European Journal of Cardiovascular Medicine

A stress response consisting of increased levels of serum cortisol, serum ACTH and catecholamines in the first weeks after acute stroke has been known since the 1950s.The serum cortisol and serum ACTH response has been identified in both cerebral infarction and intracerebral haemorrhage. High s-cortisol levels and s-ACTH have been related to poor outcome. It is, however, not known whether this adrenal glucocorticoid stress response is beneficial or harmful to the damaged brain.

Some researchers suggested that the association between high stress hormone levels and less favorable outcome could be related to cardiac abnormalities resulting from the increased levels of stress-hormones. Whether the stress response is just an epiphenomenon to stroke severity or independently contributes to prognosis remains uncertain. Furthermore, the stress response has not yet been put in perspective by evaluation in the context of parameters generally assumed to be of importance in acute stroke. There are many clinical variables like symptom severity and advanced age which are identified as potential predictors of outcome in patients with acute stroke. But there is an immense need to detect a biomarker for predicting the outcome of acute stroke. The period that ensues after the event of acute stroke can be regarded as a reaction to a stressful event. This stress response causes the activation of the hypothalamo–pituitary–adrenal (HPA) axis and sympathetic nervous system. In acute stroke the first measurable alterations are the endocrine changes because of the alteration in HPA axis. One of the HPA axis- related hormones is cortisol which has a robust circadian rhythm wherein the levels peak typically in the early hours of the day and decline later on.

Cortisol has got a significant effect on the glucose, fat and protein metabolism and cardiovascular reactivity. There are studies which showed that high serum cortisol level associated with very much decreased physical function and impaired level of consciousness. Fiorentino et al showed that salivary cortisol levels can be used as biological marker for identifying patients who are prone for acquiring lower benefits from inpatient rehabilitation services. It is also proved in many studies that, increased cortisol concentrations have been observed in acute ischemic stroke and SAH.  Certain studies have found that increased serum and urinary cortisol level in patients with acute stroke is related to larger infarct volume, greater stroke severity and poor outcome, including death. After the acute event, increased serum cortisol level is significantly associated with acute confusional state.

The primary objective of this study dissertation is to test the hypothesis that increased single serum cortisol level is associated with increased severity of acute ischemic stroke. Though cortisol level has diurnal variations it has been showed that the normal circadian rhythm of cortisol is suspended during acute stroke and there is no variation of cortisol level in serum throughout the day due to perturbations in the HPA axis.

So this study was designed to study the correlation of serum cortisol on stroke severity.

A total of 68 patients were included in the study. The patients were recruited from the Department General Medicine and Psychiatry, Malla Reddy Institute of Medical sciences. Written informed consent was taken from all the patients.

All patients were included in the study who was admitted within 6 hours in the hospital after the episode of stroke. Patients were excluded if age < 18 years, other acute lifethreatening diseases and pregnancy. 

Three patients were excluded from the study as o9ne patient withdrew consent and two patients had another final diagnose than stroke. 

Vital signs such as blood pressure, pulse rate, body temperature were continuously monitored. Scandinavian Stroke Scale (SSS)xx was monitored in all patients from admission. SSS was performed every 2 hours in the first 24 hours, every 4 hours in the next 48 hours and then daily up to day 7.

At follow-up of 3 months SSS, blood pressure and pulse rate were assessed. Cerebral infarction or intracerebral haemorrhage was diagnosed on the basis of clinical findings and CT-scan in all patients. Atrial fibrillation was diagnosed by 12-lead ECG on admission or by continuous ECG-monitors. CT scan of each patient was performed and follow-up CT-scan at 7-8 days.

Blood samples were obtained for routine investigation and estimation of serum cortisol. No patients had blood samples drawn for cortisol determination between 01:00 and 07:00 am.

Thus a total 64 study population was obtained after all exclusions and was included in the study.

Statistical analysis 

Statistical analysis was performed by SPSS 21.0 for Windows. Normal distribution was assessed. Student’s t test was used in comparing means of independent, normally distributed, continuous variables. Stratifications were based on the median of SSS score. Multivariate logistic regression was performed after assessing the normal distribution. A significance level of 0.05 was selected.

A total of 90 individuals who had CT brain scans performed at the time of admission and were confirmed to have had an acute stroke were included in the study. The patients' ages ranged from 43 to 88 years old, minimum and maximum, respectively. Of the 90 patients, 46% had an acute stroke while they were between the ages of 50 and 59. Additionally, there were roughly 50% men and 50% women. The cortisol level was 637 nmol/L on average. Out of the 90 patients, 42% were not diabetics and 58% were. Of the total, 42% were normotensives and 58% were hypertensives. The mean systolic blood pressure of the 90 cases was 146 mm Hg, while mean diastolic blood pressure was 93 mm Hg. Acute ischemic stroke affected 78 out of the 90 patients, while the acute hemorrhagic stroke affected 12. Of the 78 cases of acute ischemic stroke, 28 had an infarct in the region of the anterior cerebral artery, 57 in the region of the middle cerebral artery, and 13 in the region of the posterior cerebral artery. Of the 22 cases of acute hemorrhagic stroke, 21 involved bleeding in the MCA area and 1 involved bleeding in the ACA region. It is evident that MCA area infarct and haemorrhage were present in the majority of patients. The average time was 11.53 hours, and the average SSS score was 22.90. Out of the 90 patients, 49 showed up in less than eight hours, 35 in between nine and fifteen hours, and six in between sixteen and twenty-four hours. Less than 15 in 20 patients out of 90 had an SSS score. The mean SSS score fell into the severe category at 10, with 74 individuals having scores between 16 and 30 and 11 patients having scores over 30. Serum cortisol levels were less than 500 nmol/L in patients with a score of less than 15 and more than 700 nmol/L in patients with a score of more than 30.

