Open Access

High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery: a prospective cohort study

  • Dong-Liang Mu1,
  • Dong-Xin Wang1Email author,
  • Li-Huan Li2,
  • Guo-Jin Shan1,
  • Jun Li1,
  • Qin-Jun Yu2 and
  • Chun-Xia Shi2
Critical Care201014:R238

https://doi.org/10.1186/cc9393

Received: 11 July 2010

Accepted: 30 December 2010

Published: 30 December 2010

Abstract

Introduction

The pathophysiology of postoperative delirium remains poorly understood. The purpose of this study was to examine the relationship between serum cortisol level and occurrence of early postoperative delirium in patients undergoing coronary artery bypass graft (CABG) surgery.

Methods

A total of 243 patients undergoing elective CABG surgery were enrolled. Patients were examined twice daily during the first five postoperative days and postoperative delirium was diagnosed by using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Blood samples were obtained between 7 a.m. and 8 a.m. on the first postoperative day and serum cortisol concentrations were then measured. Multivariate logistic regression analyses were performed to identify risk factors of postoperative delirium.

Results

Postoperative delirium occurred in 50.6% (123 of 243) of patients. High serum cortisol level was significantly associated with increased risk of postoperative delirium (OR 3.091, 95% CI 1.763-5.418, P < 0.001). Other independent risk factors of postoperative delirium included increasing age (OR 1.111, 95% CI 1.065-1.159, P < 0.001), history of diabetes mellitus (OR 1.905, 95% CI 1.001-3.622, P = 0.049), prolonged duration of surgery (OR 1.360, 95% CI 1.010-1.831, P = 0.043), and occurrence of complications within the first day after surgery (OR 2.485, 95% CI 1.184-5.214, P = 0.016). Patients who developed postoperative delirium had a higher incidence of postoperative complications and a prolonged duration of postoperative ICU and hospital stay.

Conclusions

Delirium was a common complication after CABG surgery. High serum cortisol level was associated with increased risk of postoperative delirium. Patients who developed delirium had outcomes worse than those who did not.

Introduction

Delirium is a common complication after cardiac surgery. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), delirium is a transient mental syndrome characterized by (a) disturbance of consciousness with a reduced ability to focus, sustain, or shift attention; (b) change in cognition (such as memory deficit, disorientation, or language disturbance) or development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia; and (c) disturbance developing over a short period of time (usually hours to days) and tending to fluctuate during the course of the day [1]. The reported incidences of delirium after cardiac surgery varied from 3% to 72% [25], and the occurrence of postoperative delirium is associated with multiple adverse effects, such as self-extubation, prolonged hospital stay, increased health-care costs, and high mortality rate [611].

Despite the numerous studies, the pathophysiology of delirium remains poorly understood [12, 13]. As a universal phenomenon, delirium is frequently identified after major complicated surgery (including cardiac and vascular surgery) but rarely noted after minor ambulatory surgery (such as cataract surgery) [5, 1416]. These findings suggest that the stress response induced by surgical stimuli might play an important role in the pathogenesis of postoperative delirium.

Cortisol is one of the most important stress hormones in humans. Its secretion is proportional and positively correlated to the severity of surgical stimuli [17, 18]. A reciprocal control, the hypothalamic-pituitary-adrenal axis, exists between the brain and glucocorticoid hormones. Under stressful conditions, the brain promotes adrenocortical function via hypothalamic corticotrophin-releasing hormone. On the other hand, glucocorticoids act at specific receptors in the hypothalamus, thus producing negative feedback mechanisms.

It has long been observed that high levels of circulating glucocorticoids might have harmful effects on the brain and cause psychiatric symptoms [1921]. This is because there are glucocorticoid receptors in the hippocampus and frontal lobe, the regions that are closely associated with cognition. The effects of glucocorticoids on cognition follow an inverted U-shape dose response relationship; that is, memory is impaired by sustained glucocorticoid levels that are too low or too high but is improved by proportionate glucocorticoid level [22].

However, the relationship between circulating cortisol level and the occurrence of postoperative delirium has not been fully demonstrated. A recent study by Shi and colleagues [23] found that elevated serum cortisol level was associated with increased incidence of postoperative delirium in critically ill patients after noncardiac surgery. We suppose that the occurrence of postoperative delirium in patients undergoing cardiac surgery is also related to stress response and, thus, the elevated circulating cortisol level. The purpose of this study was to examine the association between serum cortisol level and occurrence of early postoperative delirium in patients undergoing coronary artery bypass graft (CABG) surgery.

Materials and methods

The study protocol was approved by the clinical research ethics committees of Peking University First Hospital and Beijing Fuwai Hospital. All patients gave written informed consent.

Patients

This was a prospective cohort study. The inclusion criteria were consecutive adult patients who were referred to Beijing Fuwai Hospital for elective CABG surgery from March 2008 to July 2008. The exclusion criteria were as follows: (a) previous cardiothoracic surgery, (b) history of schizophrenia, (c) history of adrenal gland disease, (d) history of glucocorticoid therapy for more than 7 consecutive days within 1 year, (e) preoperative left ventricular ejection fraction of less than 25% (echocardiography, Simpson's method), and (f) concomitant surgery other than CABG, such as valvular replacement.

Anesthesia, surgery, and postoperative care

Patients were premedicated with midazolam (7.5 mg by mouth) and morphine (10 mg intramuscularly). Anesthesia was induced with fentanyl (5 to 10 μg/kg), etomidate (0.2 to 0.3 mg/kg), and rocuronium (0.6 mg/kg). Anesthesia was maintained with midazolam (0.1 to 0.2 mg/kg), fentanyl (20 to 30 μg/kg), isoflurane (0.5% to 1%), and propofol (2.4 to 4.0 mg/kg per hour during cardiopulmonary bypass). Muscle relaxation was maintained with supplemental doses of vencuronium. Intraoperative monitoring included 5-lead electrocardiogram, radial arterial pressure, central venous pressure, pulse oxygen saturation, end-tidal expiratory carbon dioxide, nasopharyngeal temperature, bladder temperature, and urine output. A pulmonary artery catheter was inserted when necessary.

The type of surgery (on-pump or off-pump surgery) and the number of bypass grafts were determined by the surgeons. All patients underwent CABG surgery through a median sternotomy. Aortic palpation was used to detect atherosclerosis and, if present, to select an appropriate site for cannulation and clamping. For patients undergoing off-pump surgery, distal anastomoses were performed with the help of an Octopus tissue stabilizer (Medtronic, Inc., Minneapolis, MN, USA). Proximal anastomoses were then fashioned onto the aorta by means of a single side-clamp. Nasopharyngeal temperature was maintained above 35°C, and systolic blood pressure was kept at 80 mm Hg or greater throughout the procedure.

