Introduction

Delirium is an etiologically non-specific organic cerebral syndrome characterized by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behavior, emotion and the sleep–wake schedule. The duration is variable and the degree of severity ranges from mild to very severe [1].

Postoperative delirium typically develops 1–4 days after an operation and results in longer hospital stay, additional nursing care, and greater medical costs [2]. Studies have also shown that postoperative delirium is associated with an increased risk of mortality [3]. Although the mechanisms underlying the development of postoperative delirium are not well understood, the most significant risk factors that have been shown to be involved in the process are age, cognitive impairment, coexisting medical conditions, and psychotropic medication use [2,3].

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and liver resection is the only potential curative treatment option for those patients. It has been reported that patients with chronic liver diseases or impaired liver function are at increased risk for developing delirium after a surgical procedure [4]. However, the risk factors for developing delirium after hepatectomy for HCC patients have not been well investigated. Yoshimura et al. [5] once revealed that advanced age, impaired liver function, and advanced cancer stage affect the development of postoperative delirium after liver resection for HCC; yet, the case number enrolled was small. Thus, we conducted a large-scale study to investigate preoperative, intraoperative, and postoperative factors associated with the development of delirium after hepatectomy for HCC patients.

Materials and Methods

Results

A total of 34 patients out of 401 developed postoperative delirium; the incidence was 8.4%. In the majority of those who developed postoperative delirium, symptoms and signs of the syndrome occurred on postoperative day 2 with a mean duration of 3.61 ± 3.708 days (Table 1).

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Table 1. Onset and duration of postoperative delirium.

https://doi.org/10.1371/journal.pone.0119199.t001

Table 2 illustrates the demographic and clinical pathological features and the perioperative and postoperative features of the two groups are presented in Table 3. The mean hospital stay was 9.18 ± 3.145 days for patients who did not develop delirium and 13.32 ± 8.608 days for those presented with postoperative delirium (p = 0.026).

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Table 2. Characteristics of patients in the delirium and non-delirium groups.

https://doi.org/10.1371/journal.pone.0119199.t002

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Table 3. Perioperative and postoperative features of patients in the delirium and non-delirium groups.

https://doi.org/10.1371/journal.pone.0119199.t003

In patients with postoperative delirium, most of them had good liver function according to the Child Pugh classification (Child Pugh A: 94.1%; B: 5.9%). Regarding the degree of liver fibrosis, there was no significant difference between the two groups (Table 2).

According to the univariate analysis, advanced age (> 71 years old), low BMI index (< 23.02 kg/m²), low albumin level before operation (< 3.64 g/dL), lung disease comorbidity, history of hypnotic drug use, prolonged operative time (> 190 minutes), major liver resection (≥ 3 segments), postoperative hemoglobin level, and postoperative infection complications were factors associated with the development of postoperative delirium (Table 4).

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Table 4. Risk factors for postoperative delirium by univariate analysis and multivariate analysis.

https://doi.org/10.1371/journal.pone.0119199.t004

Multivariate analysis revealed that advanced age (OR = 1.133; 95% CI: 1.071–1.200), prolonged operative time (OR = 1.009; 95% CI: 1.000–1.017), a decreased postoperative hemoglobin level (OR = 0.777; 95% CI: 0.613–0.983), and history of hypnotic drug use (OR = 3.074; 95% CI: 1.045–9.039) were independent risk factors for the development of postoperative delirium after hepatectomy (Table 4).

Patients who developed delirium after hepatectomy were significantly older than those who did not show signs of delirium (71.24 ± 7.447 vs. 61.23 ± 11.228, p<0.001) and had a longer operative time (190.91 ± 153.027 vs. 136.04 ± 47.225, p = 0.045) than patients who did not develop the syndrome. Furthermore, patients who developed delirium had a significantly lower mean postoperative hemoglobin level than patients who did not show symptoms or signs of the syndrome (10.16 ± 2.682 vs. 11.84 ± 1.723, p<0.001).

Discussion

Advanced age, impaired liver function, and advanced cancer stage were independent risk factors for postoperative delirium after hepatectomy for HCC was once discovered by Yoshimura et al [5] and the incidence of post-operative delirium was 17%. In our study, the incidence decreased to 8.4% and besides advanced age; we found that a history of hypnotic drug use, prolonged operation time, and low postoperative hemoglobin concentration were also independent risk factors for the development of delirium after hepatectomy.

