To the best of our knowledge, this is the first study to evaluate the association of the TyG index with hospital and ICU mortality in critically ill stroke patients. The main findings are as follows: (1) the TyG index is an independent predictor for hospital and ICU mortality in patients with critically ill stroke; (2) the hospital and ICU mortality correlated proportionally with the increment of TyG index, implicating the linearity of TyG index as an indicator of critically ill stroke; (3) subgroup analysis demonstrated TyG index was associated with increased risk of hospital and ICU death in critically ill IS, but not in HS.
The TyG index, as the product of fasting plasma glucose and triglyceride, is a novel index that has been well recognized as a simple and reliable surrogate of IR.[12] The homeostatic model assessment of IR (HOMA-IR) has been traditionally used to estimate IR.[13] However, insulin levels must be required to calculate the HOMA-IR index. Compared with the inconvenient HOMA-IR, the TyG index does not require levels of insulin and may apply to all of the patients and healthy population. Recent studies indicated that the TyG index has been shown to be superior to HOMA-IR in predicting IR.[14] Furthermore, several studies conducted in Asia and Europe validated the strong association between TyG and incidence of diabetes mellitus.[12, 15] Won et al. reported the TyG index was independently associated with arterial stiffness in a relatively healthy Korean population.[16] Other studies demonstrated the TyG index was an independent predictor of coronary artery calcification progression and risk of cardiovascular diseases.[8, 17] In addition, previous studies suggested the TyG index predicted severity and outcomes in patients with acute coronary syndrome.[6, 18, 19] Wang et al. reported the TyG index predicted future cardiovascular events in patients with diabetes and acute coronary syndrome independently of known cardiovascular risk factors.[7] However, in a previous study based on a Caucasian population, the TyG index displayed an insignificant association with stroke.[20] Later, another study based on the same Caucasian cohort, identified metabolic health and obesity states groups based on TyG index was significantly associated with the risk of IS.[21] Additionally, a recently published epidemiological investigation expanded the use of TyG index as a direct marker for the risk of IS.[10] However, no relevant study focus on the association between TyG index and outcome of stroke. The present study investigated the relationship between the TyG index and the hospital mortality in critically ill stroke on eICU database. We found that the TyG index was significantly associated with mortality in ICU stroke after adjusting for confounding factors. Furthermore, the TyG index had a continuous linear correlation with the mortality of ICU stroke.
Although the mechanism underlying the relationship between the TyG index and stroke is not fully elucidated, the TyG index has been deemed as a useful atherogenic indicator linked to IR and metabolic syndrome. IR may be the mechanism in increasing mortality in stroke. Firstly, IR may increase proinflammatory cytokines and enhance prothrombotic responses, thus exacerbating damage in the brain after stroke.[22, 23] Secondly, IR may cause sympathetic activity and catabolism in muscles, thus enhancing muscle loss and leading to poor functional outcomes.[24] Thirdly, IR may increase platelet adhesion, enhance atherosclerosis progression, facilitate plaque instability, and therefore contribute to severity of stroke, via promoting apoptosis of vascular smooth muscle cells macrophages, and endothelial cells.[25, 26] Fourthly, recent evidence has proved that triglyceride and glucose disorder are the risk factors of stroke, while the formula of TyG index is composed of triglyceride and glucose.[27, 28] Lastly, IR may augment the role of modifiable risk factors of stroke, such as hypertension, atrial fibrillation.[10] Although the present study had showed the association between TyG index and poststroke outcomes, the underlying molecular mechanisms involved in this association should be further investigated in the future study.
Stroke accounts for almost 5% of all disability-adjusted life-years and 10% of all deaths worldwide.[2] From different epidemiological surveys, stroke mortality in different periods varies from 5%-72 %.[29, 30] Stroke mortality has been declining since the early 20th century.[31] The reasons for this are not completely understood, although the decline is welcome.[31] However, due to the increasing complexity of stroke treatment and severe conditions, an increasing proportion of acute stroke patients are being admitted to an ICU.[32, 33] A study including 4958 consecutive stroke patients reported 347 (7.0%) patients required ICU admission at any time point during their index hospitalization.[4] In-hospital mortality of ICU stroke reported in the literature varies widely, highly depending on the patient characteristics. A previous small study found the mortality was 38.7% (43/111) in stroke patients requiring ICU admission.[32] An United States study including 448 ICU stroke patients provided hospital mortality was 30%.[34] Recently, a prospective observation trial reported the mortality was 7.5% in critically ill stroke patients.[35] These patients with high hospital mortality mainly associated with older age, poor neurological severity at admission, high APACHE score, impaired consciousness, intracranial hemorrhage and need for mechanical ventilation.[32, 33] Moreover, functional outcomes in survivors appear to be poor.[36] The current study based on eICU database, indicated the hospital and ICU mortality were 10.3% and 5.0%, respectively. Furthermore, we found a new risk factor, the TyG index, for the mortality of critically ill stroke.
In subgroup analysis, we demonstrated TyG index was associated with increased risk of hospital and ICU death in critically ill IS, but not in HS. In agreement with previous GBD 2016 report, we did not estimate the mortality due to subarachnoid hemorrhage and intracerebral hemorrhage separately.[1] Of the total number of prevalent strokes, over 80% were IS. However, the number of global deaths due to IS was slightly lower than the number due to HS deaths.[1] In contrast, a previous neurology ICU study demonstrated HS was more frequent than IS (71.9% vs 28.1%).[37] Several studies, including our present study, described TyG index was a useful marker in IS. However, to our knowledge, no relevant study has evaluated the relationship between the TyG index and HS. Although previous studies had focusing on the relationship between IR and HS, the results had been discrepancy. The Rotterdam study and the Uppsala study had previously examined the association between IR and risk of HS, finding virtually no evidence of an association.[38, 39] Later, a large United States stroke cohort showed IR may be a protective effect on HS.[40] In the current study, we did not observe a significant association of the TyG index with all-cause death in critically ill HS in either unadjusted or adjusted analysis.
Although our study based on a large multicentre critical care database, it still has some limitations. First, this was a retrospective analysis derived from an observational study, which could not definitively establish causality. Second, the eICU v2.0 did not contain the data on head imaging, neurological severity scores, and follow-up outcomes after discharge. Residual confounding could exist. Third, the baseline levels of plasma glucose and triglyceride could be affected by the use of antidiabetic and lipid-lowering drugs before ICU admission. The TyG index might have changed during hospital; therefore, it is unknown whether the change in the TyG index could have predicted the mortality. Fourth, we did not measure HOMA-IR because the examination of insulin levels is not included in the eICU v2.0. Last, the data were from the United States, and thus the results may not apply fully to ICUs elsewhere with different practices or resources.