American Journal of Emergency Medicine (2013) 31, 161-165

Original Contribution

Relation of serum cortisol to delirium occurring after acute coronary syndromes

Yucel Colkesen MD ^a,?, Semih Giray MD ^b, Yarkin Ozenli MD ^c,

Nurzen Sezgin MD ^d, Isa Coskun MD ^e

^aFaculty of Medicine, Department of Cardiology, Baskent University, Adana 01250, Turkey ^bFaculty of Medicine, Department of Neurology, Baskent University, Adana 01250, Turkey ^cFaculty of Medicine, Department of Psychiatry, Baskent University, Adana 01250, Turkey ^dFaculty of Medicine, Department of Biochemistry, Baskent University, Adana 01250, Turkey

^eFaculty of Medicine, Department of Cardiovascular surgery, Baskent University, Adana 01250, Turkey

Received 31 May 2012; revised 1 July 2012; accepted 7 July 2012

Abstract

Background: Delirium can be associated with cardiac system disorders. Stress plays an important role in the pathogenesis of postoperative delirium. Cortisol is one of the most important stress hormones in humans. We aimed to investigate whether a relation exists between serum cortisol and the degree of delirium after acute coronary syndromes .

Methods: We enrolled 52 consecutive patients who presented with ACS and were hospitalized in the coronary care unit. Patients were examined daily by a single psychiatrist, and delirium was diagnosed by using the Delirium Rating Scale (DSR). Blood samples were obtained at 6:00 AM of the next morning after admission.

Results: The mean age was 66 years (SD, +-6 years), and 52% were men. Delirium occurred in 25 patients (48%). The median score on the DRS was 17 for the delirious patients and 5 for the nondelirious. Median cortisol levels were significantly different between the delirium and nondelirium groups (13.9 vs 6.2 ug/dL; P b .01). There were significant correlations between the cortisol levels and the severity of the delirium based on DRS scores as well as between the cortisol levels and the presence of delirium (r = 0.65 and 0.74, respectively; P = .01). In a linear logistic regression model, cortisol predicted the occurrence of delirium (? = .81; P b .01). In receiver operating characteristics analysis, the optimal cutoff value of cortisol to predict delirium was 10.8 ug/dL, with 96% sensitivity and 89% specificity.

Conclusion: Delirium was common after ACS, and serum cortisol levels correlated with the degree of delirium and the risk of delirium.

(C) 2013

Introduction

* Corresponding author. Tel.: +90 5334795944; fax: +90 32232712798.

E-mail address: [email protected] (Y. Colkesen).

The American Psychiatric Association defines delirium as a transient mental syndrome characterized by (i) disturbance of consciousness with a reduced ability to focus, sustain, or shift attention; (ii) change in cognition (such as memory

0735-6757/$ - see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2012.07.001

deficit, disorientation, or language disturbance) or develop- ment of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia; and

(iii) disturbance developing over a short period (usually hours to days) and tending to ftuctuate during the course of the day [1]. Delirium may occur due to several general medical conditions [2]. The most common underlying causes are central nervous and cardioPulmonary system disorders, Metabolic disorders, and systemic illnesses [3].

Cortisol is one of the most important stress hormones in humans. Its secretion is proportional to and positively correlated with the severity of illness in hospitalized Medical patients [4]. It has long been observed that high levels of circulating glucocorticoids might have harmful effects on the brain and cause Psychiatric symptoms [5,6].

The relationship between circulating cortisol level and the occurrence of delirium after acute coronary syndrome (ACS) has not been fully demonstrated. We hypothesize that the occurrence of delirium after ACS is also related to the stress response and, thus, elevated circulating cortisol levels. The purpose of this study was to examine the association between serum cortisol levels and occurrence of delirium after ACS.

