CLINICAL INVESTIGATION

Higher Dose Dexamethasone Increases Early Postoperative Cognitive Dysfunction Qiwu Fang, MD,* Xiaoyan Qian, CRNA,* Jianxiong An, MD, PhD,* Hui Wen, MD,* Doris K. Cope, MD,w and John P. Williams, MDw

Objective: To investigate the effects of intravenous administration of dexamethasone on early postoperative cognitive dysfunction (POCD). Methods: In this prospective randomized trial, 1000 patients with facial spasm undergoing microvascular decompression (MVD) were randomly assigned to receive normal sodium (Dex-0 group, n = 333), dexamethasone 0.1 mg/kg (Dex-1 group, n = 333), or dexamethasone 0.2 mg/kg (Dex-2 group, n = 334). Exclusion criteria included: a history of neurologic or mental disease, renal failure, active liver disease, cardiac or pulmonary dysfunction, endocrine, metabolic, or peptic ulcer disease, a history of past surgery, 1SD on any test. Patients who experienced >2 deficits were considered to have experienced early POCD. Results: Nine hundred and fifty-four patients completed both preoperative and postoperative neuropsychological testing. Within the 3 groups: Dex-0 group, n = 319; Dex-1 group, n = 320 and Dex-2, n = 315. POCD occurred in 71 patients (22.3%) in the Dex-0 group, in 66 patients (20.6%) in the Dex-1 group, and 99 patients (31.4%) in the Dex-2 group. POCD was significant among the 3 groups (P = 0.003). Partitions of w2 method was applied for multiple comparisons showing that Dex-2 group was significantly different from Dex-1 and Dex-0 groups.

Received for publication August 3, 2013; accepted September 30, 2013. From the *Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University & Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, China; and wDepartment of Anesthesiology, University of Pittsburgh, Pittsburgh, PA. The authors have no funding or conflicts of interest to disclose. Correspondence: Jianxiong An, MD, PhD, Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University & Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beiyuan Rd 3#, Beijing 100012, China (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins

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Conclusions: Administration of higher dose of dexamethasone (0.2 mg/kg) increases the incidence of POCD in the early postoperative period after microvascular decompression under general anesthesia. Key Words: dexamethasone, postoperative cognitive dysfunction, microvascular decompression (J Neurosurg Anesthesiol 2014;26:220–225)

D

examethasone is used extensively in the perioperative setting as it is a high-potency, long-acting glucocorticoid with little mineralocorticoid effects. It may prevent postoperative nausea and vomiting,1 improve analgesia and decrease opioid consumption,2–5 significantly decrease the incidence and severity of sore throat and hoarseness after general anesthesia,6 and antagonize the inflammatory reaction in the postoperative peroid.7 It has been shown to affect cognitive function and brain structures by changing the level of brain corticosteroids.8–11 Furthermore, in vitro animal studies show dexamethasone induces brain cell apoptosis12 with learning and memory impairment associated with amyloid and tau protein.13–19 Early postoperative cognitive dysfunction (POCD) is a common perioperative complication,20 with definitive causes not yet clearly identified. Past studies have shown a link between cognitive dysfunction, depth of anesthesia21,22 and systemic inflammatory reactions.23,24 Dexamethasone has been shown to suppress this response, however few studies regarding the effects of dexamethasone on POCD are available. The aim of this study was to determine whether single-dose administration of dexamethasone at 2 doses during the induction of general anesthesia induction would affect the incidence of early POCD.

MATERIALS AND METHODS Patients After obtaining IRB approval and informed consent, 1000 ASA physical status I-II patients aged 40 to 60 years suffering with facial spasm requiring microvascular decompression (MVD) were studied. All subjects gave informed consent to participate in the study but were blinded to its objectives. They were randomly divided using a computer-generated randomization table into J Neurosurg Anesthesiol



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3 groups, Dex-0 (n = 333), Dex-1 (n = 333), and Dex-2 (n = 334). Exclusion criteria included: a history of neurologic or mental disease, renal failure, active liver disease, cardiac or pulmonary dysfunction, endocrine, metabolic, or peptic ulcer disease, a history of surgery, 0.05) (Fig. 2). All of the tests were carried out in the hospital. The 3 groups were comparable with respect to age, body mass index, education, the presence of hypertension, and BIS level before anesthesia (Table 1). There were no significant between-group differences in neuropsychological test scores before surgery (Table 2). The SD for each test was computed from the combined preoperative scores of all groups. The duration of anesthesia was measured from onset of induction to the point of extubation. The duration of surgery was timed from initial incision to completion of suturing. There were no clinically or statistically significant differences among groups in the duration of anesthesia or surgery (Table 3). BIS values were counted every minute; there were no statistically significant group differences during anesthesia or surgery (Table 3). The anesthetic drugs and cardiovascular medication were recorded after operation. Propofol and remifentanil were recorded by total dose administered; cardiovascular medications were recorded by the number of cases receiving these medications. There were no statistically significant differences in anesthetic drugs and cardiovascular medications among the 3 groups (Table 4). At day 1 and day 5 after the surgery, the Brice method was applied to evaluate intraoperative awareness and none was detected. Postoperative PCA was continued for 2 days, but no statistically significant difference was found among the 3 groups (Table 5).

