pain, and inflammatory responses are common after surgery. However, dexmedetomidine can cause bradycardia and hypotension, which remains a concern during lengthy reconstructive procedures requiring careful haemodynamic management.<\/p>\n Although perioperative dexmedetomidine has been evaluated for delirium prevention in several surgical populations, the available evidence remains inconsistent and may depend on patient characteristics, surgical type, dose regimen, timing of administration, and postoperative care setting.10<\/a>,11<\/a> Patients undergoing head and neck cancer surgery with free-flap reconstruction have been underrepresented in previous studies. This population has unique perioperative challenges, including oncological resection, microvascular reconstruction, airway-related discomfort, communication barriers, pain, sleep disturbance, inflammation, and intensive flap monitoring. Whether intraoperative dexmedetomidine infusion can reduce postoperative delirium in this specific high-risk population without increasing haemodynamic instability or postoperative complications remains uncertain.<\/p>\n The parent trial primarily evaluated postoperative recovery quality and postoperative complications, with postoperative delirium (POD) prespecified as a secondary outcome. In this delirium-focused secondary analysis, we evaluated the association between intraoperative dexmedetomidine and POD in patients undergoing head and neck cancer surgery with free-flap reconstruction. The primary outcome was POD within the first 5 postoperative days; secondary outcomes included postoperative sleep, pain, inflammatory biomarkers, recovery measures, and perioperative safety. We hypothesized that intraoperative dexmedetomidine would be associated with a lower incidence of POD and improved early postoperative outcomes without an increase in adverse events.<\/p>\n Methods This was a delirium-focused secondary analysis of a single-centre, randomized, double-blind, placebo-controlled trial conducted at the Guangxi Medical University Affiliated Stomatological Hospital in Nanning, China. Participants were recruited between January 2023 and July 2023, with follow-up through postoperative day 60. The study protocol was approved by the Ethics Committee of Guangxi Medical University Affiliated Stomatological Hospital (approval No. 2022094). Written consent was obtained from each participating patient. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300067376) on January 5, 2023. Postoperative delirium was prospectively assessed and prespecified as a secondary outcome in the parent trial. In this delirium-focused secondary analysis, postoperative delirium was the main outcome of interest.<\/p>\n Patients<\/p>\n We considered patients aged > 18 yr old with head and neck cancer and an American Society of Anesthesiologists (ASA) physical status of I\u2013III who were scheduled for elective surgery requiring free-flap reconstruction under general anaesthesia. A Mini-Mental State Examination (MMSE) score was required (maximum score 30, with higher scores being better). Cognitive dysfunction was defined as an MMSE score <17 in patients without formal education, <20 in patients with primary school education, and <24 in patients with middle school education or higher. Patients with cognitive dysfunction were excluded from enrolment. The Mini-Mental State Examination (MMSE) is a copyrighted instrument and was used with written permission from PAR, Inc. We excluded patients who were allergic to dexmedetomidine, used long-term psychotropic medications or drug abuse, language impairment, severe bradycardia, sick sinus syndrome or second-to-third degree atrioventricular block, or severe hepatic or renal dysfunction.<\/p>\n Randomisation and Masking<\/p>\n Patients were randomly assigned in a 1:1 ratio to receive dexmedetomidine or placebo. The allocation sequence was generated before enrolment, and assignments were concealed in sequentially numbered, opaque, sealed envelopes by personnel not involved in clinical management or outcome assessment.<\/p>\n An independent staff member prepared the study drug according to treatment allocation. Dexmedetomidine was diluted to 4 \u03bcg mL\u22121, and placebo consisted of an equivalent volume of normal saline. Both preparations were labelled as study drug and were indistinguishable in appearance. Patients, anaesthesiologists, surgeons, ward clinicians, and outcome assessors were masked to treatment allocation.