Acute ischemic stroke is as critical and satisfactory results can be obtained when iv r-tPA ± thrombectomy is applied at an early stage, namely, clinical recovery increases sequelae rate and mortality decrease. The major parameters that can serve as predictory criteria for clinical prognosis include size of the infarct, duration of the intervention, and location of the occluded artery. However, we believe that the glucose values of patients during this period could also give a preliminary idea of the clinical process. We found that the glucose fluctuation noted in the early days of the disease was significantly associated with parameters, such as clinical severity, degree of sequelae, and mortality rate. To reveal the effects of this connection on the above parameters more clearly and meaningfully, we formed a group that included only patients who underwent acute treatment (iv r-tPA ± thrombectomy). Time to treatment from disease onset was 171.4 ± 51.9 min, which is optimal for treatment. In similar studies in literature, a single glucose value was usually analyzed along with all treatment options. Therefore, we wanted to draw attention to the fluctuation of glucose in the first several days, including groups of acute intervention.
Hyperglycemia is an extremely important factor in the development of atherosclerosis and associated vascular complications [9]. The importance of various metabolic abnormalities and subsequent formation of reactive oxygen radicals in pathophysiology are discussed in detail below.
Acute hyperglycemia initially disrupts nitric oxide synthesis, causing disturbances in the production of prothrombotic and vasoactive substances [9]. Vasoconstriction leads to microcirculation and increases ischemia, as post-thrombosis recanalization cannot be achieved [10]. Increased lactate production in brain due to hyperglycemia is considered to be associated with a decrease in penumbra in stroke patients [11]. In addition, hyperglycemia and hyperinsulinemia, which occur in acute ischemic stroke, can reduce fibrinolytic activity and increase the ratio of plasminogen activators–inhibitors, thus reducing the effect of iv r-tPA and recanalization [12]. Based on these two outcomes, we can say that hyperglycemia causes a vicious cycle in stroke patients as a cause and result of treatment success. In other words, we can assume that if this cycle is broken, clinical recovery will accelerate. We noted this in our study, for instance we found higher mortality rates in patients with glucose of ≥ 200 mg/dl for 4 days. Patients were evaluated 1 month after the post-stroke for clinical improvement. When we examine the relationship of baseline glucose values to mRS scores on the 30th day, while the mRS was 4.19 ± 1.2 in patients with glucose ≥ 200 mg/dl, it was 3.24 ± 1.1 in patients with < 200 mg/dl. As a result, when we consider the 30th day mRS scores of patients with glucose < 200 mg/dl, we found that these patients showed a higher rate of clinical improvement.
A study on ischemic stroke conducted with experimental animal models shows that monocyte/macrophages, which are neuroprotective, non-inflammatory cells involved in neurogeneration, are decreased in ischemic brain, where hyperglycemia occurs. The study also indicates that glucose metabolites, such as alpha-dicarbonyl, one of the final products of glycolization in ischemic brain tissue, increases in hyperglycemic mice [13]. Another experimental study emphasizes that hyperglycemia causes brain edema by increasing the permeability of the blood brain barrier and release of inflammatory mediators [14]. Some studies also suggest that hyperglycemia aggravates the clinical prognosis by causing an increase in the size of the existing infarction. In a study conducted with experimental animals, the MCAs of the animals were subjected to occlusion by suturing. Blood glucose levels were brought to 140–200 mg/dl (mild hyperglycemia) and 240–350 mg/dl (severe hyperglycemia) with 30 and 60% glucose solutions, respectively. There was no significant difference between the mild hyperglycemic group and the control group in terms of infarction size, while a significant increase in infarction size was found in animals with severe hyperglycemia (p = 0.029) [15].
We evaluated the relationship between clinical severity and glucose levels over 4 days, which is the focus of our study, based on the NIHSS score at admission. Accordingly, we showed that glucose levels were higher in the severe patient group (NIHSS < 16) compared with the mild to moderate patient group (NIHSS < 16). This result was valid for all 4 days when glucose levels were recorded and yielded a significant statistical result in favor of poor prognosis.
In terms of mortality, the course of glucose was similar in the group of severe patients. Therefore, the analysis of glucose follow-up reveals that glucose elevation is directly related to and increases the mortality risk. Another interesting result was that glucose peaked on day 2 in deceased patients and the severe group of patients with baseline and 24th hour NIHSS ≥ 16. We did not encounter a similar peak on day 2 in mild to moderate and surviving patients. Based on this result, we can assume that the clinical prognosis is more likely to deteriorate, especially in patients whose blood sugar cannot be controlled in the first 24 h. However, the prognosis should not be concluded based on the glucose level on day 1; waiting for days 2 and 3 and checking for a peak can provide better prediction.
