The retrospective cohort study based on the MIMICIV database showed that patients who had higher level of NT-proBNP with acute ischemic stroke in intensive care unit had higher levels of creatinine and higher levels of urea nitrogen, more cardiovascular and renal complications, higher score of Charlson comorbidity index and Sapsii. After adjusted for covariates that may affect the level of NT-proBNP and mortality, we found that higher NT-proBNP indicates higher mortality in patients with acute ischemic stroke in intensive care unit, the results keep robust in patients without heart failure. However, there seems to be no relationship between NT-proBNP and ventricular tachycardia and endotracheal tube.
Although NT-proBNP is mainly used for the diagnosis and evaluation of heart failure, with its widespread clinical application12, abnormal NT-proBNP levels can be seen in patients with hypertension, renal disease, sepsis13, chronic obstructive pulmonary disease14. As heart-brain connections have drawn clinical attention for a long time15, studies about NT-proBNP and nervous system disease were performed. There is a significant positive correlation between cardiac ejection fraction and gray matter density across the whole frontal and parietal medial cortex and the NT-proBNP has a significant negative correlation with gray matter density in the medial and posterior cingulate cortex but also in precuneus and hippocampus16. NT-proBNP is not noly related with prognosis of nervous system disease disease, but also affected magnetic resonance images of magnetic resonance (MR) images. Higher serum NT-proBNP levels are associated with volumetric and microstructural MR imaging markers of subclinical brain damage and dementia16, 17. NT-proBNP is also a predict factor of stroke, but the study population is limited to Japanese18. Once transient ischemic attack appeared, NT-proBNP indicates a morbidity of stroke19. Elevation of NT-proBNP can also be seen in patients with acute ischemic stroke20, even they were not concomitant with heart failure or other heart disease21. Before ischemic stroke happened, NT-proBNP could act as a predict factor, as mentioned in Ebihara’s study22, which performed a 4.7-year follow up. Once the acute ischemic stroke attacked, NT-proBNP can serve as a factor that predict the complication and the prognosis after reperfusion threapy9, 23. Sometimes, ischemic stroke appeared without obvious causes, then NT-proBNP may indicate that a paroxysmal atrial fibrillation might lead to the incident24–27. There are also some studies on the relationship between BNP and the prognosis of stroke patients28, with follow-up time of months to years7, 29–31, however, there is currently no research on the short-term prognosis of BNP in critically ill patients.
Our study tried to meet the insufficiency of previous studies and the outcome shows the increase of NT-proBNP predict high mortality in 7 days in patients with acute ischemic stroke in intensive care unit. The mechanisms result in the association of high NT-proBNP levels with high mortality of critically ill patients with acute ischemic stroke remains unclear, but there are research can provide evidences. First, complex comorbidities are usual among critical ill patients admit to intensive care unit. Diseases such as renal disease, infection, chronic obstructive pulmonary disease can increase NT-proBNP level. When the AIS happened, the sympathetic nervous system was over activated, which prompted cardiac sympathetic nerve activity, then enhanced pressure on ventricular wall resulted in elevation of NT-proBNP. According to the present studies, the synthesis and release of BNP is regulated by autonomic nervous system32, 33, once AIS attacked, the autonomic nervous system will be activated for stress or injure of related aera34. With the elevation of BNP, sodium excretion can be promoted, which could low down the osmotic pressure and impair the perfusion of occluded aera35–37.
Even though the molecular mechanism and signal pathway about elevation of NT-proBNP are not clear, there are potential mechanisms may explain it. Protein kinases JNK and p38 can be activated by cytokines, death receptors, mitogens, cellular stress38 and the JNK and p38 pathways regulate apoptosis, inflammation, and cellcycle arrest39. By binding the JNK and p38 pathway, brain injure can be alleviated40. The JNK and p38 pathways play crucial roles in cardiomyocyte hypertrophy, by using inhibitor of JNK and p38 pathway, both the cardiomyocyte hypertrophy and BNP secretion were alleviated41. As protein kinases JNK and p38 was involved in process of brain injure and BNP secretion, it may be the potentional molecular mechanism for elevation of NT-proBNP in patients with AIS.
There are several limitations in our study. First, NT-proBNP is not widely used in nervous system disease previously. Patients who got NT-proBNP test might suffer from hypoxia, tachypnea, tachycardia and NT-proBNP might be mainly used in differential diagnosis of heart failure. So bias may occur and we put partial pressure of oxygen into the study and excluded patients with heart failure for sensitivity for anylysis. Second, as NT-proBNP is not widely used in nervous system disease, we got 460 patients who met the inclusion criteria. The sample size was relatively small. Third, conditions of patients who admitted to intensive care unit were sophisticated, we put the most common factors like age, sex, vital sign, partial pressure of oxygen and clinical scores into consideration, while information of echocardiography, computed tomography scan or magnetic resonance imaging of brain are not available.