Image: ©iStockphoto. 

Image: ©iStockphoto. 

“It is certainly plausible that both cognitive dysfunction and improvement are tightly modulated by the immune response.” 

POSTOPERATIVE cognitive dysfunction (POCD) is a subtle decline in cognitive trajectory, which is directly attributable to a surgical, anesthetic, or adverse perioperative event. POCD is a controversial topic in perioperative medicine; unlike delirium and dementia, there is no consensus on the definition for POCD, nor is it a recognized diagnosis in the Diagnostic and Statistical Manual of Mental Disorders . Patients who suffer a “sentinel” perioperative event such as a stroke may experience a persistent decline in cognitive trajectory. However, many studies have found— although without determining the preoperative cognitive trajectory—that even without a clinically obvious neurological event, POCD occurs frequently in elderly patients in the first few weeks after surgery.1,2Interestingly, studies that have tracked cognition beyond 6 months postoperatively have generally found that, without a sentinel event, POCD tends to resolve in the majority of patients.1,3This does not necessarily imply that early POCD is not an important problem. Indeed, early POCD has been associated with impaired function, premature departure from the workforce, and early mortality;4however, it remains unclear whether early POCD is a marker or mediator of a disease process. As many studies have focused on the first 3 months postoperatively, it is likely that this has created a distorted view on the prevalence, severity, and duration of POCD. Furthermore, the research community has largely ignored the possibility that some patients might actually improve cognitively after successful surgery. A recent meta-analysis of cardiac surgery studies surprisingly found that persistent postoperative cognitive improvement (POCI) might actually be more common than POCD.5POCI can be defined as an improved cognitive trajectory (either cognitive improvement or deceleration of cognitive decline) relative to the preoperative trajectory that is directly attributable to a successful perioperative outcome. POCI must be differentiated from “resolved POCD” in which patients experienced a decline in their cognitive trajectory, but then recovered to their predicted preoperative cognitive course. Given that both POCD and POCI have been observed after surgery, it is important to consider what mechanisms could account for both of these processes. Insights into this intriguing question are provided in this issue of ANESTHESIOLOGY by Degos et al .6Their work in a mouse model suggests a narrative in which neuroinflammation drives early POCD, and failure of neuroinflammation to resolve could promote persistent POCD. However, resolution of neuroinflammation could allow reversal of POCD or even a shift toward POCI.

Degos et al.  show that the innate immune response may lead to short-term POCD in their mouse model of tibial surgery.6Equipped with a sophisticated genomic model that allows identification of infiltrating immune cells, they show that an influx of innate immune cells contributes significantly to postoperative memory impairment, which may be analogous to a “sickness behavior” in the mice.6They then demonstrate, with use of clodrolip to deplete phagocytic cells, that it is these cells that mediate the innate immune reaction to surgery, by contributing a host of proinflammatory cytokines. It is important to note that while the authors refer to these infiltrating phagocytic cells as macrophages, they do not formally identify them, hence it is unclear whether these cells are actually neutrophils, monocytes or macrophage. In concert with previous data,7–9the study intriguingly implies that perioperative manipulation of the innate immune response could improve cognitive outcomes. The findings of Degos et al.  are paralleled by two other studies10,11and a linked Editorial12in this month’s ANESTHESIOLOGY, which have implicated neuroinflammation in anesthetic-induced apoptosis in the developing rodent brain. This is of particular interest as Shu et al.  recently showed that augmenting inflammation in the neonatal rat brain with noxious stimuli exacerbated anesthetic-induced apoptosis.13It is currently unclear whether surgery exacerbates the neuroinflammatory response to anesthesia in neonatal animals, and this must be investigated expeditiously.

