The main findings of our study were that high early serum glucose levels significantly correlated with high incidence of DCI in both PAN-SAH and NPAN-SAH patients, despite similar time-dependent changes in DCI and non-DCI groups. In addition, high serum glucose levels on admission were associated with high WFNS. Multivariate logistic regression analysis showed that admission serum glucose was a significant and independent predictor for DCI occurrence in both PAN-SAH and NPAN-SAH patients. To our knowledge, this is the first article to illustrate the association of serum glucose and occurrence of DCI after AN-SAH.
AN-SAH occurs in approximately 15% of SAH patients, and is characterized as either PAN-SAH or NPAN-SAH according to their bleeding patterns [3]. Although the overall prognosis is good, a certain percentage of AN-SAH patients still have DCI and poor outcome, especially NPAN-SAH [4, 5]. It is generally believed that patients with NPAN-SAH have a worse neurological outcome and a higher incidence of complications than PAN-SAH patients, which is consistent with our findings [3, 25]. The prognosis of NPAN-SAH is considered similar to that of aSAH [5]. Therefore, it is necessary to identify early risk factors of DCI and unfavorable outcome in AN-SAH. However, few studies have focused on factors related to the occurrence of DCI in AN-SAH patients thus far.
Previous studies have verified the relationship between serum glucose and DCI or vasospasm after aSAH. One study found that post-aSAH symptomatic vasospasm significantly correlated with admission serum glucose levels (p = 0.003), which was congruent with our findings. However, in multivariate analysis, admission glucose levels were not a significant predictor of symptomatic vasospasm (OR, 0.99 [95% CI, 0.99–1.01]) [26]. In another study, maximum serum glucose levels shortly after aSAH were associated with an increased risk of DCI (p = 0.002). Multivariate analysis showed that glucose was an independent predictor of DCI (OR, 1.17 [95% CI, 1.05–1.30]) [6]. This is consistent with the results we found in patients with AN-SAH. However, this study differs in that it defined DCI as a new hypodensity on CT not otherwise explained by cerebral infarction due to DCI after admission. To more accurately understand the relationship between serum glucose and DCI after AN-SAH, we also analyzed the mean, maximum, minimum, range, SD, and CV of serum glucose shortly after admission. In addition, another study found that the serum glucose/potassium ratio was an independent predictor of cerebral vasospasm after aSAH [27].
Although the mechanisms underlying the relation between serum glucose and risk of DCI are still unclear, the SAH-induced stress response may explain this association. Catecholamines, glucagon, and corticosteroids are the main hormones involved in causing hyperglycemia [27]. Neurogenic stress can cause the release of these hormones, which may induce inflammation and cause systemic damage [28]. Elevation of serum catecholamine concentrations, which induce sympathetic activation, has been confirmed after aSAH, and was found to be associated with a poor outcome [29]. One study found that early sympathetic activation after bleeding reflected the severity of aSAH, and was related to the development of DCI and poor outcomes [30]. A cohort study showed that using a beta-blocker to inhibit sympathetic activity was associated with a lower incidence of cerebral vasospasm in patients with aSAH [31]. An experimental study also confirmed the correlation between sympathetic suppression and decreased cerebral vasospasm after SAH [32]. Therefore, elevated serum glucose after SAH may reflect the stress response and severity of the neurological insult. In the present study, patients with higher serum glucose on admission showed had increased severity when assessed using WFNS, as well as increased risk of DCI. NPAN-SAH patients have higher serum glucose levels, as well as higher clinical and radiological severity than PAN-SAH patients. This may reflect that NPAN-SAH patients have a stronger stress response and more severe neurological damage when compared with PAN-SAH patients, and may explain the higher risk of DCI in patients with NPAN-SAH. However, after controlling for some risk factors, including WFNS and mFS, the admission serum glucose was still associated with the occurrence of DCI, suggesting that there might be other mechanisms mediating the link between serum glucose and risk of DCI.
It remains unclear whether hyperglycemia plays a role in the occurrence of DCI or if it is just a stress response to SAH. Previous studies have shown that hyperglycemia may exacerbate secondary brain injury after stroke [33]. Moreover, hyperglycemia provides an abundant substrate for anaerobic glycolysis in ischemic brain tissue, which leads to excessive lactate accumulation, acidosis, and cell death [34]. In a rat SAH model, hyperglycemia exacerbated cerebral vasospasm by dysregulating endothelial nitric oxide synthase (eNOS) and inducing nitric oxide synthase (iNOS) [35]. Another experimental study indicated that hyperglycemia may activate the extrinsic caspase cascade through the extracellular regulated kinase (ERK) signal pathway to contribute to neuronal apoptosis after SAH [36]. Aggressive glucose management may help improve outcome in aSAH [33]. However, some studies held an opposite view. A previous prospective study found that hyperglycemia preceded aSAH onset, as evidenced by the elevated glycated hemoglobin (HbA1c) levels, but did not lead to poor outcome [37]. Low cerebral glucose, which is related to severe metabolic distress, may exert deleterious effects in patients with aSAH [38]. Intensive glycemic control with insulin after aSAH may reduce cerebral glucose, leading to worse outcome [39, 40]. However, some studies have shown that increasing serum glucose through enteral nutrition could increase cerebral glucose levels without causing abnormal cerebral glucose metabolism, which may improve the prognosis of patients with aSAH [41, 42]. Therefore, post-SAH hyperglycemia may be a protective factor in the brain that compensates for insufficient cerebral glucose after brain injury.
Our study is the first to examine the relationship between early serum glucose levels and risk of DCI in patients with AN-SAH. In this study, high serum glucose at admission correlated with high WFNS, indicating that admission serum glucose may reflect the severity of AN-SAH. Serum glucose levels at admission and early after admission, which may reflect the degree of SAH-induced stress, were significantly associated with the occurrence of DCI in both PAN-SAH patients and NPAN-SAH patients. Multivariate analysis showed that admission serum glucose was an independent predictor of DCI risk after PAN-SAH or NPAN-SAH. Since serum glucose is routinely collected in SAH patients, it seems to be a convenient method to identify patients at high risk of DCI after AN-SAH to guide intensive care. It remains unclear whether the elevated serum glucose after AN-SAH has a harmful effect. Therefore, tight glycemic control is not recommended.
Several limitations of this study should be considered. First, we did not study stress-related indicators after AN-SAH. Other parameters must be collected to further establish the relationship between serum glucose and DCI risk. Second, due to the mild condition and short hospital stay of AN-SAH patients, we only collected the serum glucose data in the first five days after admission. In addition, glucose infusion, diet, drug use, and number of glucose measurements during hospitalization were not taken into account as a potential confounder, which may have introduced bias. Third, potential bias may exist in how DCI is defined. To address this problem, we defined the DCI according to the criteria of the previous study [24]. Two senior neurologists who were blind to the clinical information independently evaluated the DCI. Additionally, we did not record the specific time when the patients developed DCI. Fourth, because patients with missing radiological and serum glucose data often have better neurological status at admission, our results likely apply to patients in a moderately worse condition at admission. Finally, our study was retrospective and conducted at a single center. A multicenter collaborative prospective validation with an increased cohort size is recommended in future studies.