Methods

Patients and study protocol

The study sample was composed of 52 consecutive patients admitted to the Coronary intensive care unit with a diagnosis of ACS between April 2007 and May 2008. Patients with ACS are not hospitalized elsewhere at our institution. Patients were divided into 2 groups based on the presence of delirium. Twenty-five patients had manifesta- tions of delirium after ACS, and 27 nondelirious patients with ACS composed the control group. The exclusion criteria included patients who were referred from another hospital and had been hospitalized there for one or more days and those who were unconscious, in a stupor, or coma and those who had a history of stroke, dementia, alcohol withdrawal, depression, or anxiety. We also excluded patients who had delirium on the day of admission. Patients who were transferred for cardiovascular surgery were not enrolled. Informed consent was obtained from patients or their closest proxy agent (if they were unable to provide informed consent) during the first day of hospitalization.

The study was approved by the Ethics Committee of

Baskent University.

Definition of ACS

The diagnosis of ACS was defined by the presence of 2 of the following 3 criteria: (a) typical chest pain lasting more than 30 minutes and not relieved by sublingual nitroglycerine; (b) more than 0.1 mV ST-segment elevation

in 2 anatomically contiguous leads or more than 0.2 mV in leads V₁ and V₂; and (c) elevation of levels of the MB fraction of creatine kinase or troponin I at least 3 times the upper reference limit. Based on the findings, patients were diagnosed as unstable angina (USAP), Non-ST-segment elevation myocardial infarction (non-STEMI), and ST- segment elevation myocardial infarction (STEMI). The patients’ sociodemographic characteristics, medications for ACS, and Laboratory test results were recorded at the time of admission to the coronary intensive care unit. All patients initially received 300 mg aspirin (orally, everyday), intra- venous heparin, ?-blockers orally, intravenous nitroglycer- ine, and 30 mg lansoprazol (orally, everyday). History of alcohol and Substance use disorders, major depression, medical diseases, and coronary bypass surgery were provided by the patients or their relatives.

Delirium assessment

Patients were assessed every day by the same psychiatrist (YO) from the first day of their hospitalization to discharge. The diagnosis of delirium was determined by criteria according to the American Psychiatric Association [1]. To establish the severity of delirium, we used the Delirium Rating Scale (DRS) [7]. This scale consists of 10 items scored from 0 to a maximum of 3 or 4. Delirium is defined by a score of 10 points or higher. According to this scale, scores between 10 and 17 are defined as mild delirium, scores between 18 and 28 are accepted as moderate delirium, and scores between 29 and 32 denote severe delirium. A Turkish version was used [8].

Measurement of serum cortisol level

Blood samples were obtained at 6:00 AM in the next morning of the day of admission. Serum cortisol concentra- tion was measured with a solid-phase, competitive chemi- luminescent enzyme immunoassay (Lyphochek Markers Control, Trilevel #600; Bio-Rad Laboratories, Richmond, CA) in a calibrated IMMULITE 1000 analyzer (Diagnostic Products Corporation, Los Angeles, CA). The expected values for morning serum cortisol in our laboratory ranged from 5 to 25 ug/dL.

Statistical analysis

All statistical analyses were performed with the SPSS statistical package (version 17.0; SPSS, Inc, Chicago, IL). The Shapiro-Wilk test was used to evaluate the normality of data. Continuous variables are presented as mean +- SD or median (interquartile range). Data were compared with the use of the independent-samples t test or the Mann-Whitney U test. Categorical variables are presented as number of patients (percentage) and were compared with the use of the ?2 test. spearman correlation coefficient was used to assess

the correlation between DRS, presence of delirium, and serum cortisol level. A Linear regression analysis was used to detect associations between cortisol and other parameters, with delirium as the dependent variable. Receiver operating characteristic curve analysis was performed to iden- tify the optimal cutoff value of cortisol (at which sensitivity and specificity would be maximal) for the prediction of delirium. Area under the curve (AUC) was calculated as measurements of the accuracy of the tests and was compared by using the Z test. Two-sided P values of less than .05 were regarded as significant.