<\/p>\n Procedures<\/p>\n Propofol (2.5\u20133.0 \u03bcg mL\u22121) and sufentanil (0.2\u20130.3 ng mL\u22121) were given for anaesthetic induction at target-controlled infusion, and Cisatracurium (0.15\u20130.2 mg kg\u22121) were given for neuromuscular block. After tracheal intubation, patients were mechanically ventilated with a tidal volume of 8\u201310 mL kg\u22121 actual body weight and a respiratory rate of 10\u201312 bpm to maintain end-tidal carbon dioxide (ETCO2) of 35\u201345 mmHg. After induction of anaesthesia and stabilisation of vital signs, subjects assigned to the dexmedetomidine group were given a continuous infusion of dexmedetomidine (Yangtze River Pharmaceutical Group Co, Ltd, Jiangsu, China) at a rate of 0.3 \u03bcg kg\u22121 h\u22121 until 1\u00a0h before the end of surgery. Subjects in the placebo group were given comparable volumes of normal saline.<\/p>\n Anaesthesia was maintained with target-controlled propofol 2.5\u20133.0 \u03bcg mL\u22121 and sufentanil 0.2\u20130.3 ng mL\u22121. The propofol target concentration was adjusted to maintain a BIS of 40\u201360, while sufentanil was adjusted according to haemodynamic responses to surgical stimulation. Cisatracurium was infused at 5\u20137 mg h\u22121 for neuromuscular blockade. During osteotomy and tumour resection, controlled hypotension was permitted, targeting a mean arterial pressure of 60\u201370 mmHg or a systolic blood pressure reduction not exceeding 30\u201340% from baseline. Controlled hypotension was limited to 30 min. During other surgical periods, systolic blood pressure was maintained within 20% of baseline whenever possible.<\/p>\n Intraoperative fluid therapy consisted primarily of lactated Ringer\u2019s solution, with colloid administered according to an approximate crystalloid-to-colloid ratio of 3:1. Tramadol 100 mg was administered intravenously approximately 10 min before the end of surgery. At the end of surgery, airway management, including retention of the endotracheal tube or tracheostomy, was determined by the surgical team according to airway and surgical requirements. Subjects recovered from anaesthesia in the postanaesthesia care unit (PACU), or an intensive care unit (ICU). The environment was generally quiet and comfortable Subjects were not normally given pharmaceutical treatments to reduce delirium, but clinicians were allowed to give any drugs they deemed necessary.<\/p>\n Outcomes<\/p>\n Outcome assessment was done by research members who were trained before the study and not involved in the clinical care of patients. The primary endpoint of the present analysis was the incidence of delirium during the first 5 postoperative days. Delirium was assessed once daily from postoperative day 1 through postoperative day 5 using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for critical care patients,14<\/a> or the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) for wards assessments,15<\/a> combined with the Richmond Agitation Sedation Scale (RASS).16<\/a> All diagnostic tests were conducted by investigators blinded to treatment.<\/p>\n For patients with delirium, time to onset, duration, number of delirium-positive days, and motor subtype were recorded. Motor subtype was classified using RASS findings during delirium-positive assessments. Hyperactive delirium was defined by consistently positive RASS scores (+1 to +4), hypoactive delirium by consistently neutral or negative RASS scores (\u22123 to 0), and mixed delirium by both positive (+1 to +4) and neutral or negative RASS scores (\u22123 to 0) during the delirium period.<\/p>\n Other outcomes included postoperative sleep quality, sleep disturbance, pain intensity, recovery-related questionnaire outcomes, adverse events, and postoperative complications. Sleep quality was assessed using the Numeric Rating Scale (NRS; an 11-point scale where 0 indicated the best possible sleep and 10 indicated the worst possible sleep) at baseline, on postoperative days 0\u20136, and on postoperative day 60. Postoperative sleep disturbance during postoperative days 0\u20131 was prespecified as an NRS score of \u22656 on either day.17<\/a> Pain intensity both at rest and with movement was assessed using the NRS (an 11-point scale where 0 indicated no pain and 10 indicated the worst possible pain) at the end of surgery and on postoperative days 1\u20137. Anxiety and depressive symptoms were assessed with the Generalized Anxiety Disorder-7 scale and Patient Health Questionnaire-9, respectively, preoperatively and on postoperative days 7 and 60. The Postoperative Quality Recovery Scale (PQRS) was administered preoperatively and on postoperative day 7; the PQRS cognitive domain was also assessed on postoperative day 60.