POD remains a very common, acute, under-recognized problem in older adults following total joint arthroplasty (TJA) and is associated with a variety of severe cognitive and functional disorders. Given the aging population, the economic and health burden of POD is very likely to increase. Although the underlying pathologic mechanisms between delirium and these adverse outcomes are uncertain, there is no doubt that POD is highly distressing to patients, family members, and providers, indicating an urgent need for prevention of POD through identifying effective predictors 29. The current meta-analysis extensively analyzed the early predictors of postoperative delirium. Thirty-one predictors were available for meta-analysis, of which 9 predictors were statistically significant: advanced age, dementia, hypertension, diabetes, stroke, psychiatric illness, use of sedative-hypnotics, lower preoperative levels of hemoglobin, and lower preoperative MMSE score.
Demographic predictors
Advanced age has been recognized as a well-established predictor for POD 30, 31. Consistently, the results of our meta-analysis showed that patients with POD were 3.8 years older on average than those without. Furthermore, the average age of the population undergoing TJA is 71 years, and most patients are over 65 years old according to a previous study 32. Therefore, the patient population under this study is at a high risk of POD. The high incidence of POD in elderly patients may be attributed to higher comorbidities, age-related changes in organ and brain composition, pharmacodynamics, renal function, and metabolism 33.
Among other demographic predictors, gender, BMI, education, and smoking were not found to be significantly related to the occurrence of POD. Contrary to our hypothesis and previous literature 27, 28, 34, this analysis did not verify a significant correlation between alcohol abuse and POD, but there was significant heterogeneity. Through sensitive analysis, we found one study 19 with a small sample size had a great influence on the pooled result. After the exclusion of this study, the I2 value lowered to 0%, and the significance changed, indicating alcohol abuse was still likely to be a potential predictor of POD.
Physical status-related predictors
The present study showed that multiple comorbidities significantly increased the risk of POD after TJA. This fact suggested that the POD group tended to have more comorbidities and poorer preoperative physical conditions than the control group. Previous research supported the idea that preoperative health status was a major consideration for postoperative adverse events 35.
We also found that preoperative cognitive impairment assessed by MMSE could predict the occurrence of POD. MMSE, as a preliminary screening, can detect people who are less likely to be delirious with about 93–97% accuracy 36. In this meta-analysis, the mean MMSE score in the case group was only 0.4 points lower than that in the control group, emphasizing that even mild cognitive impairment increased the risk for delirium. Therefore, cognitive testing should be part of a standardized procedure for the preoperative clinical assessment of TJA patients. It was also believed that the pathophysiological mechanisms of delirium may be like some neurodegenerative processes (such as dementia), both of which involved abnormal inflammatory responses or dysfunction of the cholinergic system 19, 37. The onset of delirium reflects the underlying vulnerability of the brain, cognitive impairment, and an increased risk of dementia in the future 38; Similarly, dementia is also an important predictor of POD, as demonstrated by this meta-analysis. In the meantime, we must point out that MMSE, as a relatively insensitive clinical cognitive measurement tool, could not be capable of detecting some subtle cognitive changes. However, these slight cognitive changes may still indicate a high risk for POD 22, suggesting that we must use more sensitive tools to detect these subtle cognitive changes. Otherwise, this may lead to irreversible consequences as patients age.
Surgery-related predictors
In our analysis, under normal surgical conditions, surgery-related factors, such as blood loss, type of anesthesia, type of surgery, and operation time, did not seem to have a significant effect on the occurrence of POD after TJA. It was worth noting that there was a high degree of heterogeneity in studies on intraoperative blood loss and operation time, which indicated that the results should be treated with caution. According to the previous research and this fact, we believed that the factors related to surgery still should not be ignored, but it also suggested that the incidence of POD could be reduced by standardizing surgical operation and improving surgical management 39, 40.
Drug‑related predictors
Our results confirmed that the use of sedative-hypnotics could contribute to POD after TJA. In recent years, benzodiazepine receptor agonists (benzodiazepines and non-benzodiazepines) have been reported to cause cognitive decline and delirium, which supported our findings 39, 41. Excitingly, new insomnia drugs have been found that might reduce the risk of delirium, such as ramelteon and suvorexant, which selectively target receptors in the pineal gland and hypothalamus (melatonin and orexin receptors), respectively. Furthermore, the potential value of ramelteon and suvorexant against delirium was further verified in a randomized clinical trial 42, 43. Therefore, for patients with a high risk of POD, it may be considered to replace benzodiazepine receptor agonists with these drugs preoperatively.
It is reported that 12–39% of the occurrence of POD in the elderly is related to medications. Due to pharmacodynamics and pharmacokinetics changes, the high prevalence of multiple drugs, and the existence of coexisting diseases, drug-induced delirium is becoming more common in this population 44. Strengthening patient consultation, improving medication management, and reducing multi-drug use may be beneficial to the alleviation of this problem.
laboratory predictors
Our meta-analysis found a significant correlation between low preoperative hemoglobin levels and POD. Recent studies have shown that anemia was significantly associated with cognitive decline and the development of dementia 45, 46. Furthermore, studies have suggested that anemia is an independent risk factor for delirium in hospitalized elderly patients 47. A possible explanation is that low hemoglobin levels reflect the inflammatory state associated with chronic disease, and inflammation may play an important role in the pathological mechanism of delirium 48, 49. Therefore, low preoperative hemoglobin levels can indirectly predict the high incidence of POD. Notably, there is still no conclusive evidence that correcting preoperative hemoglobin levels can reduce the risk of postoperative delirium 26. Therefore, for elderly patients with low preoperative hemoglobin levels, it is necessary to reduce other potential risk factors of POD and take preventive measures in advance.
Limitations
Some limitations should be emphasized. First, criteria for diagnosing delirium were not uniform across studies and have varied over time, which could lead to bias. Although publication bias and sensitivity analyses have been performed to consolidate the reliability of the results, these data still required careful interpretation. Second, this meta-analysis was limited in accurately determining the relative magnitude of the predictive power of different factors, as this would inevitably be influenced by changes in important methodological factors (such as length of follow-up and experience of the assessors) in different studies. Third, there were no randomized controlled trials in the included literature, which might affect the quality of the results. Fourth, because sufficient separate data on POD in primary total hip arthroplasty or revision arthroplasty were not available, we could not perform relevant subgroup analyses, although they were important indicators that should be evaluated. Considering the above limitations, more well-designed studies which focus the predictors of the POD following TJA are required in the future.