For patients undergoing on-pump surgery, cardiopulmonary bypass was established with a Stöckert S3 roller pump (Stöckert Instrumente GmbH, Munich, Germany), a membrane oxygenator (Maxima Forte; Medtronic, Inc.), and a 40-μm arterial blood filter (Dideco, Mirandola, Italy). Moderate hypothermia (32°C) and α-stat acid-base management were used. Perfusion pressure was kept at 60 to 80 mm Hg, and a pump flow was maintained between 2 to 2.4 L/min per m2. After all distal anastomoses were completed, the aortic cross-clamp was removed, and proximal anastomoses were then performed by means of a single side-clamp on the aorta.

After surgery, all patients were transferred to the intensive care unit (ICU) intubated and were placed on mechanical ventilation. Propofol and morphine were routinely administered for sedation and analgesia. Midazolam was administered as required. Extubation and ICU discharge were decided by attending intensivists. Hospital discharge was decided by the attending surgeon. Patients were followed up until 28 days after surgery. Definitions of postoperative complications are shown in Table 1.
Table 1

Definitions of postoperative complications

Complications

Requirements for acceptance

Cardiac insufficiency

Requirement of inotropic support for more than 24 hours or intra-aortic balloon pump support or both

Arrhythmia

New-onset arrhythmia confirmed by 12-lead electrocardiogram and necessitated medical treatment or electroversion or both

Myocardial infarction

Increase of troponin T concentration above the hospital laboratory's myocardial infarction threshold and either new Q waves (duration of at least 0.03 seconds) or persistent changes (4 days) in ST-T segment

Respiratory insufficiency

Requirement of mechanical ventilation for more than 24 hours

Stroke

Appearance of persisted new focal neurologic deficit and confirmed by neurologic imaging study

Sepsis

Two or more of systemic inflammatory response syndrome criteria, with known or suspected evidence of infection

Pleural effusion

Confirmed by chest x-ray film and necessitated aspiration or surgical drainage

Surgical bleeding

Requirement of reoperation to stop bleeding

Measurement of serum cortisol level

Blood samples were obtained between 7 and 8 a.m. on the first postoperative day. BD tubes (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) were used throughout the study. Prior to the assay, the samples were kept refrigerated for no longer than 12 hours at 4°C. Serum cortisol concentration was measured with a solid-phase, competitive chemiluminescent enzyme immunoassay in a calibrated IMMULITE 1000 analyzer (Diagnostic Products Corporation, Los Angeles, CA, USA). The intra-assay and interassay coefficients of variation at various concentrations were less than 5.6% and less than 8.2%, respectively. The normal range is 138 to 690 nmol/L in the laboratory where measurements were performed.

Delirium assessment

Delirium assessment was performed in two steps. First, level of sedation (level of arousal) was assessed by means of the Richmond Agitation Sedation Scale (RASS) [24, 25]. This is a 10-point scale with four levels of anxiety or agitation (+1 restless to +4 combative), one level representing an alert and calm state (0), and five levels of sedation (-5 = nonarousable to -1 = drowsy). If the patient was deeply sedated or was unarousable (-4 or -5 on the RASS), assessment was stopped and then was repeated later. If RASS was above -4 (-3 through +4), assessment was continued to the next step. Second, delirium was diagnosed by means of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) [26, 27]. This is an instrument designed to diagnose delirium in nonverbal, critically ill patients. It indicates four features of delirium: (a) acute onset of mental status changes or a fluctuating course, (b) inattention, (c) disorganized thinking, and (d) altered level of consciousness. To meet the diagnostic definition of delirium, a patient must display both (a) and (b) and either (c) or (d).

Prior to the study, the physician performing the assessment of delirium (D-LM) was trained by a psychiatrist to use CAM-ICU. Definition and examples of delirium features were explained and discussed. For the purpose of training and standardization, eligible patients were randomly selected and each patient was independently evaluated by the investigator (according to CAM-ICU) and the psychiatrist (according to DSM-IV) during the same observational period. The process continued until agreement for the diagnosis of delirium reached 100%. During the study phase, patients were assessed for delirium twice daily (from 6 to 8 a.m. and from 6 to 8 p.m.). For each patient, delirium assessment was performed until the fifth postoperative day or the disappearance of delirious symptoms for two consecutive days. Study personnel who assessed delirium were blinded to the treatment details and the serum cortisol results.

Statistical analysis

Continuous variables are presented as mean ± standard deviation (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). Data were compared with the use of the chi-square test or the Fisher exact test. The effect of serum cortisol level on the occurrence of postoperative delirium was assessed with the use of multivariate logistic regression analyses. Initially, baseline and perioperative variables were evaluated for univariate association with postoperative delirium. Variables that were significant in univariate analyses (P < 0.10) were included in a multivariate logistic regression model to determine the risk-adjusted predictors of delirium. Two-sided P values of less than 0.05 were regarded as significant. All statistical analyses were performed with the SPSS statistical package, version 14.0 (SPSS Inc., Chicago, IL, USA).

Results

Two hundred seventy-six patients underwent elective CABG surgery during the study period, and 258 matched the criteria of selection. Among the eligible patients, 243 gave written consent and were enrolled in this study (Figure 1). The perioperative variables of all enrolled patients are listed in Tables 2 and 3.
Figure 1

Flow diagram of the study. LVEF, left ventricular ejection fraction.

Table 2

Preoperative variables

Variable

All enrolled patients

(n = 243)

Non-delirious patients

(n = 120)

Delirious patients

(n = 123)

P value

Age, years

61.0 ± 8.3

58.3 ± 8.0

63.6 ± 7.7

< 0.001

Body mass index, kg/m2

26.1 ± 3.5

26.2 ± 3.9

26.0 ± 3.0

0.643

Education, years

10.4 ± 4.4

10.4 ± 4.3

10.4 ± 4.4

0.992

Female gender

43 (17.7%)

21 (17.5%)

22 (17.9%)

0.937

Previous medical history

    

   Hypertension

161 (66.3%)

75 (62.5%)

86 (69.9%)

0.221

   Previous myocardial infarctiona

114 (46.9%)

55 (45.8%)

59 (48.0%)

0.739

   Diabetes mellitus

89 (36.6%)

36 (30.0%)

53 (43.1%)

0.034

   Hyperlipidemia

96 (39.5%)

47 (39.2%)

49 (39.8%)

0.915

   Arrhythmia

58 (23.9%)

26 (21.7%)

32 (26.0%)

0.426

   Stroke

31 (12.8%)