A number of studies have shown that patients of advanced age are prone to develop delirium after operations mainly due to cholinergic deficiency [17] and dopaminergic excess [18]. Acetylcholine may play a role in many of the symptoms of delirium. Excess anticholinergic activity is associated with behavioural inhibition, whereas anticholinergics are associated with hyperactivity. Elderly patients are more vulnerable to anticholinergic effects as the functionality of cholinergic transmission decreaseswith age. Dopamine is an neurotransmitter for motor function, attention and cognition; which is important in the genesis of delirium.

There are five types of dopamine receptors in human, activation of D1 and D5 receptors increases secretion of acetylcholine, whereas D2, D3 and D4 activation might decrease acetylcholine secretion. D1 and D2 receptors decrease with age, which could increase the likelihood of delirium in elderly patients. Though the pathophysiology of postoperative delirium is not well understood, those are indirect evidence why the elderly are prone to develop postoperative delirium.

O'Keeffe et al found that drug-related side effects may contribute to postoperative delirium in the elderly [19]. In a systematic review article, Steiner [14] reported that use of hypnotic agents such as benzodiazepines, opioids and anticholinergic agents are precipitating factors for the development of postoperative delirium. Guidelines published by the National Clinical Guideline Center [20] also mentioned that many pharmacological agents, such as benzodiazepines, antipsychotics, anticholinergic, H2-receptor antagonists, mood stabilizing drugs, non-steroidal anti-inflammatory drugs, and opioids are risk factors for delirium. In our institution, benzodiazepines such as Alprazolam, Lorazepam and Zolpidem are the most common hypnotic agents prescribed for insomnia; this might explain why patients who took hypnotic agents were at risk of developing postoperative delirium. Moreover, Benzodiazepines and opioids are frequently administered during operations for sedation and analgesia. We thought this might be the reason that patients with long operation time tended to experience postoperative delirium.

Yoshimura et al [5] found that decreased albumin concentration after hepatectomy was a risk factor for postoperative delirium. Although this was not observed in our study, we did find that patients with hypoalbuminemia before operation were at greater risk of developing postoperative delirium. This condition was also observed by Robinson et al [21]. Whether hypoalbuminemia is a consequence of liver injury caused by HCC or liver dysfunction due to aging is not clear; however, low serum albumin level has been shown to affect the metabolism of drugs and to be associated with postoperative delirium [22–24].

In our study, low postoperative hemoglobin level was associated with the incidence of postoperative delirium after hepatectomy for HCC. This issue was not mentioned in Yoshimura’s study and was first discovered to be risk factors for delirium in HCC patients. Older patients tend to have respiratory comorbidities such as hypoxia and hypercapnia, which reduce cerebral circulation flow and may lead to postoperation delirium. Indeed, in our study, the proportion of patients with respiratory comorbidities was higher in the delirious group than in the non-delirious group. Furthermore, intraoperative blood loss is hard to be avoided in liver resection operation due to liver dysfunction with cirrhosis change and coagulopathy. As a result, we adjust the time interval and frequency of the Pringle maneuver during the operation to reduce liver injury. In this study, we found that low postoperative hemoglobin level was an independent risk factor for delirium. Although a similar finding has been reported in other studies [25, 26], those studies involved small sample sizes. To the best of our knowledge, our study is the first large-scale study to reveal that low postoperative hemoglobin level is a risk factor for delirium after hepatectomy for HCC. We suggest that maintaining hemoglobin levels > 11 g/dL might help reduce the risk of postoperative delirium.

In this study, we also investigated whether room occupancy in hospital wards had an impact on the development of postoperative delirium. In Taiwan, the National Health Insurance program covers the cost of hospital stay as long as a patient stays in a four-bed occupancy hospital room. We thought that four patients with care assistants in the same space might influence each other especially, sleep rhythm. As a result, we discovered that there was no significant difference in the proportion of patients who stayed in four-bed rooms between the delirium group (18 of 34, 52.9%) and the non-delirium group (167 of 367, 45.5%) (p = 0.405).

Conclusion

Although the mechanism of postoperative delirium is not well understood, numbers of studies have shown that patients with postoperative delirium tend to have prolonged hospital stay, worse postoperative outcome and an increased risk of short- and long-term mortality. In this study, we found that advanced age, prolonged operative time, postoperative low hemoglobin level and history of hypnotic drug use are independent risk factors for postoperative delirium.