Other strengths to the article by Degos et al . include the robust statistical approach and interaction analyses to examine how different factors modulate the immune response and subsequent cognition.6Nonetheless, it remains unclear how the innate immune response can be safely manipulated to reduce the burden of short-term POCD. As the authors point out, although manipulation of proinflammatory cytokines (such as tumor necrosis factor-α or interleukin-1) might reduce memory dysfunction in animal models, it may also predispose to infective complications in the perioperative period.6–8For similar reasons it is likely that the use of clodrolip,6to deplete phagocytic innate immune cells, could increase the burden of perioperative complications. As such, the authors appropriately express caution regarding the clinical translation of this therapy. The actual type of innate immune cells that infiltrate the hippocampus to provoke memory dysfunction remains unclear. It is probable that combinations of neutrophils and monocytes (the latter may locally differentiate into macrophages) typically arrive in successive waves, instituting a classical immune response. Further studies should identify the cell type responsible for the cognitive dysfunction and the chemotactic factors responsible for this influx. Other targeted immune modulatory therapies should be tested in this animal model. Nonspecific immunosuppression might be ineffective; perioperative steroids are routinely administered in many centers but no salutary effect on POCD has been demonstrated.

Neuroinflammation drives acute changes in neurotransmission, so effects on cognition seem entirely plausible. For example, tumor necrosis factor-α builds up in the brain during wakefulness, driving the need for sleep and affecting cognition.14Therefore, it is unsurprising that, in the short term, surgery should induce an “adaptive sickness behavior” perhaps to aid recovery and healing from the trauma of surgery (i.e. , patients feel the need to rest/sleep). In this context, perioperative manipulation of inflammation to reduce the adaptive sickness behavior may not actually be beneficial. However, in certain predisposed individuals, perioperative inflammation may drive severe impairment in cognition manifesting as delirium.15,16Hence for cognition, perioperative neuroinflammation may not be a problem unless it produces a severe deficit. Furthermore, the reduced disease burden after successful surgery, coupled with a decrease in neuroinflammation, could be expected to improve cognitive function in many subjects in the longer term. It is certainly plausible that both cognitive dysfunction and improvement are tightly modulated by the immune response.

After the initial neuroinflammation subsides, the potential for POCI is an exciting prospect after adult surgery. Successful surgical intervention may remove the cognitive burden imposed by pain, inflammation, and functional limitation. This concept is not merely theoretical; in patients suffering from chronic back pain, surgical treatment or facet joint injections led to POCI, which was associated with structural brain changes.17However, in situations where POCI occurs, it follows that there was a preoperative decline, and few studies have evaluated preoperative cognitive trajectories,1,18perhaps explaining why POCI has largely been ignored as a concept. A rising criticism of the associated preclinical work is that POCI will be hard to identify in preclinical models using healthy, young animals, where surgery is artificially induced (i.e ., there is no pathology driving the need for surgery). In such models, the animals are unlikely to be declining cognitively before the experimental surgery. Aging animals might provide a superior model,19but again the lack of pathology typical in the human surgical context (e.g. , major joint arthritis) remains an important limitation in animal simulations.

Degos et al.  have performed another rigorous study that provides insights into how neuroinflammation might drive postsurgical memory dysfunction.6Although their study does not reveal a therapy for immediate clinical translation, it is an important step on the route to understanding perioperative cognitive changes. From a clinical perspective, we currently know little about the predisposing factors that may determine whether a patient will experience POCD or POCI. Therefore, it is challenging to design a clinical trial to investigate a putative therapy in a vulnerable cohort. An appropriate initial course might be to attempt to identify the patients who are at greatest risk of POCD. Patients who experience delirium after surgery probably constitute a cohort at risk of experiencing early and persistent POCD, as delirium might be a marker of vulnerability and neuroinflammation.15,16Once we understand how perioperative care may influence an individual’s cognitive trajectory, we can study disease processes and test therapies in the subgroups that are most likely to benefit. However, premature clinical trials of immune modulatory therapies may unnecessarily treat many patients, and render them susceptible to the side effects of the therapy, including immune suppression. For the present, surgeons, anesthesiologists, and other perioperative clinicians should implement plans to limit the trauma of surgery, to treat pain effectively, to prevent postoperative complications, and to promote early mobilization and rehabilitation. When surgery is successful and general health improves, it is likely that cognition will similarly be enhanced.

*Wellcome Department of Imaging Neuroscience, Department of Surgical Outcomes Research Centre & Anaesthesia, University College London, London, United Kingdom. † Department of Anesthesiology and Surgery, Washington University School of Medicine, St. Louis, Missouri.

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