11 (9.2%)

20 (16.3%)

0.097

   COPD

6 (2.5%)

1 (0.8%)

5 (4.1%)

0.213

   Renal dysfunctionb

9 (3.7%)

4 (3.3%)

5 (4.1%)

1.000

   Chronic smokingc

79 (32.5%)

40 (33.3%)

39 (31.7%)

0.787

   Alcoholismd

34 (14.0%)

21 (17.5%)

13 (10.6%)

0.119

Habitual benzodiazepine use

23 (9.5%)

12 (10.0%)

11 (8.9%)

0.778

Previous general anesthesia

17 (7.0%)

9 (7.5%)

8 (6.5%)

0.761

Preoperative LVEF, percentagee

58.0 ± 9.6

59.4 ± 8.4

56.7 ± 10.5

0.024

Preoperative CCS class

   

0.736

   I

53 (21.8%)

24 (20.0%)

29 (23.6%)

 

   II

126 (51.9%)

63 (52.5%)

63 (51.2%)

 

   III

53 (21.8%)

26 (21.7%)

27 (22.0%)

 

   IV

11 (4.5%)

7 (5.8%)

4 (3.3%)

 

Preoperative NYHA functional class

   

0.089

   I

77 (31.7%)

45 (37.5%)

32 (26.0%)

 

   II

131 (53.9%)

62 (51.7%)

69 (56.1%)

 

   III

35 (14.4%)

13 (10.8%)

22 (17.9%)

 

Preoperative EuroSCORE score

2.6 ± 2.1

2.0 ± 1.8

3.2 ± 2.1

< 0.001

Data are presented as mean ± standard deviation or number of patients (percentage). aMyocardial infarction of more than 1 month before surgery. bSerum creatinine of greater than 177 μmol/L. cSmoking of more than 20 cigarettes per day within 1 month. dConsumption of an equivalent of 150 mL of alcohol per week. eResults of echocardiography (Simpson's method). CCS, Canadian Cardiovascular Association; COPD, chronic obstructive pulmonary disease; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Table 3

Perioperative variables

Variable

All enrolled patients

(n = 243)

Non-delirious patients

(n = 120)

Delirious patients

(n = 123)

P value

Duration of anesthesia, hours

5.00 ± 1.19

4.81 ± 1.13

5.18 ± 1.22

0.017

Dosage of fentanyl, μg/kg

24.9 ± 6.1

24.6 ± 6.0

25.2 ± 6.1

0.386

Dosage of etomidate, mg/kg

0.23 ± 0.08

0.23 ± 0.08

0.23 ± 0.08

0.970

Use of anticholinergic drugs

97 (39.9%)

49 (40.8%)

48 (39.0%)

0.773

Duration of surgery, hours

4.00 ± 1.16

3.81 ± 1.13

4.18 ± 1.16

0.011

On-pump surgery

114 (46.9%)

56 (46.7%)

58 (47.2%)

0.939

Coronary artery bypass grafts, number

3.3 ± 0.8

3.2 ± 0.8

3.3 ± 0.7

0.365

Blood transfusion of at least 400 mL

9 (3.7%)

1 (0.8%)

8 (6.5%)

0.036

APACHE II scorea

6.43 ± 3.25

5.56 ± 3.03

7.28 ± 3.24

< 0.001

Serum cortisol concentration, nmol/L

549.9 ± 300.2

473.6 ± 305.4

625.6 ± 275.9

< 0.001

Serum cortisol levelb

   

< 0.001

   Level 1

20 (8.2%)

12 (10.0%)

8 (6.5%)

 

   Level 2

145 (59.7%)

90 (75.0%)

55 (44.7%)

 

   Level 3

78 (32.1%)

18 (15.0%)

60 (48.8%)

 

Duration of sedation, hours

10.0 (7.0-13.0)

9.5 (7.0-12.0)

10.5 (7.8-14.0)

0.045

Use of benzodiazepines

63 (25.9%)

28 (23.3%)

35 (28.5%)

0.362

Duration of mechanical ventilation, hours

14.8 (12.2-18.0)

13.9 (11.9-15.8)

16.0 (13.2-19.3)

< 0.001

Postoperative LVEF, percentagec

54.8 ± 8.7

56.3 ± 8.5

53.4 ± 8.7

0.008

Postoperative complications

    

   Cardiac insufficiency

48 (19.8%)

16 (13.3%)

32 (26.0%)

0.013

   Arrhythmia

18 (7.4%)

5 (4.2%)

13 (10.6%)

0.057

   Myocardial infarction

1 (0.4%)

1 (0.8%)

0 (0.0%)

0.494

   Respiratory insufficiency

4 (1.6%)

0 (0.0%)

4 (3.3%)

0.122

   Surgical bleeding

5 (2.1%)

1 (0.8%)

4 (3.3%)

0.370

   Sepsis

5 (2.1%)

0 (0.0%)

5 (4.1%)

0.060

   Pleural effusion

13 (5.3%)

7 (5.8%)

6 (4.9%)

0.741

   Stroke

1 (0.4%)

0 (0.0%)

1 (0.8%)

1.000

Postoperative complications within 1 dayd

67 (27.6%)

21 (17.5%)

46 (37.4%)

0.001

Postoperative complications within 5 daysd

82 (33.7%)

26 (21.7%)

56 (45.5%)

< 0.001

Postoperative complications within 28 daysd

86 (35.4%)

28 (23.3%)

58 (47.2%)

< 0.001

Data are presented as mean ± standard deviation, number of patients (percentage), or median (interquartile range). aScored using worst values over the first 24 hours after surgery. bThe normal range is 138 to 690 nmol/L. Level 1 indicates a serum cortisol concentration of less than 138 nmol/L, level 2 between 138 and 690 nmol/L, and level 3 of greater than 690 nmol/L. cResults of echocardiography (Simpson's method) performed before discharge from the hospital. dComplications that occurred before or during the 1st, 5th, or 28th postoperative day. APACHE II, Acute Physiology and Chronic Health Evaluation II; LVEF, left ventricular ejection fraction.

One hundred twenty-three patients developed delirium after surgery, resulting in an overall postoperative delirium rate of 50.6% (123 of 243). Among patients who developed delirium, the median (interquartile range) time of occurrence of the initial delirious symptom was 1 (1 to 2) day after surgery. In 97.6% of the delirious cases (120 of 123), the initial symptom occurred within the first 3 days after surgery (Figure 2). The median duration of postoperative delirium (that is, the duration between the initial symptom and the last symptom) was 2 (1 to 4) days.
Figure 2

Number of patients whose first episode of delirious symptoms occurred during the postoperative period. Note that in 97.6% of the delirious cases (120 of 123), the initial symptom occurred within the first three days after surgery. POD, postoperative delirium.

