Shandong Province is one of the most populous provinces in China, with a population of approximately 100 million, and it is the origin of Confucian culture. Delirium is associated with culture because it deeply affects the population at almost every level, especially at the psychological level. Therefore, an investigation of delirium in Shandong Province has special meaning. To the best of our knowledge, this study is the first Chinese multicenter analysis of delirium.
Approximately 22% of patients experienced delirium at least once during the ICU stay, similar to our previous study (28.75%). Patients with delirium were likely to have a longer duration of mechanical ventilation, ICU stay, and hospital stay. In the univariate analysis, age, SOFA score, a history of cerebrovascular disease and impaired renal function were risk factors for delirium. Most therapeutic interventions were associated with delirium in the univariate analysis, including enteral nutrition, artificial airways, nasogastric tubes, use of restraint straps and sedative medications, such as midazolam, propofol and butorphanol. Among the patient’s vital signs and laboratory examinations reported on the day of assessment, body temperature and BUN and CRP levels were risk factors for delirium.
Consistent with previous studies, age and disease severity have always been risk factors for delirium[24, 25]. Patients with delirium may more frequently be over 65 years of age and have SOFA scores ≥ 2. Unlike previous studies, no difference in APACHE II scores was observed between patients with and without delirium. We found a large number of errors in the APACHE II scoring process, which may explain this result. We are performing additional research to address this discrepancy.
Although hypertension was identified as a risk factor for ICU delirium in a systematic review, hypertension was not associated with delirium in our study, even in the univariate analysis. Moreover, alcohol abuse is one of the most commonly identified risk factors for delirium in Western countries, but in our prior study, we did not find that an alcohol abuse history affected the development of delirium in critically ill Chinese patients, and alcoholics were seldom affected by delirium. Alcohol abuse may be associated with the culture of the society. Therefore, we did not collect any data on alcohol use in the present study.
These risk factors, such as age and severity of illness, are uncontrollable or even immutable for ICU patients. One of the aims of the current study is to differentiate modifiable risk factors and treat these factors in a systemic manner.
Midazolam, butorphanol, and propofol were risk factors for delirium in the univariate analysis. Consistent with other studies, midazolam remained an independent risk factor for delirium in the multivariate analysis. Benzodiazepines and propofol have high affinities for the γ-aminobutyric acid receptor in the central nervous system, and their administration leads to alterations in the levels of numerous neurotransmitters thought to be deliriogenic. Thus, reducing sedative exposure might be an important intervention to improve patient outcomes. However, in our study, 22.0% of patients used midazolam, suggesting that we should reduce the use of long-acting sedatives as much as possible in the future and monitor the sedation status of patients more frequently.
Regarding short-acting agents, several studies have shown that dexmedetomidine may be helpful to minimize the depth and duration of sedation with a potential reduction in the time to extubation and days of delirium in the ICU[28, 29]. However, in our study, dexmedetomidine was not correlated with the occurrence of delirium, potentially due to the difference in sedation depth compared with other studies.
Pain is one of the most commonly reported stressors for ICU patients. The negative physiological and psychological consequences of unrelieved pain in ICU patients are significant and long lasting. Therefore, sufficient analgesia should be ensured in all ICU patients, and potentially painful procedures should be mitigated with a preventive analgesic approach[11, 30]. We found that the proportion of analgesics used in this study was small, and butorphanol was a risk factor in the univariate analysis. Little research has been conducted on butorphanol, especially its effects on delirium. Few studies have compared the superiority of fentanyl to butorphanol in ICU analgesia. Because opioid side effects depend on the dose, these drugs must be compared in equianalgesic doses. We hypothesize that butorphanol may affect delirium by affecting gastrointestinal function. eCASH emphasizes the need to reduce total opioid exposure to avoid adverse effects such as feeding intolerance, constipation and ileus.
Gastric tubes, visible clocks, enteral nutrition, physical restraints, artificial airways, and mechanical ventilation were related to delirium in the univariate analysis, consistent with previous research results. Most ICU patients have varying degrees of gastrointestinal dysfunction, and indwelling gastric tubes are common. Few studies have shown the relationship between nutrition and delirium, but our research shows that patients receiving enteral nutrition have a lower risk of delirium than those receiving parenteral nutrition. The specific reasons for providing early EN are to maintain gut integrity and modulate stress and the systemic immune response to attenuate disease severity. A study focusing on the effect of early enhanced enteral nutrition on patients with a head injury found that enhanced EN appears to accelerate neurological recovery and reduce both the incidence of major complications and postinjury inflammatory responses. However, the mechanism is unclear.
Therefore, the study described above reminds us that gastrointestinal function, not nutrition modes, may play an important role in delirium. In patients receiving enteral nutrition, the brain-intestinal axis may regulate central nervous system function. However, the relationship between gastrointestinal function and delirium requires further testing.
Patients treated with mechanical ventilation were more likely to develop delirium in the ICU setting than those without mechanical ventilation, consistent with other studies. In the univariate analysis, the incidence of delirium in patients with tracheal intubation or tracheotomy was higher than that in other patients. The probable explanations are that these patients had a more serious illness and needed larger doses of sedatives and analgesics, and the findings may also be related to noise, sleep deprivation, patient-care interaction and the mode of mechanical ventilation. Based on current evidence, the causal relationship between these factors is difficult to distinguish, but we should try different methods, including protocols, to help patients wean from ventilation. Measures should be implemented to shorten the mechanical ventilation time as soon as possible.
The ICU environment will also affect the development of delirium in patients potentially because of different noise and light levels due to the ICU architectural design[16, 35]. Physical restraints are important means to ensure patient safety, handle agitation and prevent unplanned extubation. However, the incidence of delirium is high when physical restraints are used on patients. Restrictions on the use of restraints in the ICU are required to reduce the occurrence of delirium.
Even compared with our own previous study, the risk factors that affect delirium are different. The potential explanations are described below. (1) The spectrum of disease varied as the range of participants expanded. (2) Medical staff in different ICUs have different levels of knowledge of delirium (as mentioned in our previous study), leading to differences in the implementation of interventions and evaluations, especially delirium evaluations. (3) The occurrence of delirium is related to the territorial culture.
The study also has several limitations. First, as a drawback of observational studies, some unknown or untestable confounding factor(s) affect our internal validity. Second, the study lasted for 27 months, during which changes in therapeutic interventions and cognition might have affected the results. Third, the routine practice for each participating ICU was not the same, which may lead to bias. Additionally, this study was carried out in Shandong Province, China, where the ICU setting may be different from other provinces in China and other countries, which may limit the external validity of the study. Third, we did not follow the patients to determine the long-term effect of delirium on patient prognosis.
Defined delirium risk factors may help practitioners prevent or implement appropriate therapies to reduce delirium in ICU patients and improve their prognosis. We expect that after the success of the study, more ICU medical staff will recognize, pay attention to and routinely evaluate patients for a delirium diagnosis. Therefore, the incidence of delirium will soon be gradually reduced, and the prognosis of ICU patients will be improved.