Assessed for eligibility n=1248 patients Excluded 248 1. Not meeting inclusion criterion n=229 2. Decline to participate n=19

Fourteen patients dropped out in the Dex-0 group Dex-0 group (n=319)

Dex-1 group (n=333)

Dex-2 group (n=334)

Thirteen patients dropped out in the Dex-1 group

Nineteen patients dropped out in the Dex-1 group

Dex-1 group (n=320)

Dex-2 group (n=315)

FIGURE 1. CONSORT diagram showing the flow of participants through each stage of our randomized trial.

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Fourteen patients dropped out in the Dex-0 group

Two patients refused due to cerebrospinal rhinorrhea.

Three patients refused due to dizziness.

Twelve patients thought they were cured and the tests were not needed.

Thirteen patients dropped out in the Dex-1 group

One patient refused due to dizziness.

Thirteen patients thought they were cured and the tests were not needed.

Three patients refused due to dizziness. Nineteen patients dropped out in the Dex-2 group One patient refused because they experienced cerebellar hemorrhage.

Two patients refused because their facial spasm was not improved.

FIGURE 2. Detailed reasons for 46 patients dropping out.

POCD occurred in 71 patients (22.3%) in the Dex-0 group, 66 patients (20.6%) in the Dex-1 group, and in 99 patients (31.4%) in the Dex-2 group. The incidence of POCD was statistically significantly different between the 3 groups, P = 0.003. The sample size of 954 who completed preoperative and postoperative tests allowed us to achieve the power of 0.85, based on the incidence of early POCD between 20.6% in Dex-1 group and 31.4% in Dex2 group at a 0.05 significance level. Furthermore, partitions of w2 method demonstrated the incidence of POCD

TABLE 1. Demographic Data of the 3 Groups (Mean ± SD or No. Cases)

Randomized n=1000 Dex-0 group (n=333)

Nine patients thought they were cured and the tests were not needed.

Items Sex (male/female) Age (y) BMI Education (y) Case of hypertension BIS preanesthesia

Dex-0 (n = 319)

Dex-1 (n = 320)

Dex-2 (n = 315)

P

121/198 48.0 ± 5.77 23.8 ± 3.30 10.6 ± 2.67 86

117/203 48.9 ± 5.35 23.9 ± 2.94 10.9 ± 2.86 81

130/185 48.0 ± 5.60 24.4 ± 2.92 11.0 ± 2.78 100

0.457 0.085 0.070 0.290 0.173

95 ± 2.3

96 ± 2.2

96 ± 2.2

0.629

BMI indicates body mass index.

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Higher Dose Dex Increases Cognitive Dysfunction

TABLE 2. Group Mean Raw Scores for All Test Subscales at the Preoperative Assessment (Mean ± SD) Tests Mental control Visional rational Paired associate verbal learning Digit span forward Digit span backward Digit symbol Trails A Pegboard dominant hand Pegboard nondominant hand

Dex-0 (n = 319)

Dex-1 (n = 320)

Dex-2 (n = 315)

P

All Patients (n = 954)

87.1 ± 13.1 11.6 ± 2.07 16.8 ± 2.73 7.84 ± 1.42 4.62 ± 1.10 44.6 ± 13.5 95.9 ± 27.3 61.6 ± 12.7 67.3 ± 15.6

87.4 ± 14.2 11.7 ± 2.10 16.7 ± 2.76 7.97 ± 1.47 4.61 ± 1.04 46.4 ± 14.9 90.8 ± 28.9 63.9 ± 13.3 70.0 ± 15.0

85.5 ± 14.1 11.8 ± 1.90 16.4 ± 2.53 7.94 ± 1.46 4.56 ± 1.02 44.4 ± 13.9 91.3 ± 31.4 62.8 ± 13.1 68.0 ± 13.1

0.051 0.057 0.070 0.805 0.188 0.087 0.135 0.978 0.077

86.7 ± 13.8 11.7 ± 2.03 16.7 ± 2.68 7.92 ± 1.45 4.60 ± 1.05 45.1 ± 14.1 92.7 ± 29.3 62.8 ± 13.1 68.4 ± 14.6