Four patients died within 28 days after surgery, resulting in an overall 28-day mortality rate of 1.6%. Two of them died of intractable ventricular fibrillation on the 1st and 3rd postoperative day, respectively. Because of unarousable sedation or coma, these two patients were not assessed for delirium. The other two patients died of circulatory failure and multiple organ failure on the 10th and 26th postoperative day, respectively. Both of them experienced early postoperative delirium.

Variables that were significant in univariate analyses (P < 0.10) are listed in Table 4. Patients with high serum cortisol level had a significantly higher incidence of postoperative delirium (P < 0.001) (Figure 3). After the multicollinearity was tested, two variables were excluded from further multivariate logistic regression analysis because of high correlation with others (duration of anesthesia versus duration of surgery, Pearson correlation coefficient = 0.967, P < 0.001; serum cortisol concentration versus serum cortisol level, Spearman correlation coefficient = 0.867, P < 0.001). There was only a weak correlation between serum cortisol concentration and APACHE II (Acute Physiology and Chronic Health Evaluation II) score on arrival in the ICU (Kendall correlation coefficient = 0.122, P = 0.008). No significant correlation existed between serum cortisol concentration and duration of surgery (Pearson correlation coefficient = -0.003, P = 0.963), use of cardiopulmonary bypass (Kendall correlation coefficient = -0.018, P = 0.735), or duration of mechanical ventilation in the ICU (Pearson correlation coefficient = -0.018, P = 0.790). So the above four variables were included in the multivariate analysis. On the other hand, since most of the delirious cases were diagnosed on the first day after surgery, we included only the complications that occurred before or during the first postoperative day in the multivariate analysis.
Table 4

Predictors of postoperative delirium.

Variable

Univariate analysesa

Multivariate logistic regression analysisb

 

P value

Odds ratio

(95% CI)

P value

Age, years

< 0.001

1.111 (1.065-1.159)

< 0.001

History of diabetes mellitus

0.035

1.905 (1.001-3.622)

0.049

Preoperative LVEF, percentage

0.026

-

-

Preoperative NYHA functional class

0.029

-

-

Preoperative EuroSCORE score

< 0.001

-

-

Duration of surgery, hours

0.013

1.360 (1.010-1.831)

0.043

Duration of anesthesia, hoursc

0.020

-

-

Blood transfusion of at least 400 mL during surgery

0.048

-

-

Postoperative APACHE II score

< 0.001

-

-

Serum cortisol concentration, nmol/Lc

< 0.001

-

-

Serum cortisol level, every level increased

< 0.001

3.091 (1.763-5.418)

< 0.001

Postoperative LVEF, percentage

0.009

-

-

Postoperative cardiac insufficiencyc

0.015

-

-

Postoperative arrhythmiac

0.065

-

-

Postoperative complications within 1 daye

0.001

2.485 (1.184-5.214)

0.016

Postoperative complications within 5 daysc,e

< 0.001

-

-

Postoperative complications within 28 daysc,e

< 0.001

-

-

aOccurrence of postoperative delirium was modeled as a function of a single predictor. bOccurrence of postoperative delirium was modeled as a function of all predictors that differed (P < 0.10) in the univariate analyses. Excluded were nine cases with missing values for at least one of the risk factors in the model. Multivariate logistic regression analysis was performed by using a forward (conditional) stepwise procedure. cVariable was not included in the multiple logistic regression analysis. dThe normal range is 138 to 690 nmol/L. Level 1 indicates a serum cortisol concentration of less than 138 nmol/L, level 2 between 138 and 690 nmol/L, and level 3 of greater than 690 nmol/L. eComplications that occurred before or during the 1st, 5th, or 28th postoperative day. APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Figure 3

Relationship between serum cortisol level and incidence of postoperative delirium (POD) after coronary artery bypass graft surgery. Patients with a higher serum cortisol level had a significantly higher incidence of POD (P < 0.001). Level 1 indicates a serum cortisol concentration of less than 138 nmol/L, level 2 indicates a serum cortisol concentration of between 138 and 690 nmol/L, and level 3 indicates a serum cortisol concentration of greater than 690 nmol/L.

As a result, 11 variables were consecutively subjected to a stepwise logistic regression analysis. Five were identified as independent predictors of postoperative delirium (Table 4). Of particular note was that high serum cortisol level was associated with significantly increased risk of postoperative delirium in this risk-adjusted analysis (odds ratio [OR] 3.091, 95% confidence interval [CI] 1.763 to 5.418; P < 0.001). Replacement of serum cortisol level with serum cortisol concentration in nanomoles per liter did not change the results, and high serum cortisol concentration remained an independent risk factor of postoperative delirium (OR 1.002, 95% CI 1.000 to 1.003; P = 0.006).

Comparison between patients with or without postoperative delirium showed that the former group had significantly more occurrences of postoperative complications, prolonged duration of ICU stay, and prolonged duration of postoperative hospital stay. The former group also tended to have greater medical expense during hospitalization (Tables 3 and 5).
Table 5

Outcomes of patients

Variable

Non-delirious patients (n = 120)

Delirious patients (n = 123)

P value

Number of postoperative complications per patient

  

0.001

   0

92 (76.7%)

65 (52.8%)

 

   1

24 (20.0%)

51 (41.5%)

 

   2

4 (3.3%)

6 (4.9%)

 

   ≥3

0 (0.0%)

1 (0.8%)

 

Duration of ICU stay, hours

22.0 (21.0-46.0)

45.3 (22.8-87.3)

< 0.001

Duration of postoperative hospital stay, days

7 (7-7)

7 (7-10)

< 0.001

Total costs of hospitalization, ×1,000 CNY

54.9 (48.1-63.8)

57.6 (51.0-67.4)

0.057

Data are presented as number of patients (percentage) or median (interquartile range). CNY, Chinese Yuan; ICU, intensive care unit.

Discussion

In the present study, we demonstrated that, in patients undergoing CABG surgery, elevated serum cortisol level on the first day after surgery was highly correlated with increased risk of postoperative delirium. Other independent risk factors included increasing age, history of diabetes mellitus, longer duration of surgery, and occurrence of complications within the first day after surgery. Our study also confirmed that outcomes were worse in patients who developed postoperative delirium: they had a higher incidence of postoperative complications, prolonged durations of postoperative ICU and hospital stay, and a tendency to greater medical expense during hospitalization.