<\/p>\n Venous blood samples were collected before anaesthesia induction, immediately after surgery, and on postoperative days 1, 2, and 3. Samples were centrifuged at 3000 rpm for 15 min at room temperature, and serum was stored at \u221280\u00b0C until analysis. Serum interleukin-6, tumour necrosis factor-\u03b1, and S100 calcium-binding protein B concentrations were measured by enzyme-linked immunosorbent assay according to the manufacturer\u2019s instructions. White blood cell count was extracted from the hospital laboratory information system at predefined perioperative time points.<\/p>\n Safety outcomes included intraoperative bradycardia, hypotension, hypertension, arrhythmia, cumulative duration of haemodynamic events. Bradycardia was defined as heart rate less than 55 bpm or a decrease of more than 20% from baseline. Hypotension was defined as systolic blood pressure less than 90 mmHg or a decrease of more than 20% from baseline. Tachycardia was defined as heart rate greater than 100 bpm or an increase of more than 20% from baseline. Hypertension was defined as systolic blood pressure greater than 160 mm Hg or an increase of more than 20% from baseline. Postoperative complications during hospitalisation included pulmonary infection, flap vascular compromise, flap necrosis, wound infection, and other clinically relevant complications.<\/p>\n Statistical Analysis<\/p>\n Statistical analyses were performed with IBM SPSS Statistics version 26.0, Python version 3.10, and GraphPad Prism version 10.0. Postoperative delirium within the first 5 postoperative days was the primary outcome of the present secondary analysis and a prespecified secondary outcome of the parent trial. The parent trial designated postoperative recovery quality and postoperative complications as primary outcome. Its sample size was prospectively determined from pilot estimates of POD incidence (10% with dexmedetomidine vs 40% with placebo). With a two-sided \u03b1 of 0.05, 90% power, and 1:1 allocation, 39 patients per group were required. Allowing for up to 20% attrition, the target sample size was 98 patients (49 per group). No separate sample-size calculation was undertaken for the present secondary analysis. The analysis was performed on a complete-case basis and included all randomized patients with available outcome data; missing outcome data were not imputed.<\/p>\n Continuous variables were assessed for distributional characteristics by inspection of histograms and Q\u2013Q plots and with the Shapiro\u2013Wilk test. Approximately normally distributed variables are presented as mean \u00b1 standard deviation and were compared with independent-samples t tests. Skewed continuous variables and ordinal variables are presented as median with interquartile range and were compared with Mann\u2013Whitney U-tests. Categorical variables are presented as number and percentage and were compared with Pearson \u03c72-tests or Fisher\u2019s exact tests, as appropriate.<\/p>\n The incidence of postoperative delirium was compared between groups using the Pearson \u03c72 or Fisher\u2019s exact tests, as appropriate. Unadjusted risk ratios (RRs) with 95% confidence intervals were calculated from the observed event proportions. Univariable and multivariable logistic regression models were used to evaluate the association between dexmedetomidine and postoperative delirium, with placebo as the reference. The multivariable model included treatment group, age, preoperative Mini-Mental State Examination score, and operative time. Adjusted associations from the multivariable logistic regression model are expressed as odds ratios (ORs) with 95% confidence intervals. Given the between-group difference in total intraoperative fluid volume, a sensitivity analysis additionally included total fluid volume in the multivariable model.<\/p>\n Time to first postoperative delirium was analyzed with the Kaplan\u2013Meier method, with patients who did not develop delirium censored on postoperative day 5 or at the last available delirium assessment. Between-group differences were assessed with the Log rank test, and hazard ratios with 95% confidence intervals were estimated with a univariable Cox proportional hazards model.<\/p>\n Repeated-measures outcomes were analyzed with linear mixed-effects models including treatment group, time, and the group-by-time interaction as fixed effects, with patient ID as a random intercept. Model-based between-group contrasts at individual time points were estimated when appropriate and are reported as mean differences with 95% confidence intervals. Other postoperative recovery outcomes, inflammatory biomarkers, questionnaire scores, and safety outcomes were analyzed according to their measurement scale and distribution. Questionnaire-score differences were summarized with Hodges\u2013Lehmann estimates and 95% confidence intervals. Binary safety outcomes and postoperative complications were summarized as risk ratios with 95% confidence intervals; for outcomes with zero events in one group, a continuity correction was applied.