The cortisol mean values for the infarct and haemorrhage were 665 and 7.99, respectively; the standard deviations were 16.7 and 7.99, with a P value of 0.067. Therefore, it was discovered using an unpaired t-test that there is no significant link between blood cortisol levels and infarction or haemorrhage.

              The SSS and serum cortisol correlation coefficient was -0.990, showing a significant link. High serum cortisol levels were associated with lower SSS scores, and the p-value was < 0.001, indicating statistical significance.

In our study, we found that serum cortisol was positively correlated to RBS, severity of AIS, and functional outcome of AIS at 1, 4, and 24 weeks. Serum cortisol showed a significant association with mortality at 1, 4, and 24 weeks after AIS.

During the follow-up of patients for functional outcome at 1, 4, and 24 weeks using mRS, a positive correlation of outcome was observed with serum cortisol levels on the day following admission at all these intervals and found to be significant (p < 0.001) with Pearson's correlation coefficient value of 0.676, 0.654, and 0.650, respectively. This shows that higher stress response and higher serum cortisol during AIS displayed worsened functional outcomes during short- and long-term follow-up. Various studies in the past correlated serum cortisol levels at baseline to the outcome of AIS at various intervals varying from zero to one year. Zierath. reported a significant relationship between serum cortisol and outcome at 1, 3, 6, and 12 months. ^[1] They found that higher cortisol levels were associated with worse outcomes at these intervals, but the relationship attenuated over time with p-value being <0.001, <0.001, 0.007, and 0.050, respectively, for these intervals. Neidert et al. also concluded that cortisol levels on day 1 after admission mirrored the stroke severity at 90 days and one year. ^[2] A stroke per se indicates a poor outcome, but the stress response with one of its manifestations as increased cortisol itself leads to worse outcomes mediated by catabolism, increased blood glucose levels, and heart rate. Thus, the increased serum cortisol level showed secondary effects such as neuronal ischemic injury precisely at the hippocampus. ^[3] A disturbance in the hippocampus function might cause disturbances in the HPA axis as the hippocampus holds a role in feedback regulation of the HPA axis, potentiating cortisol response in addition to the physiological stress response. This stress response is also related to adverse cardiac outcomes including arrhythmias or myofibrillar degeneration and immune dysregulation causing an increased incidence of infections resulting in higher morbidity and mortality. ^[4] The adverse cardiac effects also result from simultaneous sympathetic activation due to stress response. Some studies have shown no significant correlation between cortisol and ischemic stroke. ^[5] However, all of these studies involved a small number of patients, included patients with mild stroke severity only, or used sedatives concomitantly (midazolam or fentanyl), which may have caused variation in the results.

Regarding the mortality after stroke at 1, 4, and 24 weeks, we found a significant association between serum cortisol on day one after admission and mortality at these intervals. We found the levels of cortisol at baseline to be higher in the patients who died than those who survived at these intervals with a p-value of <0.001 for all intervals. Fassbender et al. also reported an early and persisting activation of the hypothalamic-pituitary-adrenal axis, and it shows a significant association with disease severity. ^[6] Marklund et al. found that higher serum cortisol levels on day 1 predicted both 28-day and one-year mortality. ^[7] Similar observations were also reported in Neidert et al.'s study where the cortisol levels predicted the day 90 and one-year mortality. ^[8] On day 90 in Zi et al.'s study and day 7 in Agarwal et al.'s study, serum cortisol levels displayed a significant association with mortality in acute stroke patients. ^[9]

In our study, we observed a positive correlation (r = 0.785) between the severity of AIS (NIHSS) and serum cortisol levels. AIS is a stressful event resulting in stimulation of the HPA axis causing increased serum cortisol levels. As the severity of stroke increases, a higher stress response is mounted resulting in an increased value of serum cortisol. Previous studies done by Neidert et al. and Zi et al. also found a positive correlation between NIHSS and serum cortisol, and it was significant (p < 0.0001). ^[10]

A positive correlation between RBS and serum cortisol (r = 0.273, p = 0.006) can be attributed to higher stress response in hyperglycemia as well as the hyperglycemic effect of cortisol and other stress hormones. Other studies have found a similar correlation, including a multivariate analysis by Zi et al.'s study with an odds ratio of 1.33 per unit increase in glucose level (p < 0.0001). ^[11] In another study done by Christensen et al., univariate analysis showed a significant association between glucose level and stroke severity with a regression value of 0.22, and it was significant (p = 0.007). ^[12]

The limitations of the study were less sample size and the lack of estimation of other stress markers such as adrenocorticotropic hormone (ACTH), noradrenaline, adrenaline, and other hormones involved in the stress response.

A stress response during AIS showed increased serum cortisol levels. This response is positively correlated to RBS, the severity of AIS as assessed using NIHSS, and the outcome of AIS at 1, 4, and 24 weeks as assessed using mRS, and it also showed a significant association with mortality. Therefore, serum cortisol values could be considered as a prognostic indicator of severity, outcomes, and mortality at intervals of 1, 4, and 24 weeks. This could be due to higher stress response in AIS causing a higher amount of stress hormones including cortisol and activation of the sympathetic system. As discussed, this has been associated with various deleterious effects that contribute to higher morbidity and mortality. Thus, the serum cortisol at baseline can be considered a marker of severity, mortality, and short- and long-term prognosis after AIS.

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