The reported incidences of postoperative delirium varied from 3% to 72% after all types of cardiac surgery and from 3% to 50% after CABG surgery [26, 2832]. A recent study by Rudolph and colleagues [33] reported a rate of 52%. The reasons that produce this great variation include difference in patient population (such as age, severity of illness and type of procedure), sensitivity of the screening instrument, and local medical practice (such as routine practice and critical care environment). Although, in our study, patients were relatively young and underwent low-risk closed-chamber surgery [34, 35], the incidence is higher than some previously reported ones. This is perhaps because we assessed delirium twice daily for five consecutive days after surgery and thus detected more delirious cases. Even though it was not found to be a significant risk factor, the frequent use of anticholinergics during surgery in our study is another possible reason for this higher incidence.

The cause of delirium is typically multifactorial [12]. Delirium occurs as a result of a complex interrelationship between predisposing and precipitating factors [12, 36]. Numerous studies have been performed to find out the risk factors for developing postoperative delirium, and there is substantial heterogeneity in the findings [36, 2832]. Increasing age is a universally identified risk factor of delirium [2, 12, 36], suggesting that the naturally aged brain might be the basis of the occurrence of delirium. A history of diabetes mellitus is associated with increased incidence of almost all kinds of cerebral complications after cardiac surgery, including stroke [37], cognitive dysfunction [38], and delirium [39, 40]. This is perhaps because long-standing diabetes mellitus increases the prevalence of intracerebral atherosclerotic disease [41]. On the other hand, a long duration of surgery indicates a more complex procedure and the occurrence of postoperative complications means a more eventful recovery, and both long duration of surgery and postoperative complications have also been found to be associated with the occurrence of delirium [3, 42, 43].

Preoperative psychiatric disorders, such as depression and cognitive impairment, are also strong predictors of postoperative delirium [33, 44]. In the present study, only one patient who was previously diagnosed with schizophrenia and was taking antischizophrenic drugs at the time of surgery was excluded from the study for psychiatric reasons. This did not seem to produce patient selection bias.

It was reported that off-pump CABG surgery was associated with less frequent postoperative delirium [4]. However, this topic is controversial. Recent studies did not confirm that off-pump procedure or less cerebral emboli improved neurologic outcomes in patients undergoing CABG surgery [45, 46]. Furthermore, it was found that systemic stress hormone response triggered by off-pump surgery was comparable with that after conventional on-pump surgery [47]. In the present study, there were no differences in the incidence of delirium (58/114 versus 65/129; P = 0.939) and the serum cortisol concentration (558.0 ± 342.6 nmol/L versus 542.9 ± 259.1 nmol/L; P = 0.702) between patients undergoing on- or off-pump surgery. We therefore combined on- and off-pump surgeries and included the type of surgery in the analyses. The results showed no significant relationship between the type of surgery and the occurrence of postoperative delirium.

It has long been known that stress and high circulating glucocorticoid level can produce deterioration in neuropsychological function [19]. Studies showed that persistently elevated glucocorticoid levels may affect neurochemical transmission and lead to structural changes in hippocampal neurons [48]. Psychiatric symptoms are common adverse effects in patients undergoing systemic corticosteroid therapy [20]. For patients after acute ischemic stroke, high serum cortisol level was significantly correlated to the presence of acute confusional state [49]. In the preliminary study by McIntosh and colleagues [50], the occurrence of postoperative delirium was associated with a significant and unusually prolonged increase in circulating cortisol level. In a recent study, Shi and colleagues [23] found that high serum cortisol level was associated with increased incidence of postoperative delirium after noncardiac surgery.

We did not monitor the time-course changes of serum cortisol level in our study. In the ISPOCD2 (International Study of Postoperative Cognitive Dysfunction), salivary cortisol concentrations were monitored for a 3-month period. Peak levels were found in the morning of the first postoperative day [51]. For patients undergoing cardiac surgery, studies also found that serum cortisol concentrations peaked in the first postoperative day or from 4 to 12 hours after surgery and then recovered gradually toward baseline during several days [52, 53]. In this study, we collected blood samples in the early morning of the first postoperative day in order to get a relatively high serum cortisol level. The normal range of morning serum cortisol concentration in our hospital laboratory is 138 to 690 nmol/L, which is broadly the same as that of other laboratories [54]. For the convenience of analyses, we divided the serum cortisol concentrations into three levels according to the normal range (that is, level 1 is lower than 138 nmol/L, level 2 is within normal range, and level 3 is higher than 690 nmol/L).

Our study demonstrated, for the first time, that elevated serum cortisol level is significantly correlated with increased incidence of delirium in patients after cardiac surgery. In our results, the number of new delirious cases was highest on the first postoperative day and decreased rapidly across time, with 97.6% of the delirious cases occurring within the first three days after surgery. The median (interquartile range) duration of delirious symptoms was 2 (1 to 4) days. The time course of postoperative delirium is similar to the reported changes of serum cortisol level after cardiac surgery [52, 53]. This accordance also indicates a relationship between serum cortisol level and occurrence of postoperative delirium.

It remains unknown whether hypercortisolemia is a cause or an effect of postoperative delirium. Studies found that an older population and patients with diabetes mellitus have an increased baseline cortisol level and an attenuated negative feedback mechanism that inhibits further secretion of cortisol and are more reactive to stressful stimuli [5557]. In clinical settings, these two populations are prone to develop postoperative delirium [26, 2832, 39, 40]. An earlier study of delirium in patients with lower respiratory tract infection showed that older patients who were nonsuppressor on the dexamethasone suppression test were at increased risk for developing delirium during acute illness [58]. It is possible that abnormal hypothalamic-pituitary-adrenal function plays a basic role in the mechanism of delirium.

Surgery-related stress is not the only factor that contributes to the elevated cortisol level. In the present study, we did not find significant correlations between serum cortisol concentration and duration of surgery, use of cardiopulmonary bypass during surgery, or duration of mechanical ventilation in the ICU. Velissaris and colleagues [47] reported a similar cortisol response curve in patients undergoing on- and off-pump surgery. Other conditions (such as anxiety, depression, and cognitive impairment) are also related to higher serum cortisol concentration [55, 59]. However, we did not perform screen tests for these conditions in this study. On the other hand, 20 patients (8.2%) in our study had a serum cortisol concentration that was lower than normal in the morning of the first postoperative day. The possible reason is that etomidate was used for anesthesia induction in all patients. It has been found that a single dose of etomidate can cause adrenal inhibition for 12 to 24 hours [60]. However, this did not seem to produce significant adverse effects in our study since only one of these patients needed inotropic therapy for more than 24 hours and no glucocorticoid replacement therapy was administered in the ICU.