<\/p>\n Because this was a secondary analysis and multiple secondary or exploratory outcomes were evaluated, no formal adjustment for multiplicity was performed. Accordingly, p values for outcomes other than the primary endpoint of this secondary analysis should be interpreted as nominal and exploratory. All tests were two-sided, and p < 0.05 was considered statistically significant.<\/p>\n Results<\/p>\n Of 115 patients screened, 100 underwent randomization. Before randomization, 12 patients were excluded because they did not meet the inclusion criteria and 3 declined to participate. During follow-up, outcome data were unavailable for 1 patient in the placebo group and 3 in the dexmedetomidine group were; 96 patients were included in the analysis (49 placebo group and 47 dexmedetomidine) (Figure 1<\/a>). Baseline characteristics were generally similar between groups. Demographic variables, tumor-related characteristics, comorbidities, and preoperative cognitive status did not differ significantly between groups (Table 1<\/a>). Perioperative variables were likewise comparable, including flap type, extent of neck dissection, operative duration, anesthesia duration, flap ischemia time, blood loss, intraoperative hypotension, cumulative duration of hypotension, norepinephrine use, and atropine use. Total intraoperative fluid volume was higher in the dexmedetomidine group than in the placebo group (4617 \u00b1 992 mL vs 4112 \u00b1 841 mL, p = 0.008; Table 2<\/a>).<\/p>\n Table 1 Clinical Characteristics of Subjects at Baseline<\/p>\n
<\/p>\n Table 2 Intraoperative and Perioperative Characteristics<\/p>\n
<\/p>\n Figure 1 CONSORT flow diagram of the study. Patient enrollment, randomization, follow-up, and analysis.<\/p>\n
<\/p>\n During the first 5 postoperative days, postoperative delirium occurred in 7 of 47 patients (14.9%) in the dexmedetomidine group and 17 of 49 patients (34.7%) in the placebo group (Figure 2A<\/a>). In the time-to-event analysis, time to first postoperative delirium differed between groups (log-rank p = 0.026; Figure 2B<\/a>). The hazard of postoperative delirium was lower with dexmedetomidine than with placebo (HR, 0.40; 95% CI, 0.18\u20130.88). In univariable analysis, dexmedetomidine was associated with lower odds of postoperative delirium than placebo (OR, 0.33; 95% CI, 0.12\u20130.89; p = 0.029; Table 3<\/a>). This association remained significant after adjustment for age, MMSE score, and operative time (adjusted OR, 0.31; 95% CI, 0.10\u20130.92; p = 0.036). In a sensitivity analysis additionally adjusting for total intraoperative fluid volume, the association was materially unchanged (adjusted OR, 0.31; 95% CI, 0.10\u20130.96; p = 0.043). In the adjusted model, higher MMSE score was associated with lower odds of postoperative delirium (adjusted OR per point, 0.68; 95% CI, 0.50\u20130.93; p = 0.015; Table 3<\/a>), whereas age showed a borderline association (p = 0.061). Operative time was not significantly associated with postoperative delirium.<\/p>\n Table 3 Univariable and Multivariable Logistic Regression Analyses for Postoperative Delirium<\/p>\n
<\/p>\n Figure 2 Postoperative delirium (POD) outcomes. (A) Incidence of POD during postoperative days 1\u20135. Error bars indicate 95% confidence intervals. (B) Cumulative incidence of POD during postoperative days 1\u20135. p value was calculated using the Log rank test.<\/p>\n Abbreviations: POD, postoperative delirium; CI, confidence interval.<\/p>\n
<\/p>\n Among patients who developed delirium, the distribution of motor subtypes was broadly similar between groups, although the number of events was small. Hyperactive delirium accounted for 42.9% of cases in the dexmedetomidine group and 35.3% in the placebo group, whereas hypoactive delirium occurred in 42.9% and 41.2%; mixed delirium was less common in both groups. Delirium occurred most frequently on postoperative day 1, and neither time to onset nor duration differed significantly between groups. Median duration was 2.0 (2.0\u20133.0) days in the dexmedetomidine group and 2.0 (2.0\u20134.0) days in the placebo group (Table 4<\/a>).<\/p>\n Table 4 Postoperative Delirium and Recovery Outcomes in the Placebo and Dexmedetomidine Groups<\/p>\n
