In this retrospective case-control study, we found that a lower preoperative SUA level was associated with a higher risk of POD. Meanwhile, a higher NLR value and increased duration of surgery were also indicated as independent risk factors of POD in elderly after hip fracture. The incidence of POD after hip fracture surgery was 15.8% in our study.
A recent study reported the neuroprotective potential of UA in animal models and clinical trials[15]. Moreover, epidemiological data have indicated an inverse association between UA and several neurological disorders. An emerging body of evidence has indicated that a lower SUA level is associated with poorer cognitive function and increased risk of mild cognitive impairment[12, 16]. Furthermore, a decreased SUA level is related to a markedly higher risk of progressing to Alzheimer's disease dementia from a non-demented state[17, 18] and the development of nonmotor symptoms in patients with Parkinson's disease[10]. No previous study has investigated the correlation between SUA levels and POD, we found that a lower SUA level was an independent risk factor for POD in elderly patients with hip fracture surgery.
The exact underlying pathophysiology of POD is elusive and several biological models of delirium have been proposed, including neuro-inflammation, neuro-aging, neuro-endocrine stress, neurotransmitter dysregulation, oxidative stress, sleep/wake dysregulation, and network dysconnectivity[19]. The widely accepted theory is the “oxidative stress hypothesis,” which states that cerebral tissue is susceptible to oxidative damage because of its high oxygen requirement for metabolism, high level of polyunsaturated fatty acid, and low concentration of antioxidant resources[20]. As a natural antioxidant, the antioxidant properties of UA include the capacity to neutralize and scavenge prooxidant molecules, such as hydroxyl radicals, hydrogen peroxide, and peroxynitrite and to suppress the Fenton reaction, chelate transition metals, and prevent lipid peroxidation[21, 22]. Moreover, several studies showed that in vitro cultures, urate markedly enhanced survival of dopaminergic neurons in a model of spontaneous cell death. Urate’s protective effects have also been found in vivo, and URAT1 and GLUT9 expressed in mouse astrocytes reportedly protect dopaminergic neurons from cellular oxidative stress through intracellular accumulation of UA[23]. Thus, based on the biochemical ability of UA, there is indeed evidence for the neuroprotective role of SUA.
We also found that increased length of surgery and NLR could serve as independent risk factors for POD in elderly patients undergoing hip fracture surgery. Numerous studies have established operation time as a risk factor for POD in various types of surgical procedures[24, 25]. There is no doubt that longer surgery duration indicates a more complex procedure with severe surgical stimulation and may result in greater acute inflammatory responses[25, 26]. The neuroinflammatory hypothesis is a widely accepted explanation for the development of POD[27]. It has been hypothesized that acute peripheral inflammatory stimulation, brain parenchymal cell activation, and proinflammatory cytokine expression could lead to neuronal cell apoptosis and synaptic dysfunction[27]. NLR, as a reliable measure of systemic inflammation, has been shown to be a good predictor of outcomes for neurological and psychiatric disorders in previous studies[28, 29]. The close association between inflammation and POD may be a possible explanation for the relationship between elevated NLR values and POD in our study. Notably, the trauma may have already initiated the inflammatory cascade in patients with hip fracture. It was likely that increasing inflammatory mediators induced by anesthesia-surgical intervention contribute to the risk of POD[30].
Consistent with previous studies, our analyses revealed a longer length of hospital stay in patients with POD. Prolonged length of stay can delay the patient’s ability to recover their nutritional status[31]. However, there was no significant difference in the incidence of pneumonia and thrombosis between the POD and non-POD groups in our analysis. The causes of pneumonia and thrombosis are complex and include not only prolonged recumbency, but also the location and duration of surgery and pre-existing underlying diseases. Multidisciplinary cooperation to develop a reasonable surgical plan may reduce the incidence of postoperative complications.
Although we found something interesting, but this study has limitations. The major limitation is the bias caused by retrospective design. However, we used a matched study to minimize the effect of confounding factors such as selection bias. Pairing characteristics were carefully selected, including age, sex, and anesthesia type which have tight relationship with POD[32–35]. Meanwhile, we improved a chart-based method which has been validated previously for identifying POD from medical records [13]. A retrospective study published in EJA also showed a 15.7% incidence of POD[14], which was similar to our findings. This supports the idea that delirium can be assessed with good accuracy in a retrospective way and the method is more appropriate for clinical situation and retrospective research application. Another limitation is that the lack of control over relevant confounding factors (i.e. dementia and cognitive impairment) and small sample size may affect the interpretation accuracy, our results should be interpreted cautiously and a prospective study with a large sample size is required.