There are several limitations of this study. First, we did not perform baseline psychiatric and cognitive screening tests. It was reported that preoperative mental disorders (such as depression, cognitive impairment, and dementia) are strong predictors of postoperative delirium [33, 44]. These factors are not included in the multivariate analysis in our study and thus may interfere with the final results. Second, serum cortisol concentrations were not measured at baseline. They were measured at only one time point after surgery. We were unable to determine whether patients with elevated baseline serum cortisol level were more prone to develop postoperative delirium and whether the time course of postoperative delirium was exactly correlated with that of serum cortisol level. Third, we did not observe the long-term effects of surgery on postoperative cognitive dysfunction. Therefore, we could not, as Koster and colleagues [61] had, determine whether there is an association between postoperative delirium and long-term outcomes. Fourth, our study did not reveal the causal relationship between the elevated cortisol level and the occurrence of delirium. Hypercortisolemia may have a direct impact on delirious symptoms, but it is also possible that hypercortisolemia merely reflects the stress associated with delirium [62]. Therefore, further study is needed to illuminate the mechanisms by which circulating cortisol level may affect delirium.

Conclusions

The results of our study showed that delirium was a common complication after CABG surgery. High serum cortisol level was associated with increased risk of postoperative delirium. Patients who developed delirium had outcomes that were worse than those who did not.

Key messages

  • Postoperative delirium was a common complication after coronary artery bypass graft surgery.

  • High serum cortisol level was associated with increased risk of postoperative delirium. Whether this relationship is causal or due to other confounders is still unclear.

  • Patients who developed delirium had outcomes that were worse than those who did not.

Abbreviations

CABG: 

coronary artery bypass graft

CAM-ICU: 

Confusion Assessment Method for the Intensive Care Unit

CI: 

confidence interval

DSM-IV: 

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

ICU: 

intensive care unit

OR: 

odds ratio

RASS: 

Richmond Agitation Sedation Scale.

Declarations

Acknowledgements

The authors gratefully acknowledge Xin-Yu Sun (Psychiatric Department, Peking University Sixth Hospital) for her psychiatric consultation and Sai-Nan Zhu (Department of Medical Statistics, Peking University First Hospital) for her help with the statistical analysis.

Authors’ Affiliations

(1)
Department of Anesthesiology and Surgical Intensive Care, Peking University First Hospital
(2)
Department of Anesthesiology, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