<\/p>\n Compared with placebo, dexmedetomidine was associated with less sleep disturbance during postoperative days 0\u20131 (51.1% vs 71.4%; RR, 0.72; 95% CI, 0.51\u20131.00; p = 0.040). Sleep quality score on postoperative day 0 was lower in the dexmedetomidine group than in the placebo group (3.0 [2.0\u20135.0] vs 4.0 [4.0\u20136.0], p = 0.003), whereas the between-group difference was no longer significant on postoperative day 1 (p = 0.441). The maximum head and neck pain score during postoperative days 1\u20137 was also lower in the dexmedetomidine group (4.0 [3.0\u20135.5] vs 5.0 [3.0\u20136.0], p = 0.041; Table 4<\/a>).<\/p>\n In mixed-effects analyses, significant time effects were observed for head and neck pain, sleep quality, and serum IL-6 (all p < 0.001; Table 5<\/a>), indicating postoperative change over time. For head and neck pain and sleep quality, neither the overall group effect nor the group-by-time interaction was significant. For sleep quality, post hoc analysis showed a between-group difference only on postoperative day 0 (mean difference, \u22121.35; 95% CI, \u22122.18 to \u22120.52; p = 0.002) (Figure 3<\/a>).<\/p>\n Table 5 Linear Mixed-Effects Models for Repeated Measures of Head and Neck Pain, Sleep Quality, and Serum IL\u20136<\/p>\n
<\/p>\n Figure 3 Postoperative trajectories of pain and sleep quality. (A) Head and neck pain assessed by Numeric Rating Scale (NRS) from the end of surgery to postoperative day 7. (B) Sleep quality scores also assessed by NRS from baseline to postoperative day 60. Data are expressed as mean \u00b1 SEM. No significant differences were observed between groups at any time point.<\/p>\n Abbreviations: NRS, Numeric Rating Scale; POD, postoperative day.<\/p>\n
<\/p>\n Preoperative IL-6 levels were similar between groups. At the immediate postoperative assessment, IL-6 was lower in the dexmedetomidine group than in the placebo (188.00 [109.37\u2013327.00] pg\/mL vs 250.29 [153.13\u2013471.88] pg\/mL, p = 0.034), with no significant differences observed on postoperative day 1\u20133 (Supplementary Table S1<\/a>). In the mixed-effects model, IL-6 showed a group-by-time interaction (p = 0.001); post hoc testing showed lower IL-6 levels in the dexmedetomidine group on postoperative day 0 (mean difference, \u221283.25; 95% CI, \u2212118.20 to \u221248.30; p < 0.001) (Figure 4A<\/a>). White blood cell count, tumor necrosis factor-\u03b1, and S100\u03b2 were similar between groups at all assessed time points (Supplementary Table S1<\/a>), with no clear separation in postoperative S100\u03b2 trajectories (Figure 4B<\/a>).
\n<\/p>\n Figure 4 Postoperative changes in serum biomarkers of inflammation and neurological injury. (A) Serum IL-6 levels. *p < 0.05 vs Placebo group. (B) Serum S100\u03b2 levels. No significant differences were observed between groups at any time point. Data are expressed as mean \u00b1 SEM. P values were calculated using a mixed effects model followed by Bonferroni post hoc test.<\/p>\n Abbreviations: IL-6, interleukin-6; Preop, preoperative; POD, postoperative day.<\/p>\n
<\/p>\n The incidences of early postoperative adverse events, including emergence agitation, emergence shivering, nausea and vomiting, somnolence, postoperative hypoxemia, and postoperative hypotension, were similar between groups. Intraoperative hemodynamic and cardiovascular adverse events were also comparable, with no significant between-group differences in overall arrhythmia, bradycardia, tachycardia, premature atrial contractions, premature ventricular contractions, intraoperative hypotension, or intraoperative hypertension (Supplementary Table S2<\/a>). Additional postoperative complications recorded during hospitalization, including delayed emergence, pulmonary infection, flap vascular compromise, flap necrosis, and wound infection, were likewise similar between groups (Supplementary Table S3<\/a>). Questionnaire-based outcomes, including overall PQRS scores, the PQRS cognitive domain assessed through postoperative day 60, GAD-7, and PHQ-9 scores, did not differ significantly at any assessed postoperative time point (Supplementary Table S4<\/a>).<\/p>\n Discussion<\/p>\n In this secondary analysis of a randomized and placebo-controlled trial, our results suggest that dexmedetomidine infusion was associated with a lower incidence of delirium in the first 5 days after surgery in patients undergoing head and neck cancer surgery with free-flap reconstruction. The association persisted after adjustment for age, preoperative cognitive function, and operative time. Dexmedetomidine was also associated with better subjective sleep quality, lower maximum head and neck pain scores, and an attenuated early postoperative IL-6 response, without a significant increase in the incidence of adverse events.