In a comprehensive literature study on this topic, hyperglycemia, as one of the causal factors of the negative consequences of stroke, was identified as a changeable risk factor, and it was concluded that the risk of mortality decreases in case of blood sugar regulation [16]. According to a meta-analysis study, each 1 mmol/L increase in blood sugar increases the negative clinical course by 8% and the rate of intracranial hemorrhage by 9% [17]. Acute hyperglycemia detected in acute stroke patients leads to in-hospital mortality and insufficient post-discharge functional recovery in non-diabetic patients. It is also suggested that hyperglycemia is not always associated with DM but can also be considered a stress response to hypercortisolism [16]. In this study, individuals with no DM history had a high risk of severe disease progression, which supports the conclusion in the previous sentence. In addition to transient hyperglycemia, HbA1c is also significantly higher in severe patients compared with mild to moderate ones. This may also suggest that severe patients are prone to diabetes or are in the prediabetic stage.
In a study conducted between 2000 and 2003, the effect of glucose level on recanalization time and clinical outcomes were investigated in acute stroke patients receiving iv thrombolysis. In addition, the intra-arterial obstruction rate was monitored with a transcranial doppler ultrasonography. The NIHSS of the hyperglycemic group was 17.0 ± 5.5% and the occlusion rate was 52.2%, while the NIHSS of the normoglycemic group was 15.8 ± 5.5% and the occlusion rate was 31.4% (p = 0.05). The recanalization success rate of hyperglycemic and normoglycemic patients was 24.6 and 39%, respectively, which was significantly lower in the hyperglycemic group (p = 0.001). When the average recanalization time was compared between hyperglycemia and normoglycemia, it was found to be longer in hyperglycemic patients. In addition, recanalization times were 163 ± 79 min and 131 ± 90 min in severe hyperglycemia and less severe hyperglycemia (glucose:140–200 mg/dl), respectively (p = 0.045). Based on these data, it was reported that if hyperglycemia is present in acute stroke patients, the success rate of recanalization after iv r-tPA is lower [8].
One hundred and three acute stroke patients with mean age of 55.5 ± 15.3 years were included in a prospective study conducted in Ethiopia in 2016. The first glucose value measured was ≥ 140 mg/dl in 49.5% of the patients. The glucose value of normoglycemic patients was 119.9 ± 13.0 mg/dl and that of hyperglycemic patients was 183.2 ± 34.5 mg/dl. Mean NIHSS was 14 in hyperglycemic patients and 11 in normoglycemic patients, while the risk of poor prognosis was 3.83 times higher in hyperglycemic patients (p = 0.041) [18]. As a result these two studies also supports our hypothesis.
In this study, we observed a steady daily increase in the 30-day mRS score in patients with severe hyperglycemia (day 1: 4.19 ± 1.2, day 2: 4.40 ± 1.05, day 3: 4.44 ± 1.33, day 4: 4.75 ± 1.48). However, no such increase was observed in patients who did not have severe hyperglycemia. In other words, we noted an increase in the risk of disability for every passing day that glucose control was not achieved. Regarding the relationship between these two groups, in 4 days, the sequelae ratio, such as the mRS score, is higher in severe hyperglycemic patients (p < 0.05). In general, based on these results, we can argue that resistant hyperglycemia in the early days negatively impacts sequelae and dependency.
In a study that supports our hypothesis, there was a significant relationship between hyperglycemia and short-term recovery and impaired functionality in patients with acute stroke; furthermore, achieving normoglycemia in the early stage of stroke positively impacted the quality of life and prognosis of patients [8]. In a similar study, hyperglycemic and normoglycemic patients were followed up for 3 months and it was found that the clinical functional capacity was lower in hyperglycemic patients (p = 0.011). As a result, it was emphasized that the post-stroke sequelae would be more severe and longer [17]. According to European Cooperative Acute Stroke Study II results, hemorrhagic transformation, adverse clinical outcomes, and increase in mortality were reported in case of 24 h or longer hyperglycemia. Furthermore, based on NIHSS and mRS scores in hyperglycemic patients, it was also emphasized that clinical improvement was worse in these patients [19]. We exclude patients who developed hemorrhagic transformation in our study. Because, some of these patients underwent decompressive surgery. We thought that stress due to decompressive surgery or hemorrhagic transformation in non-surgical patients might affect the 4-day glucose values. In addition, due to the small number of patients with hemorrhagic transformation, it was thought that it would be an insufficient population for statistical assessment. However, this issue could be discussed in a future meta-analysis with more participants.