Many previously published articles demonstrated corticosteroids could affect the cognitive function. Investigations have shown that different doses of corticosteroids had dissimilar effects on memory, with high or low dose of corticosteroids leading to memory impairment10,29–31 and medium doses leading to the opposite effect.32 Dexamethasone has been extensively used in the perioperative setting; however, few studies have focused on the correlation between dexamethasone and early POCD. We found that administration of higher dose of dexamethasone increases the incidence of early POCD in this study. The incidence of POCD was 22.3% in the placebo group, 20.6% in the Dex-1 group, and 31.4% in the Dex-2 group, respectively. There were significant differences between the 3 groups (P = 0.003). Partitions of w2 method demonstrated that the incidence of POCD in Dex-2 was significantly different compared with Dex-0 and Dex-1 group. Higher dose of dexamethasone could therefore impair cognitive functions. This was demonstrated in senile rats and patients with Alzheimer disease.15,33 One hypothesized mechanism is that dexamethasone elevates amyloid precursor protein expression and reduces its degradation, thereby increasing the toxicity of amyloid.13,14,17,19 In addition, glucocorticoids may augment

tau protein expressing and accumulation.13,16 Amyloid and tau protein can contribute to Alzheimer disease neuropathology, leading to learning and memory dysfunction. This may be a mechanism whereby the higher dose of dexamethasone increased the finding of early POCD. The anti-inflammatory effects of dexamethasone in the postoperative period are well known.7,34 However, the relationship between the inflammatory reaction and cognitive dysfunction is controversial. It has been reported that systemic inflammation is associated with an accentuated cerebral inflammatory response, which is associated with neurocognitive deficits.23,24 Recent studies in young rats did not show a link between pronounced systemic inflammation and neurocognitive impairment.35 Some human studies also failed to demonstrate a link between systemic inflammation and cognitive dysfunction after coronary artery bypass graft surgery.36,37 The result in this study showed that higher dose dexamethasone increases the incidence of POCD; however, findings in this study may not be generalized to all surgery under general anesthesia as MVD is a minimally invasive surgery with a lesser inflammatory response than coronary artery bypass surgery. In addition, unlike in other studies, inflammatory mediators were not directly measured. In this study, participants had a single diagnosis of facial spasm, experienced the same surgical procedure, MVD, nearly identical anesthetic technique, and measured anesthetic depth. Intraoperative explicit memory or intraoperative recall causes a significant impairment of postoperative recovery, and it may even cause severe psychological trauma.38–40 The subjects of our study did not suffer from awareness during anesthesia as shown

TABLE 3. Duration of Anesthesia and Surgery, and BIS Value of the 3 Groups (Mean ± SD)

TABLE 4. Anesthetic Drugs and Cardiovascular Medication of the 3 Groups (Mean ± SD or No. Cases)

was significantly different between Dex-2 and Dex-1 groups (P = 0.002), and Dex-2 and Dex-0 groups (P = 0.009). There were no statistically significantly differences between the Dex-0 and Dex-1 groups (P = 0.615) (Fig. 3).

DISCUSSION

Items Duration of anesthesia (min) Duration of surgery (min) BIS value during anesthesia

r

Dex-0 (n = 319)

Dex-1 (n = 320)

Dex-2 (n = 315)

P

115 ± 23.3

113 ± 26.2

111 ± 24.8

0.257

93 ± 21.6

91 ± 23.8

91 ± 22.4

0.458

49 ± 4.5

49 ± 4.4

49 ± 4.1

0.280

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Items Propofol (mg) Remifentanil (mg) Phenylephrine (n) Nitroglycerin (n) Isoproterenol (n) Esmolol (n)

Dex-0 (n = 319)

Dex-1 (n = 320)

Dex-2 (n = 315)

P

807 ± 215.3 1.37 ± 0.45 59 50 120 20

829 ± 192.0 1.34 ± 0.51 52 53 100 32

793 ± 201.6 1.43 ± 0.49 70 58 109 28

0.083 0.073 0.153 0.644 0.238 0.218

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TABLE 5. Awareness and VAS (Mean ± SD or No. Cases) Items Awareness (n) VAS-1* (mean ± SD) VAS-2z (mean ± SD)

Dex-0 (n = 319)

Dex-1 (n = 320)

Dex-2 (n = 315)