<\/p>\n The 34.7% incidence of POD in the placebo group was relatively high but comparable with rates of approximately 33% reported in cohorts undergoing oral cancer surgery, including free-flap reconstruction.18<\/a>,19<\/a> Although higher than the pooled incidence of 20% after head and neck cancer surgery, it remained within the reported range of 4.2\u201336.9%.20<\/a> This supports the relevance of our findings to similar high-risk surgical populations. POD incidence was lower with dexmedetomidine, consistent with previous randomized trials,21<\/a>,22<\/a> whereas POD duration and time to onset were similar between groups. Postoperative delirium is a clinically important complication associated with delayed recovery, prolonged hospitalization, long-term cognitive decline, institutionalization, and mortality.23\u201326<\/a> Patients undergoing major head and neck oncologic surgery may be especially vulnerable because of prolonged anesthesia, extensive tissue injury, airway-related discomfort, postoperative pain, sleep disruption, inflammation, and intensive postoperative monitoring. In patients requiring flap reconstruction, delirium may further compromise communication, airway safety, wound care, flap monitoring, early mobilization, and nutritional rehabilitation. Previous studies have shown that postoperative delirium is not uncommon after head and neck cancer surgery, particularly after major procedures or free flap reconstruction.20<\/a>,27<\/a>,28<\/a><\/p>\n The present findings are broadly consistent with randomized trials suggesting that dexmedetomidine can reduce postoperative delirium in selected surgical populations. Prophylactic low-dose dexmedetomidine reduced delirium in elderly patients admitted to the intensive care unit after non-cardiac surgery,21<\/a> and intraoperative dexmedetomidine reduced delirium after brain tumor resection while improving postoperative analgesia and sleep quality. However, the evidence is not uniform.22<\/a> Other trials have reported no reduction in postoperative delirium or have raised concerns about hemodynamic adverse effects.29\u201331<\/a> The present analysis extends the evidence to patients undergoing head and neck cancer surgery with flap reconstruction, a population that has been relatively underrepresented in delirium-prevention trials.<\/p>\n Dexmedetomidine produces a sleep-like sedative state through pathways related to endogenous non-rapid eye movement sleep,32<\/a> and prior studies suggest that it may improve postoperative sleep quality.33<\/a>,34<\/a> In the present analysis, dexmedetomidine was associated with less early sleep disturbance, although the between-group difference in sleep quality was limited to postoperative day 0. Dexmedetomidine is analgesic,35<\/a>,36<\/a> the lower maximum head and neck pain scores in the dexmedetomidine group. Acute pain is a significant mediator of delirium37<\/a> and dexmedetomidine may therefore have contributed to reduced delirium in treated subjects.<\/p>\n Inflammation is another plausible pathway, as systemic inflammatory activation and neuroinflammation have been implicated in postoperative delirium.38\u201340<\/a> The significant group-by-time interaction for IL-6 and lower early postoperative IL-6 concentrations in the dexmedetomidine group are consistent with attenuation of the early inflammatory response. However, S100\u03b2 did not differ between groups, indicating that the biomarker findings were not consistent across markers. The mechanistic interpretation should therefore remain cautious, particularly because mediation was not formally tested.<\/p>\n Dexmedetomidine can cause bradycardia and hypotension, which are important concerns during lengthy reconstructive surgery. Controlled hypotension was permitted intraoperatively, and norepinephrine use was numerically higher in the dexmedetomidine group, although the incidence and cumulative duration of intraoperative hypotension did not differ significantly between groups. Because vasopressor support and controlled hypotension may have influenced the observed haemodynamic profile, the respective contributions of dexmedetomidine and perioperative haemodynamic management cannot be fully disentangled. The trial was not powered to detect differences in individual adverse events; the absence of statistically significant between-group differences should therefore not be interpreted as evidence of equivalent safety.