Results

Table 1 summarizes the baseline characteristics and laboratory tests. Twenty-five patients met Diagnostic and Statistical Manual of Mental disorders (Fourth Edition, Text Revision) criteria for delirium after ACS, resulting in an overall delirium rate of 48% (25/52). The mean age of the patients was 66 +- 6 years in group with delirium and 62 +- 9 years in the group without delirium (P = .08). There were 13 men (52%) in the delirious group. In patients with delirium, 18 had USAP, and 7 had non-STEMI. In the nondelirious group, 17 had USAP, 8 had non-STEMI, and 2 had STEMI (P = .3 between groups). The mean length of

hospital stay was 6 +- 2 vs 5 +- 3 days, respectively (P = .4).

The median scores of DRS were 17 (10-26) and 5 (3-7), respectively (P b .01).

Median cortisol levels were significantly different between the delirious and nondelirious groups (13.9 and 6.2 ug/dL; respectively; P b .01) (Fig. 1). There were significant correlations between DRS and cortisol as well as presence of delirium and cortisol levels (r = 0.65 and r = 0.74, respectively; P b .01). In a linear logistic regression analysis, serum cortisol level predicted the occurrence of delirium post-ACS (? = .81; P b .01) (Table 2).

According to ROC curve analysis, the optimal cutoff value of cortisol to predict delirium was 10.8 ug/dL (96% sensitivity and 89% specificity) (AUC, 0.93 [95% confi- dence interval 0.84-1.00]; Fig. 2). We observed no sig- nificant difference between the groups of patients with and without delirium with respect to age, sex, educational level, type of ACS, history of hypertension, history of diabetes, left ventricular ejection fraction, levels of blood lipids, serum creatinine, peak troponin I, peak MB-isoform of Creatinine kinase, blood glucose, alanine aminotransferase, aspartate aminotransferase, potassium, and sodium in patients after admission for ACS.

Discussion

In the present hypothesis-generating study, we demon- strated that, in patients after ACS, elevated serum cortisol level was associated with increased risk of delirium. Whether the association of cortisol and delirium is causal is not known, but it has been suggested that stress and high circulating glucocorticoid levels can produce delirium post- ACS (5). Whether cortisol is a useful biomarker for the occurrence of delirium is unknown, but our results show that the levels correlate not only with occurrence but also with the

25

20

15

cortisol, ug/dL

10

5

0

Table 1 Baseline clinical characteristics Patients with Patients without P delirium (n = 25) delirium (n = 27)
	Age, y	66 +- 6	62 +- 9	.08
	Male sex, n (%)	13 (52)	15 (55)	.7
	Type of ACS, n (%)			.3
	USAP	18 (72)	17 (63)
	Non-STEMI	7 (28)	8 (30)
	STEMI	-	2 (7)
	LDL-C, mg/dL	112 (65-213)	102 (43-189)	.7
	Triglyceride, mg/dL	188 +- 78	164 +- 75	.3
	Creatinine, mg/dL	1.0 (0.6-6.4)	0.8 (0.4-1.6)	.9
	CK-MB, ng/mL	25 (9-51)	25 (12-179)	.2
	Troponin I, ng/mL	0 (0-8.3)	0.07 (0-50)	.1
	AST, IU/L	22 (11-87)	22 (12-161)	.8
	ALT, IU/L	16 (10-71)	24 (10-69)	.1
	Na, mEq/L	138 +- 4	139 +- 2	.4
	K, mEq/L	4.2 +- 0.4	4.2 +- 0.5	.8
	Glucose, mg/dL	90 (86-300)	100 (90-240)	.2
	Cortisol, ug/dL	13.9 (9.6-20.8)	6.2 (3.0-15.3)	b.01
	HTN, n (%)	8 (32)	11 (40)	.5
	DM, n (%)	7 (28)	10 (37)	.5
	LVEF, %	62 (20-62)	61 (38-61)	.3
	LOHS, d	6 +- 2	5 +- 3	.4
	DRS	17 (10-26)	5 (3-7)	b.01
	Abbreviations: LDL-C, low-density lipoprotein cholesterol; CK-MB, MB-isoform of creatinine kinase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HTN, hypertension; DM, diabetes mellitus; LVEF, left ventricular ejection fraction; LOHS, length of hospital stay.

