Synthesizing the risk of postoperative delirium in organ transplantation

Abstract

This letter provides a critical appraisal of the comprehensive meta-analysis by Hou et al, which synthesizes the incidence and risk factors for postoperative delirium (POD) in organ transplant recipients. Their work establishes a pooled POD incidence of 20%, with significant variability across organ types (lung 34%, liver 22%, kidney 6%), and identifies key risk factors including primary graft dysfunction, hepatic encephalopathy, and high model for end-stage liver disease/acute physiology and chronic health evaluation II scores. This commentary acknowledges the study's strength in providing a robust, trans-organ synthesis of current evidence. However, it critically discusses the substantial heterogeneity, the counterintuitive non-significance of age as a risk factor, and the unavoidable limitation of unmeasured confounders inherent in meta-analyses, such as preoperative cognitive/psychiatric status and anesthetic protocols. While the findings provide an essential evidence base for risk stratification and prevention, this letter argues that the high heterogeneity underscores the need for organ-specific analysis and calls for large-scale, prospective studies with standardized protocols to translate these findings into reliable clinical prediction tools and targeted interventions.

Key Words: Postoperative delirium; Organ transplant; Risk factors; Statistical heterogeneity; Model for end-stage liver disease/acute physiology and chronic health evaluation II scores

Core Tip: The meta-analysis by Hou et al provides a crucial summary, establishing a 20% overall incidence of postoperative delirium in organ transplant patients, with rates varying significantly by organ. Key risk factors identified, such as primary graft dysfunction and high model for end-stage liver disease/acute physiology and chronic health evaluation II scores, offer actionable targets for clinical prevention. However, the study's substantial heterogeneity and the unexpected non-significance of age as a risk factor highlight the limitations of pooling diverse studies. This commentary emphasizes that while the meta-analysis is a valuable evidence synthesis, its findings should be interpreted with caution, paving the way for future prospective, organ-specific research with standardized protocols to develop robust clinical tools.

TO THE EDITOR

Postoperative delirium (POD) remains one of the most common and consequential neuropsychiatric complications in the surgical setting, particularly among the medically complex population of organ transplant recipients. As a manifestation of acute brain dysfunction, POD is associated with a cascade of adverse outcomes, including prolonged hospital stays, increased healthcare costs, long-term cognitive impairment, and heightened mortality[1,2]. Given that organ transplantation represents a life-saving intervention for end-stage organ disease, understanding and mitigating the risk of POD is a paramount concern for clinicians in transplant surgery, intensive care, and consultation-liaison psychiatry. The literature on this topic has been extensive but often fragmented, focusing on single organ types or specific risk factors.

In this context, the systematic review and meta-analysis by Hou et al[3], is a significant and welcome contribution. By synthesizing data from 39 studies, the authors provide a comprehensive overview of the current evidence, aiming to establish a more precise estimate of POD incidence and to identify a robust set of associated risk factors. This letter seeks to critically appraise this important work, discussing its strengths, inherent limitations, and its valuable implications for both current clinical practice and future research directions.

COMPARISON WITH EXISTING LITERATURE

The work by Hou et al[3] effectively consolidates a disparate body of literature. Previous meta-analyses have often been limited to a single organ, most commonly liver transplantation[4], or have included a smaller set of risk factors. By adopting a trans-organ approach (including liver, lung, kidney, and heart), Hou et al[3] provide a broader perspective, allowing for a direct comparison of POD incidence across different transplant types. Their finding of a pooled incidence of 22% in liver transplant recipients is consistent with the ranges reported in prior syntheses[4]. The meta-analysis by Hou et al[3] provides valuable, high-level evidence by directly quantifying the POD incidence rates for specific organ transplant types, confirming prior clinical impressions. Their findings – a much higher incidence in lung transplant recipients (34%) and a substantially lower incidence in kidney transplant recipients (6%) – are consistent with a prior meta-analysis that reported a higher rate of POD in lung transplant patients (10%-33%) compared to kidney transplant patients (3%-12%)[3]. The unique pathophysiology and patient characteristics associated with each procedure contribute to these differences. For example, lung transplant recipients often have more severe pre-operative pulmonary hypertension and are more likely to undergo long, complex surgeries requiring high doses of immunosuppressants, which are known risk factors for delirium. In contrast, kidney transplant recipients generally have lower surgical complexity and better pre-operative physical status compared to those awaiting lung transplantation. The higher rate of delirium in lung transplant recipients, despite hepatic scores being a strong determinant in other cohorts, can be explained by the distinct set of risk factors associated with this specific procedure. While hepatic encephalopathy is a robust predictor in liver transplant patients, delirium in lung transplant recipients is more strongly driven by factors such as prolonged operative time, extended intensive care unit stays, severe pre-operative pulmonary hypertension, and the unique neuroinflammatory response to lung transplantation. These procedure-specific variables, rather than hepatic function alone, appear to be the dominant drivers of delirium in this patient population.

The risk factors identified in the meta-analysis – such as a history of hepatic encephalopathy, high acute physiology and chronic health evaluation II (APACHE II) and model for end-stage liver disease (MELD) scores, alcohol abuse, and preoperative infections – are largely consistent with findings from individual prospective studies and smaller reviews[5]. The meta-analysis by Hou et al[3] correctly identified hepatic encephalopathy as a significant risk factor for POD. This finding, while not a universal predictor across all transplant types, is particularly relevant to liver transplant recipients, where it represents a strong, pre-operative determinant of POD. These factors point towards a common pathway where severe underlying systemic illness, physiological stress, and pre-existing central nervous system vulnerability converge to increase the risk of POD. The unique contribution of this meta-analysis is the statistical power it lends to these associations by pooling data across multiple studies, thereby providing more robust odds ratios. For instance, the strong association with a history of hepatic encephalopathy (odds ratio = 3.19) reinforces the concept of pre-existing brain vulnerability as a major determinant of POD.

