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Ann Thorac Surg 2000;69:1420-1424
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Effects of single dose, postinduction dexamethasone on recovery after cardiac surgery

^a Department of Cardiothoracic Anesthesiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Address reprint requests to Dr Yared, Department of Cardiothoracic Anesthesiology, The Cleveland Clinic Foundation, 9500 Euclid Ave, G5, Cleveland, OH 44195
e-mail: yaredj{at}cesmtp.ccf.org

	Abstract

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Background. Corticosteroids have been recommended to facilitate rapid recovery after cardiac surgery. We previously reported that dexamethasone given after induction of anesthesia decreases the incidence of postoperative shivering. We performed a post hoc analysis of the data obtained during that study, focusing on secondary outcomes.

Methods. A total of 235 adult patients undergoing elective coronary or valvular heart surgery were randomized to receive dexamethasone 0.6 mg/kg or placebo after induction of anesthesia. Patients who had pharmacologically treated diabetes mellitus, had hypersensitivity to dexamethasone, or were receiving treatment with corticosteroids were excluded.

Results. We found that, compared with placebo, patients receiving dexamethasone were more likely to remain tracheally intubated for 6 hours or less (26.4% vs 10.0%, p = 0.020) and had a lower incidence of early postoperative fever (20.2% vs 36.8%, p = 0.009) and new-onset atrial fibrillation during the first 3 days postoperatively (18.9% vs 32.3%, p = 0.027). However, we could not demonstrate a statistical difference in the intensive care unit or hospital length of stay, or in overall morbidity and mortality. The dexamethasone-treated patients were also more likely to have a higher blood glucose on admission to the intensive care unit (186 mg/dL vs 143 mg/dL, p = 0.012).

Conclusions. Dexamethasone facilitates early tracheal extubation and is associated with a lower incidence of early postoperative fever and new-onset atrial fibrillation. Apart from a treatable decreased glucose tolerance, dexamethasone treatment was not shown to affect morbidity or mortality significantly.

	Introduction

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Methods for obtaining early tracheal extubation, as well as for early discharge from the intensive care unit (ICU) and hospital after cardiac surgery under cardiopulmonary bypass (CPB), are receiving a great deal of attention because of the impact of ICU and hospital length of stay on the cost of surgery. Multiple strategies have been recommended to facilitate this process of "fast-track" recovery, including the use of low-dose opiate anesthesia [1] and perioperative administration of corticosteroids. Inhibition of the inflammatory response to CPB by corticosteroids is thought to accelerate recovery [2, 3], decrease myocardial edema [4], and decrease postoperative fever as well as fluid and inotropic drug requirements [5]. We recently reported that a single dose of dexamethasone (0.6 mg/kg) after induction of anesthesia decreases the incidence of postoperative shivering, and that this effect is independent from the duration of CPB and surgery as well as temperature during CPB and upon ICU admission [6]. However, methylprednisolone has been reported to increase intrapulmonary shunt and to delay extubation [7]. We performed a post hoc analysis of data obtained during the study of the effects of dexamethasone on shivering, focusing on secondary outcomes such as tracheal intubation time, ICU and hospital length of stay, new-onset atrial fibrillation, and major morbidities. In this report we present the impact of dexamethasone treatment on the outcome of cardiac-related surgery.