References

  1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington, DC: American Psychiatric Association; 1994.Google Scholar
  2. Sockalingam S, Parekh N, Bogoch II, Sun J, Mahtani R, Beach C, Bollegalla N, Turzanski S, Seto E, Kim J, Dulay P, Scarrow S, Bhalerao S: Delirium in the postoperative cardiac patient: a review. J Card Surg 2005, 20: 560-567. 10.1111/j.1540-8191.2005.00134.xView ArticlePubMedGoogle Scholar
  3. Norkiene I, Ringaitiene D, Misiuriene I, Samalavicius R, Bubulis R, Baublys A, Uzdavinys G: Incidence and precipitating factors of delirium after coronary artery bypass grafting. Scand Cardiovasc J 2007, 41: 180-185. 10.1080/14017430701302490View ArticlePubMedGoogle Scholar
  4. Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Falk V, Schmitt DV, Mohr FW: Predictors of delirium after cardiac surgery delirium: effect of beating-heart (off-pump) surgery. J Thorac Cardiovasc Surg 2004, 127: 57-64. 10.1016/S0022-5223(03)01281-9View ArticlePubMedGoogle Scholar
  5. Chang YL, Tsai YF, Lin PJ, Chen MC, Liu CY: Prevalence and risk factors for postoperative delirium in a cardiovascular intensive care unit. Am J Crit Care 2008, 17: 567-575.PubMedGoogle Scholar
  6. Loponen P, Luther M, Wistbacka JO, Nissinen J, Sintonen H, Huhtala H, Tarkka MR: Postoperative delirium and health related quality of life after coronary artery bypass grafting. Scand Cardiovasc J 2008, 42: 337-344. 10.1080/14017430801939217View ArticlePubMedGoogle Scholar
  7. Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK: The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001, 27: 1892-1900. 10.1007/s00134-001-1132-2View ArticlePubMedGoogle Scholar
  8. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004, 291: 1753-1762. 10.1001/jama.291.14.1753View ArticlePubMedGoogle Scholar
  9. Morandi A, Jackson JC, Ely EW: Delirium in the intensive care unit. Int Rev Psychiatry 2009, 21: 43-58. 10.1080/09540260802675296View ArticlePubMedGoogle Scholar
  10. Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW: Costs associated with delirium in mechanically ventilated patients. Crit Care Med 2004, 32: 955-962. 10.1097/01.CCM.0000119429.16055.92View ArticlePubMedGoogle Scholar
  11. Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP: The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med 2004, 32: 2254-2259. 10.1097/01.CCM.0000110878.49476.42View ArticlePubMedGoogle Scholar
  12. Inouye SK: Delirium in older persons. N Engl J Med 2006, 354: 1157-1165. 10.1056/NEJMra052321View ArticlePubMedGoogle Scholar
  13. Gunther ML, Morandi A, Ely EW: Pathophysiology of delirium in the intensive care unit. Crit Care Clin 2008, 24: 45-65. 10.1016/j.ccc.2007.10.002View ArticlePubMedGoogle Scholar
  14. Schneider F, Böhner H, Habel U, Salloum JB, Stierstorfer A, Hummel TC, Miller C, Friedrichs R, Müller EE, Sandmann W: Risk factors for postoperative delirium in vascular surgery. Gen Hosp Psychiatry 2002, 24: 28-34. 10.1016/S0163-8343(01)00168-2View ArticlePubMedGoogle Scholar
  15. Marcantonio E, Ta T, Duthie E, Resnick NM: Delirium and psychomotor types: their relationships with outcomes after hip fracture repair. J Am Geriatr Soc 2002, 50: 850-857. 10.1046/j.1532-5415.2002.50210.xView ArticlePubMedGoogle Scholar
  16. Milstein A, Pollack A, Kleinman G, Barak Y: Confusion/delirium following cataract surgery: an incidence study of 1-year duration. Int Psychogeriatr 2002, 14: 301-306. 10.1017/S1041610202008499View ArticlePubMedGoogle Scholar
  17. Chernow B, Alexander HR, Smallridge RC, Thompson WR, Cook D, Beardsley D, Fink MP, Lake CR, Fletcher JR: Hormonal responses to graded surgical stress. Arch Intern Med 1987, 147: 1273-1278. 10.1001/archinte.147.7.1273View ArticlePubMedGoogle Scholar
  18. Widmer IE, Puder JJ, König C, Pargger H, Zerkowski HR, Girard J, Müller B: Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab 2005, 90: 4579-4586. 10.1210/jc.2005-0354View ArticlePubMedGoogle Scholar
  19. Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE: The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn 2007, 65: 209-237. 10.1016/j.bandc.2007.02.007View ArticlePubMedGoogle Scholar
  20. Warrington TP, Bostwick JM: Psychiatric adverse effects of corticosteroids. Mayo Clin Proc 2006, 81: 1361-1367. 10.4065/81.10.1361View ArticlePubMedGoogle Scholar
  21. Chrousos GP, Kino T: Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 2007, 10: 213-219. 10.1080/10253890701292119View ArticlePubMedGoogle Scholar
  22. Belanoff JK, Gross K, Yager A, Schatzberg AF: Corticosteroids and cognition. J Psychiat Res 2001, 35: 127-145. 10.1016/S0022-3956(01)00018-8View ArticlePubMedGoogle Scholar
  23. Shi CM, Wang DX, Chen KS, Gu XE: Incidence and risk factors of delirium in critically ill patients after non-cardiac surgery. Chin Med J (Engl) 2010, 123: 993-999.Google Scholar
  24. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK: The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002, 166: 1338-1344. 10.1164/rccm.2107138View ArticlePubMedGoogle Scholar
  25. Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR: Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003, 289: 2983-2991. 10.1001/jama.289.22.2983View ArticlePubMedGoogle Scholar
  26. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK: Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001, 29: 1370-1379. 10.1097/00003246-200107000-00012View ArticlePubMedGoogle Scholar
  27. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001, 286: 2703-2710. 10.1001/jama.286.21.2703View ArticlePubMedGoogle Scholar
  28. Rolfson DB, McElhaney JE, Rockwood K, Finnegan BA, Entwistle LM, Wong JF, Suarez-Almazor ME: Incidence and risk factors for delirium and other adverse outcomes in older adults after coronary artery bypass graft surgery. Can J Cardiol 1999, 15: 771-776.PubMedGoogle Scholar
  29. Eriksson M, Samuelsson E, Gustafson Y, Aberg T, Engström KG: Delirium after coronary bypass surgery evaluated by the organic brain syndrome protocol. Scand Cardiovasc J 2002, 36: 250-255. 10.1080/14017430260180436View ArticlePubMedGoogle Scholar
  30. Santos FS, Velasco IT, Fráguas R Jr: Risk factors for delirium in the elderly after coronary artery bypass graft surgery. Int Psychogeriatr 2004, 16: 175-193. 10.1017/S1041610204000365View ArticlePubMedGoogle Scholar
  31. Rudolph JL, Babikian VL, Birjiniuk V, Crittenden MD, Treanor PR, Pochay VE, Khuri SF, Marcantonio ER: Atherosclerosis is associated with delirium after coronary artery bypass graft surgery. J Am Geriatr Soc 2005, 53: 462-466. 10.1111/j.1532-5415.2005.53165.xView ArticlePubMedGoogle Scholar
  32. Rudolph JL, Jones RN, Grande LJ, Milberg WP, King EG, Lipsitz LA, Levkoff SE, Marcantonio ER: Impaired executive function is associated with delirium after coronary artery bypass graft surgery. J Am Geriatr Soc 2006, 54: 937-941. 10.1111/j.1532-5415.2006.00735.xPubMed CentralView ArticlePubMedGoogle Scholar
  33. Rudolph JL, Jones RN, Levkoff SE, Rockett C, Inouye SK, Sellke FW, Khuri SF, Lipsitz LA, Ramlawi B, Levitsky S, Marcantonio ER: Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation 2009, 119: 229-236. 10.1161/CIRCULATIONAHA.108.795260PubMed CentralView ArticlePubMedGoogle Scholar
  34. Ebert AD, Walzer TA, Huth C, Herrmann M: Early neurobehavioral disorders after cardiac surgery: a comparative analysis of coronary artery bypass graft surgery and valve replacement. J Cardiothorac Vasc Anesth 2001, 15: 15-19. 10.1053/jcan.2001.20211View ArticlePubMedGoogle Scholar