However, the finding that age was not a significant risk factor in the pooled analysis is a notable divergence from the general delirium literature, where advanced age is one of the most consistently identified and strongest non-modifiable risk factors[6,7]. While some individual transplant studies have also reported a weaker association with age compared to disease-severity indices, its complete lack of significance in this large meta-analysis is surprising and warrants careful interpretation, as discussed below.

CRITICAL APPRAISAL OF THE STUDY

The meta-analysis by Hou et al[3] is methodologically sound, adhering to established principles for systematic reviews. The authors conducted a comprehensive search of multiple databases, used clear inclusion and exclusion criteria, and assessed the quality of the included studies using the Newcastle-Ottawa Scale. The statistical analysis, including the use of a random-effects model to account for anticipated heterogeneity and the assessment of publication bias, was appropriate.

The primary strength of this study is its ambitious scope and the synthesis of a large volume of data to provide the most comprehensive estimates of POD incidence and risk factors in the transplant population to date. The organ-specific subgroup analysis of incidence is particularly insightful, as it moves beyond a single, potentially misleading, overall estimate and highlights the critical differences between transplant types. The identification of a clear set of risk factors with pooled effect sizes provides a strong evidence base for clinicians.

Despite these strengths, the study has several inherent limitations that must be carefully considered when interpreting its findings. The most significant of these is the substantial heterogeneity observed in the analyses, particularly for incidence (I² values often > 90%). While the authors correctly employed a random-effects model, such extreme heterogeneity indicates substantial variability among the included studies in terms of patient populations, surgical and anesthetic techniques, and, critically, the methods used for delirium assessment [e.g., confusion assessment method for the intensive care unit (CAM-ICU), Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, chart review]. This means that the pooled incidence of 20% should be viewed not as a precise point estimate, but as an average across highly diverse clinical scenarios. The organ-specific estimates are likely more clinically meaningful than the overall pooled numbers.

Secondly, the non-significant finding for age as a risk factor requires critical examination. This could be a true finding, suggesting that in this population of severely ill patients, disease-specific factors (like MELD or APACHE II scores) overwhelm the independent effect of age. It is also plausible that the lack of significance for age is a statistical artifact resulting from the pooling of studies with widely varying age ranges and different degrees of control for confounding variables. For example, a study focusing on younger transplant recipients (e.g., < 50 years) might not show an age effect, while one with an older cohort would. When pooled, the differing age distributions and heterogeneous control for factors like disease severity (e.g., MELD scores, APACHE II scores) may have "washed out" the age effect, making it difficult to detect in the overall analysis. This highlights the need for meta-regression analyses to better explore such effects in future studies.

Finally, as with any meta-analysis of observational studies, the results are susceptible to unmeasured confounding. Factors that are critical to delirium risk, such as preoperative cognitive status (e.g., presence of mild cognitive impairment), psychiatric comorbidities (e.g., depression, anxiety), detailed anesthetic protocols (e.g., use of benzodiazepines, depth of anesthesia), and postoperative pain management, were not consistently reported in the primary studies and thus could not be analyzed. This represents a significant limitation in fully elucidating the landscape of POD risk factors.

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

From a clinical perspective, this meta-analysis provides actionable information. The identified risk factors (high MELD/APACHE II scores, history of alcohol abuse, preoperative infection, etc.) can be used to stratify patients preoperatively to identify those at high risk for POD. These high-risk individuals can then be targeted with multicomponent prevention strategies, such as medication reviews (avoiding deliriogenic drugs), optimization of sleep and mobility, and proactive management of metabolic disturbances. The organ-specific incidence rates can help clinicians set realistic expectations, inform patient and family counseling, and guide the allocation of resources, such as consultation-liaison psychiatry or geriatric services.

The limitations of this study clearly illuminate the path for future research. There is a pressing need for large-scale, prospective, multi-center cohort studies with standardized protocols for delirium assessment, data collection, and reporting. The meta-analysis highlights the need for prospective, multi-center studies that employ standardized assessment tools such as the DSM-5 and CAM-ICU. Such studies would enable a more rigorous exploration of organ-specific risk factors, potentially leading to the development of tailored, evidence-based prediction models and prevention strategies for delirium in transplant populations. These future studies must include detailed assessments of preoperative cognitive function (using tools like the MoCA), psychiatric history, frailty, and comprehensive intraoperative data, including anesthetic agents and duration. Also, future research should also be guided by key consensus statements or systematic reviews on delirium prevention, which can provide a framework for developing and evaluating effective interventions[8].

Furthermore, the development and validation of organ-specific POD risk prediction models are a logical next step. While this meta-analysis identifies the ingredients for such models, prospective studies are needed to build and test them. Ultimately, the goal is to move from identifying risk factors to testing interventions. Randomized controlled trials of targeted prevention strategies in high-risk transplant recipients, identified using the factors confirmed in this meta-analysis, are needed to close the research loop and improve patient outcomes.

CONCLUSION

In conclusion, the meta-analysis by Hou et al[3] represents a landmark synthesis of the evidence on the incidence and risk factors of POD in organ transplant recipients. It provides the most robust estimates available to date and confirms a set of clinically relevant risk factors that can guide prevention efforts. However, the study's findings must be interpreted with caution in light of the significant heterogeneity and the potential for unmeasured confounding. Rather than being the final word on the topic, this work should be seen as a foundational summary that expertly maps the current landscape and provides a clear and compelling rationale for the next generation of prospective, standardized, and intervention-focused research in this critical area of neuropsychiatry.