P

0 0.94 ± 1.90

0 1.09 ± 2.00

0 1.19 ± 2.18

NS 0.174w

0.71 ± 1.41

0.80 ± 1.48

0.86 ± 1.61

0.487w

*First day after surgery. zSecond day after surgery. wThe P values were calculated with the use of the Kruskal-Wallis nonparametric test. NS indicates not significant; VAS, Visual Analogue Scale.

by continuous brain monitoring and for intraoperative awareness screening, allowing us to rule out awareness under anesthesia as a potential factor in the development of POCD. Psychometrically, there were over 70 reported methodologies to assess cognitive function.41 We chose to employ a battery of sensitive neuropsychological tests that have been reliably tested and standardized for the measurement of POCD.42 However, this study has several limitations worth noting. First, long-term cognitive function was not tested in the limits of this study. Long-term POCD may be more significant in middle-aged patients who are more likely to show decreased work and social function after surgery.43 Secondly, our results demonstrated that higher dose of dexamethasone impaired cognitive function, whereas the low dose had no effect and was equal to the control group. Unfortunately, this dose-effect relationship was not explored. The third limitation is that we were not able to identify the role of inflammatory mediators in the mechanism of early POCD as this was beyond the scope of the current study. In addition, the association of amyloid and tau protein production enhanced by

FIGURE 3. The incidence of POCD was statistically significantly different between the 3 groups, P = 0.003. The incidence of POCD was significantly different between the Dex-2 and Dex-1 groups (P = 0.002), and the Dex-2 and Dex-0 groups (P = 0.009). POCD indicates postoperative cognitive dysfunction.

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dexamethasone and effects on cognitive function was not elucidated in these patients.14,15,19,44 In future studies, collection and analysis of preoperative and postoperative cerebrospinal fluid samples may show changes in important biochemical markers with implications on the development of cognitive dysfunction.

CONCLUSIONS Higher dose of IV dexamethasone (0.2 mg/kg) before induction of general anesthesia in minimally invasive surgery, as compared with a lower dose (0.1 mg/kg), and IV saline increases the incidence of POCD in the early postoperative period. To prevent POCD, we should be cautious to administer high dose of dexamethasone to patients undergoing an operation. REFERENCES 1. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg. 2003;97:62–71. 2. Kardash KJ, Sarrazin F, Tessler MJ, et al. Single-dose dexamethasone reduces dynamic pain after total hip arthroplasty. Anesth Analg. 2008;106:1253–1257. 3. Karst M, Kegel T, Lukas A, et al. Effect of celecoxib and dexamethasone on postoperative pain after lumbar disc surgery. Neurosurgery. 2003;53:331–336. 4. Bisgaard T, Klarskov B, Kehlet H, et al. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial. Ann Surg. 2003;238:651–660. 5. Aminmansour B, Khalili HA, Ahmadi J, et al. Effect of high-dose intravenous dexamethasone on postlumbar discectomy pain. Spine (Phila Pa 1976). 2006;31:2415–2417. 6. Park SH, Han SH, Do SH, et al. Prophylactic dexamethasone decreases the incidence of sore throat and hoarseness after tracheal extubation with a double-lumen endobronchial tube. Anesth Analg. 2008;107:1814–1818. 7. Holte K, Kehlet H. Perioperative single-dose glucocorticoid administration: pathophysiologic effects and clinical implications. J Am Coll Surg. 2002;195:694–712. 8. Brown ES, Woolston DJ, Frol A, et al. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55:538–545. 9. Brown ES, Woolston DJ, Frol AB. Amygdala volume in patients receiving chronic corticosteroid therapy. Biol Psychiatry. 2008;63: 705–709. 10. Kirschbaum C, Wolf OT, May M, et al. Stress- and treatmentinduced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sci. 1996;58:1475–1483. 11. de Kloet ER, Oitzl MS, Joels M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci. 1999;22: 422–426. 12. Johnson S, Tazik S, Lu D, et al. The new inhibitor of monoamine oxidase, M30, has a neuroprotective effect against dexamethasoneinduced brain cell apoptosis. Front Neurosci. 2010;4:180. 13. Green KN, Billings LM, Roozendaal B, et al. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2006;26:9047–9056. 14. Li WZ, Li WP, Huang DK, et al. Dexamethasone and Abeta(2)(5)(3)(5) accelerate learning and memory impairments due to elevate amyloid precursor protein expression and neuronal apoptosis in 12-month male rats. Behav Brain Res. 2012;227:142–149. 15. Li WZ, Li WP, Yao YY, et al. Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice. Eur J Pharmacol. 2010;628:108–115. r

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Higher dose dexamethasone increases early postoperative cognitive dysfunction.

To investigate the effects of intravenous administration of dexamethasone on early postoperative cognitive dysfunction (POCD)...
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