N- 27 25

non-delirious group delirious group

Fig. 1 Difference in serum cortisol level between 2 groups.

Variables	SE	?	t	95% CI	P
Troponin I	0.006	-0.112	-1.222	0.69-1.08	.2
Age	0.006	0.07	-0.01	0.99-1.00	.9
Cortisol	0.008	0.81	9.624	0.02-0.05	b.01
LVEF	0.005	-0.009	-0.105	0.98-1.00	.9
ACS	0.083	-0.178	-1.934	0.31-2.41	.05
Sex	0.088	0.017	0.2	0.44-2.22	.8
DRS	0.005	0.616	8.418	0.03-0.05	b.01
Abbreviations: ?, coefficients; CI, confidence interval.

severity of delirium. An ROC curve shows a significant AUC with a level of 10.8 ug/dL predicting delirium with high sensitivity and specificity.

Table 2 Linear regression models predicting occurrence of delirium (R = 0.81)

We also examined the associations of serum levels of troponin I and MB-isoform of creatinine kinase, which are markers of the degree of myocardial damage, and myocardial infarction with development of delirium in patients with ACS. The serum levels of troponin I, MB-isoforms of creatine kinase, nor the presence of myocardial infarction predicted delirium in the course of ACS. There was a trend toward older patients in the delirium group, but the 4-year difference in ages between groups seems clinically insignif- icant, and there is no reason to believe that it affects either the cortisol levels or the DRS scores.

Delirium is thought to result from a combination of various structural and physiologic lesions [9]. Electrophys- iologic data display both cortical and subcortical involve- ment. Similarly, neurotransmitters in addition to acetyl

Cortisol, ug/dL

Sensitivity: 96%

Specificity: 89%

Criterion: >10.8

100

80

60

Sensitivity

40

20

0

0 20 40 60 80 100

100-Specificity

Fig. 2 Receiver operating characteristic curve for cortisol to predict delirium.

choline, dopamine, ?-aminobutyric acid, glutamate and serotonin have been implicated [10]. Delirium appears frequently among hospitalized medically ill patients. It has been reported that delirium occurs in 20% to 60% of patients in intensive care units [11] and 8% to 36% of patients undergoing cardiovascular surgery [12]. Uguz et al [13] found that incidence of delirium is not uncommon in acute myocardial infarction and its presence increases mortality.

A recent study found that elevated serum cortisol level was associated with an increased incidence of postoperative delirium in critically ill patients after noncardiac surgery [14]. There have been studies that found a relation between serum cortisol levels and postoperative cardiac surgery [15,16]. It has been suggested that stress and high circulating glucocorticoid levels can produce deterioration in neuropsy- chological function [5]. Persistently elevated glucocorticoid levels may affect neurochemical transmission and lead to structural changes in the hippocampal neurons [17]. Psychiatric symptoms are common adverse effects in patients undergoing Systemic corticosteroid therapy [18]. For patients after acute ischemic stroke, high serum cortisol levels were significantly correlated to the presence of an acute confusional state [19]. It is unclear whether hypercor- tisolemia has a direct impact on delirious symptoms. It is also possible that hypercortisolemia merely reftects the stress associated with delirium [20]. Thus, further studies are needed to elucidate the mechanisms by which circulating cortisol levels affect delirium.

Important limitations must be stated. The sample size was

small, and only a single cortisol level was measured early in each patient’s hospital course. We have not found another similar study in literature that would enable us to do a power analysis. Baseline cortisol levels were not measured, which might have added to the interpretation of the relationship between cortisol level and the occurrence of delirium. It is possible that the change in cortisol from baseline rather than the height of a single measurement would be a better reftection of the risk of delirium. Because of the low number of patients in this series, more studies are needed to identify the best cutoff level and characteristics for cortisol as a marker of delirium clinically.

Conclusion

Serum cortisol levels are associated and directly correlate with the occurrence and severity of delirium. Further studies are needed to elucidate the implications of this association for diagnosis and treatment.

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