<\/p>\n Several limitations merit consideration. POD was a prespecified secondary outcome of the parent trial and the primary outcome of the present secondary analysis. Although the parent-trial sample size was prospectively based on expected POD incidence, only 24 delirium events occurred, limiting the precision of multivariable estimates and the scope for covariate adjustment and subgroup analyses. Despite the small amount of missing outcome data, attrition bias due to the unequal loss to follow-up between groups cannot be excluded. Delirium was assessed once daily and only through postoperative day 5; given its fluctuating course, particularly in hypoactive presentations, transient episodes may have been missed, and later-onset delirium was not captured. The single-centre design and restriction to patients undergoing major head and neck cancer surgery with free-flap reconstruction may limit generalisability to other settings and surgical populations. The tidal-volume strategy (8\u201310 mL\/kg actual body weight) also differed from contemporary lung-protective practice. Total intraoperative fluid volume also differed between groups. Although additional adjustment for fluid volume did not materially alter the treatment estimate, the reason for this imbalance could not be established, and residual effects of differences in intraoperative fluid management cannot be excluded.<\/p>\n Conclusion<\/p>\n Our study indicates that intraoperative dexmedetomidine infusion was associated with a lower incidence of postoperative delirium in patients with head and neck cancer undergoing free-flap reconstruction. The administration of dexmedetomidine did not significantly increase the incidence of bradycardia, hypotension, or other events. These findings suggest the potential role of dexmedetomidine in improving early neurocognitive recovery in this high-risk surgical population. However, whether the favourable effects afforded by this application of dexmedetomidine result in improved long-term outcomes remains unknown.<\/p>\n MMSE Statement<\/p>\n An unauthorized version of the Chinese MMSE was used by the study team without permission, however this has now been rectified with PAR. The MMSE is a copyrighted instrument and may not be used or reproduced in whole or in part, in any form or language, or by any means without written permission of PAR (www.parinc.com<\/a>).<\/p>\n Data Sharing Statement<\/p>\n The data used in this study are not publicly available due to ethical restrictions related to participant privacy but can be made available from the corresponding author upon reasonable request.<\/p>\n Ethics Statements and Approval<\/p>\n This prospective study was conducted in accordance with the Declaration of Helsinki and approved by The Guangxi Medical University Affiliated Stomatological Hospital in Nanning, China (Approval Number: 2022094) and was registered with the Chinese Clinical Trial Registry (ChiCTR2300067376) prior to the enrollment of the first participant.<\/p>\n Consent to Publish Declaration<\/p>\n Written informed consent was obtained from all individual participants included in the study prior to their enrollment.<\/p>\n Funding<\/p>\n This work was supported by the Guangxi Science and Technology Base and Talent Special Project (No. AD25069060), Guangxi Key Research and Development Program (No. AB24010066), National Natural Science Foundation of China (No. 82460239), National Clinical Key Specialty Construction Project (CZ000037).<\/p>\n Disclosure<\/p>\n All authors declare no potential conflicts of interest related to the content of this manuscript.<\/p>\n References<\/p>\n 1.<\/a> Evered L, Silbert B, Knopman DS, et al. 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Oral Oncol. 2017;75:61\u201366. doi:10.1016\/j.oraloncology.2017.10.022<\/p>\n 6.<\/a> Zhu Y, Wang G, Liu S, et al. Risk factors for postoperative delirium in patients undergoing major head and neck cancer surgery: a meta-analysis. Jpn J Clin Oncol. 2017;47(6):505\u2013511. doi:10.1093\/jjco\/hyx029<\/p>\n 7.<\/a> Crawford JE, Zubair F, Baniulyte G, et al. Postoperative delirium in patients with head and neck oral cancer in the West of Scotland. Br J Oral Maxillofac Surg. 2021;59(3):353\u2013361. doi:10.1016\/j.bjoms.2020.08.116<\/p>\n 8.<\/a> Taxis J, Spoerl S, Broszio A, et al. Postoperative delirium after reconstructive surgery in the head and neck region. J Clin Med. 2022;11(22):6630. doi:10.3390\/jcm11226630<\/p>\n 9.<\/a> Ooms M, Schoo\u00df R, Puladi B, et al. Identification of risk factors for postoperative delirium in patients following intraoral reconstruction with microvascular free flaps: a matched-pair analysis. 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