  35. Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Byrne AJ, Pagel PS: Postoperative delirium and short-term cognitive dysfunction occur more frequently in patients undergoing valve surgery with or without coronary artery bypass graft surgery compared with coronary artery bypass graft surgery alone: results of a pilot study. J Cardiothorac Vasc Anesth 2010, in press.Google Scholar
  36. Girard TD, Pandharipande PP, Ely EW: Delirium in the intensive care unit. Crit Care 2008,12(Suppl 3):S3.PubMed CentralView ArticlePubMedGoogle Scholar
  37. de Oliveira DC, Ferro CR, de Oliveira JB, Malta MM, Barros Neto P, Cano SJ, Martins SK, Souza LC, Jatene AD, Piegas LS: Risk factors for stroke after coronary artery bypass grafting. Arq Bras Cardiol 2008, 91: 213-216. 234-237Google Scholar
  38. Nötzold A, Michel K, Khattab AA, Sievers HH, Hüppe M: Diabetes mellitus increases adverse neurocognitive outcome after coronary artery bypass grafting surgery. Thorac Cardiovasc Surg 2006, 54: 307-312. 10.1055/s-2006-924089View ArticlePubMedGoogle Scholar
  39. Bucerius J, Gummert JF, Walther T, Doll N, Falk V, Onnasch JF, Barten MJ, Mohr FW: Impact of diabetes mellitus on cardiac surgery outcome. Thorac Cardiovasc Surg 2003, 51: 11-16. 10.1055/s-2003-37280View ArticlePubMedGoogle Scholar
  40. Bucerius J, Gummert JF, Walther T, Doll N, Barten MJ, Falk V, Mohr FW: Diabetes in patients undergoing coronary artery bypass grafting. Impact on perioperative outcome. Z Kardiol 2005, 94: 575-582. 10.1007/s00392-005-0273-7View ArticlePubMedGoogle Scholar
  41. Weckbach S, Findeisen HM, Schoenberg SO, Kramer H, Stark R, Clevert DA, Reiser MF, Parhofer KG: Systemic cardiovascular complications in patients with long-standing diabetes mellitus: comprehensive assessment with whole-body magnetic resonance imaging/magnetic resonance angiography. Invest Radiol 2009, 44: 242-250. 10.1097/RLI.0b013e31819a60d3View ArticlePubMedGoogle Scholar
  42. Krähenbühl ES, Immer FF, Stalder M, Englberger L, Eckstein FS, Carrel TP: Temporary neurological dysfunction after surgery of the thoracic aorta: a predictor of poor outcome and impaired quality of life. Eur J Cardiothorac Surg 2008, 33: 1025-1029. 10.1016/j.ejcts.2008.01.058View ArticlePubMedGoogle Scholar
  43. Klugkist M, Sedemund-Adib B, Schmidtke C, Schmucker P, Sievers HH, Hüppe M: Confusion Assessment Method for the Intensive Care Unit (CAM-ICU): diagnosis of postoperative delirium in cardiac surgery [in German]. Anaesthesist 2008, 57: 464-474. 10.1007/s00101-008-1356-4View ArticlePubMedGoogle Scholar
  44. Kazmierski J, Kowman M, Banach M, Fendler W, Okonski P, Banys A, Jaszewski R, Rysz J, Mikhailidis DP, Sobow T, Kloszewska I: Incidence and predictors of delirium after cardiac surgery: results from The IPDACS Study. J Psychosom Res 2010, 69: 179-185. 10.1016/j.jpsychores.2010.02.009View ArticlePubMedGoogle Scholar
  45. Liu YH, Wang DX, Li LH, Wu XM, Shan GJ, Su Y, Li J, Yu QJ, Shi CX, Huang YN, Sun W: The effects of cardiopulmonary bypass on the number of cerebral microemboli and the incidence of cognitive dysfunction after coronary artery bypass graft surgery. Anesth Analg 2009, 109: 1013-1022. 10.1213/ane.0b013e3181aed2bbView ArticlePubMedGoogle Scholar
  46. Rudolph JL, Babikian VL, Treanor P, Pochay VE, Wigginton JB, Crittenden MD, Marcantonio ER: Microemboli are not associated with delirium after coronary artery bypass graft surgery. Perfusion 2009, 24: 409-415. 10.1177/0267659109358207PubMed CentralView ArticlePubMedGoogle Scholar
  47. Velissaris T, Tang AT, Murray M, Mehta RL, Wood PJ, Hett DA, Ohri SK: A prospective randomized study to evaluate stress response during beating-heart and conventional coronary revascularization. Ann Thorac Surg 2004, 78: 506-512. 10.1016/S0003-4975(03)01360-2View ArticlePubMedGoogle Scholar
  48. Fuchs E, Flügge G: Stress, glucocorticoids and structural plasticity of the hippocampus. Neurosci Biobehav Rev 1998, 23: 295-300. 10.1016/S0149-7634(98)00031-1View ArticlePubMedGoogle Scholar
  49. Olsson T, Marklund N, Gustafson Y, Näsman B: Abnormalities at different levels of the hypothalamic-pituitary-adrenocortical axis early after stroke. Stroke 1992, 23: 1573-1576.View ArticlePubMedGoogle Scholar
  50. McIntosh TK, Bush HL, Yeston NS, Grasberger R, Palter M, Aun F, Egdahl RH: Beta-endorphin, cortisol and postoperative delirium: a preliminary report. Psychoneuroendocrinology 1985, 10: 303-313. 10.1016/0306-4530(85)90007-1View ArticlePubMedGoogle Scholar
  51. Rasmussen LS, O'Brien JT, Silverstein JH, Johnson TW, Siersma VD, Canet J, Jolles J, Hanning CD, Kuipers HM, Abildstrom H, Papaioannou A, Raeder J, Yli-Hankala A, Sneyd JR, Munoz L, Moller JT: Is peri-operative cortisol secretion related to post-operative cognitive dysfunction? Acta Anaesthesiol Scand 2005, 49: 1225-1231. 10.1111/j.1399-6576.2005.00791.xView ArticlePubMedGoogle Scholar
  52. Roth-Isigkeit AK, Schmucker P: Postoperative dissociation of blood levels of cortisol and adrenocorticotropin after coronary artery bypass grafting surgery. Steroids 1997, 62: 695-699. 10.1016/S0039-128X(97)00069-XView ArticlePubMedGoogle Scholar
  53. Hoda MR, El-Achkar H, Schmitz E, Scheffold T, Vetter HO, De Simone R: Systemic stress hormone response in patients undergoing open heart surgery with or without cardiopulmonary bypass. Ann Thorac Surg 2006, 82: 2179-2186. 10.1016/j.athoracsur.2006.06.087View ArticlePubMedGoogle Scholar
  54. Gunneberg A, Astley P, Goldie DJ: A survey of endocrine function testing by clinical biochemistry laboratories in the UK. Ann Clin Biochem 1999,36(Pt 1):112.View ArticlePubMedGoogle Scholar
  55. Heffelfinger AK, Newcomer JW: Glucocorticoid effects on memory function over the human life span. Dev Psychopathol 2001, 13: 491-513. 10.1017/S0954579401003054View ArticlePubMedGoogle Scholar
  56. Chiodini I, Di Lembo S, Morelli V, Epaminonda P, Coletti F, Masserini B, Scillitani A, Arosio M, Adda G: Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance. Metabolism 2006, 55: 1135-1140. 10.1016/j.metabol.2006.04.010View ArticlePubMedGoogle Scholar
  57. Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, Epaminonda P, Masserini B, Beck-Peccoz P, Orsi E, Ambrosi B, Arosio M: Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Diabetes Care 2007, 30: 83-88. 10.2337/dc06-1267View ArticlePubMedGoogle Scholar
  58. O'Keeffe ST, Devlin JG: Delirium and the dexamethasone suppression test in the elderly. Neuropsychobiology 1994, 30: 153-156. 10.1159/000119154View ArticlePubMedGoogle Scholar
  59. Lupien SJ, Nair NP, Brière S, Maheu F, Tu MT, Lemay M, McEwen BS, Meaney MJ: Increased cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life. Rev Neurosci 1999, 10: 117-139.View ArticlePubMedGoogle Scholar
  60. Vinclair M, Broux C, Faure P, Brun J, Genty C, Jacquot C, Chabre O, Payen JF: Duration of adrenal inhibition following a single dose of etomidate in critically ill patients. Intensive Care Med 2008, 34: 714-719. 10.1007/s00134-007-0970-yView ArticlePubMedGoogle Scholar
  61. Koster S, Hensens AG, van der Palen J: The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery. Ann Thorac Surg 2009, 87: 1469-1474. 10.1016/j.athoracsur.2009.02.080View ArticlePubMedGoogle Scholar
  62. Wolkowitz OM, Burke H, Epel ES, Reus VI: Glucocorticoids. Mood, memory, and mechanisms. Ann N Y Acad Sci 2009, 1179: 19-40. 10.1111/j.1749-6632.2009.04980.xView ArticlePubMedGoogle Scholar

Copyright

© Mu et al.; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.