The main findings of the current analysis can be summarized as follows: (1) The circadian rhythm variables of heart rate, Mesor, Amplitude, and Peak time, were the independent risk factors of in-hospital mortality in stroke and critically ill patients. (2) Mesor per 10 bpm increase and Amplitude per 5 bpm increase were associated with a 1.17-fold and a 1.14-fold increase in the risk of in-hospital mortality, respectively. The risk of in-hospital mortality was highest in patients whom had Peak time reached between 12:00-18:00. (3) The effects of Mesor, Amplitude, and Peak time on in-hospital mortality were not associated with the presence of coronary artery disease, but Peak time was associated with the presence of heart failure and Mesor was associated with the presence of atrial fibrillation. (4) The effects of Mesor, Amplitude, and Peak time on in-hospital mortality were not associated with the medications use frequency and the medications action, but Amplitude was associated with the use of medications that affect heart rate and time of medications. (5) Compared with APACHE IV score only, combining APACHE IV score and circadian rhythm variables of heart rate was associated with increased discriminative ability.
Stroke is the second leading cause of death and the third leading cause of disability worldwide in the past five years [12]. Stroke patients can benefit from extensive care [13]. Previous studies using the eICU database, a multi-center intensive care unit database, found that high mechanical power of ventilation was independently associated with higher in-hospital mortality among ICU patients who received invasive ventilation for at least 48 hours [7, 14]. There is 5.5% (11,063/200,859) of the stroke patients in the database. In other studies, the mortality of stroke patients is 20%-30% [15, 16]. In the eICU database, the mortality of stroke patients is 14.1% (1,565/11,063). The study of the eICU database has found that there is a general low mortality among the patients enrolled [8], which needs to be further explored.
Identifying the indicators of severity or mortality in stroke patients may be helpful in stratifying the risk of patients, extending patients' survival time and improving their prognosis in terms of treatment. Previous studies have found that hypertension is the strongest independent risk factor for stroke [12]. Thomas Jensen et al [17]. found that the independent risk factors of stroke include diabetes mellitus. Carmine Marini et al [18]. found that the independent risk factors of stroke include atrial fibrillation. Joseph P. Broderick et al [19]. found that the independent risk factors of stroke Include heart failure. After adjusting these previous factors, we still found that variables of heart rate circadian rhythm such as Mesor, Amplitude and Peak time are independent risk factors for stroke. We also found that the effects of Mesor on in-hospital mortality is associated with the presence of atrial fibrillation, but Peak time is associated with the presence of heart failure. Circadian rhythm of heart rate was affected and regulated by adrenal, sympathetic/parasympathetic nervous system, hypothalamus and pituitary activity [20]. For the brain-injured patients, a study found that there were significant changes in the circadian rhythms of heart rate, blood pressure, body temperature, cortisol, and blood melatonin compared to healthy subjects [21]. Desynchronization between circadian rhythm and metabolism can lead to atherosclerosis and thrombosis, which can lead to serious cardiovascular events, including myocardial infarction and cardiac arrest, increasing the risk of death [22]. Our findings might be explained by the fact that serious adverse cardiovascular events caused by changes of heart rate circadian rhythm appear to be related to the rhythmic disorders of neurohormones associated with the cardiovascular system such as melatonin, after stroke [23, 24].
In the current analyses, Mesor, Amplitude, and Peak time were used to evaluate the heart rate circadian rhythm. It has been shown that in healthy people who has normal circadian rhythm, the Peak time of heart rate mainly occurs between 12:00-18:00 [25]. Another study showed that the heart rate circadian rhythm of healthy young men showed a bimodal pattern, with Peak time occurring around 10:00 and 20:00 [26]. We showed that the risk of death in stroke and critically ill patients was relatively increased when the Peak time of heart rate occurred between 12:00-18:00, whereas those who had Peak time of heart rate occurred between 18:00-24:00 or 00:00-06:00 were associated with a lower risk. Animal studies have shown that heart rate of mice normally peak at night, but this tends could be reversed after a malignant stroke [27].
In previous studies, the sports causes an increase in the Amplitude of heart rate, which decrease in healthy people who exposed to sedentary conditions [28]. We found that the mortality rate of stroke and critically ill patients increased with the increase of Mesor and Amplitudes of heart rate circadian rhythm. After the adjusted model, Mesor per 10 bpm increase and Amplitude per 5 bpm increase were associated with a 1.17-fold and a 1.14-fold increase in the risk of in-hospital mortality, respectively. Animal studies have shown a rapid increase in mean heart rate in post-malignant stroke mice, with an increase of about 100 bpm from pre-malignant stroke [27]. Mean heart rate was significantly higher in patients with stroke than in those with normotensive, and heart rate variability was greater in patients with ischemic stroke than in patients with hemorrhagic stroke [29]. At present, no evidence has been found to explain the increase in mortality with increased Amplitude of heart rate in stroke and critically ill patients, which requires further investigation. Other studies have found that in patients with essential hypertension, flat circadian rhythms predict an increased risk of cardiovascular disease and a risk of death [30]. The reason for this difference in results may be the difference in the subjects we studied, and the changes of heart rate of circadian rhythm in the influence of the difference of patients with different diseases need to be further research.
We further explored whether medications have an effect on the circadian rhythm of heart rate to predict in-hospital mortality. By orally administering the drugs according to the circadian rhythm of the physiological process and the optimal time of administration, the effectiveness of the drugs can be improved while minimizing its adverse side effects [31]. When medications that affect the heart rate were used, the heart rate increases or slows down, and the effect of heart rate amplitude on in-hospital mortality in stroke and critically ill patients was related to the use and time of medication. But this effect remains limited in circadian rhythm of heart rate predict in-hospital mortality. Perhaps the use of other medications that can significantly regulate the circadian rhythm of heart rate, such as melatonin [32], can achieve a better intervention effect on the outcome.
APACHE score is widely used to assess the severity and prognosis of critically ill patients [33]. There are four versions of APACHE score, and APACHE IV score is currently the latest version,which is based on variables within 24 hours of admission to the ICU and has good discrimination and calibration for predicting hospital mortality [34]. The APACHE IV score we use came from the eICU database [7]. APACHE IV scores include heart rate variables. We found that superimposing the characteristics of circadian rhythm of heart rate, such as Mesor, Amplitude and Peak time on the APACHE IV score could increase its predictive effect on mortality. In the future, the improvement of the APACHE IV score can be considered to plus the variable of heart rate circadian rhythm to enhance the prediction ability of mortality in stroke and critically ill patients.
Limitations
Imbalances exist among the sub-categories assessed in the current study. Although statistical methods were performed to try to estimate the true effects between groups, the inability to eliminate the impact of unmeasurable confounders, such as different management patterns in each center.
The endpoint was all-cause mortality only, which has the potential to dilute the effect of other clinical outcomes regarding circadian rhythm. However, the use of all-cause mortality reduces the risk of adjudication bias due to incomplete, skewed, or inadequate supporting evidence.
77.3% (155,285/200,859) of the ethnic groups in the eICU database are Caucasian, and because the proportion of Caucasian is relatively high, the results of the study lack an explanation for people of other races.