	Material and methods

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After Institutional Review Board approval, and informed consent, a prospective, randomized, double-blind, placebo-controlled study was undertaken. A total of 236 patients aged 20 years or older and having elective coronary or valvular heart surgery with cardiopulmonary bypass were randomly assigned to two groups. One group (DEX) received dexamethasone 0.6 mg/kg, and the other group (PL) received an equal volume of placebo (ie, saline) after induction of anesthesia but before skin incision. Patients with a history of hypersensitivity to dexamethasone or of diabetes mellitus treated with insulin or oral medications, or who were receiving therapy with corticosteroids were excluded. Patients who were enrolled in the study but returned to the operating room because of surgical bleeding, or who received additional corticosteroids or other drugs such as aprotinin that interfere with the inflammatory response, were excluded from the analysis. All patients were premedicated with oral lorazepam 0.02 to 0.04 mg/kg and received standard monitoring. Anesthetic and postoperative management including benzodiazepines, low-dose opiates, isoflurane, and neuromuscular blockers was compatible with early extubation. Cardiopulmonary bypass was performed under either normothermia or moderate hypothermia, according to surgeon preference. All patients received blood cardioplegia and were rewarmed to bladder temperature (T°BL) of 37°C before separation from CPB. Upon admission to the ICU, patients were initially ventilated. Central blood temperature (T°PA) was measured continuously in the pulmonary artery. According to ICU routine, a hot air blanket (Bair Hugger, Augustine Medical, Inc, Eden Prairie, MN) was applied for T°PA less than 35.5°C and discontinued for T°PA greater than 36.5°C. Shivering was treated with pancuronium 0.02 to 0.03 mg/kg after unconsciousness had been obtained with midazolam in 1-mg increments. Patients were weaned to continuous positive airway pressure (CPAP) and extubated according to ICU routine (ie, if patients were responsive to command, were hemodynamically stable, had appropriate gas exchange and respiratory mechanics, and chest tube drainage did not exceed 50 mL/h for 2 consecutive hours). Residual neuromuscular blockade was reversed when necessary with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Serum glucose was monitored in the perioperative period and hyperglycemia was controlled by insulin according to the preference of the anesthesiologist.

The time elapsed from ICU admission to tracheal extubation, ICU and hospital length of stay, and mortality, as well as the incidence of major neurologic, renal, cardiac, infectious, and pulmonary morbidities were obtained from the Cardiothoracic Anesthesia Database. Additional data were collected about new-onset atrial fibrillation in the first 3 postoperative days, and administration of continuous infusions of insulin, vasopressors (norepinephrine), and inotropic drugs (epinephrine, dobutamine, or milrinone) in the ICU on the day of surgery. Early postoperative fever was defined as peak T°PA of 38°C or more in the first 6 hours after ICU admission.

Statistical analysis
The primary endpoint of the randomized study was the comparison of the effect of dexamethasone versus placebo on the incidence of shivering. For the post hoc analyses, comparison of dexamethasone versus placebo on outcome, as well as complications that are categorical (eg, gender), were analyzed using ² tests unless the cell counts were small, in which case Fisher exact tests were used. Continuous measures were analyzed using t tests if the data seemed to be normally distributed, or the Wilcoxon rank sum tests for variables such as intubation time and length of stay were not normally distributed. All statistical tests were two-tailed; p values of 0.05 or less were used to define statistical significance.

	Results

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Between January 15, 1997, and September 25, 1997, a total of 236 patients were enrolled in the study. They were divided into two groups (DEX or PL), with 118 patients randomly assigned to each group. A total of 20 patients were excluded from analysis (Table 1); therefore, outcome data were obtained on 216 evaluable patients and provide the basis of this report.

The incidence of new-onset atrial fibrillation in the first 3 days postoperatively was lower in the DEX group compared with the PL group (16.0% vs 32.4%, respectively; p = 0.006). Analysis by surgical subset is presented in Table 5. There were no significant differences in mortality as well as in pulmonary, renal, neurologic, cardiac-related, and infectious morbidity between groups (Table 6).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
The primary analysis for this prospective, randomized, controlled trial demonstrated that a single dose of dexamethasone postinduction reduces the incidence of postoperative shivering in cardiac surgical patients [6]. The present post hoc analysis shows that dexamethasone facilitates early tracheal extubation and reduces the incidence of early postoperative fever as well as new-onset atrial fibrillation. However, it had no effect on intrapulmonary shunting as well as on ICU and hospital length of stay. Moreover, shivering (irrespective of the treatment group) was associated with delayed extubation and with fever.

Conflicting data exist regarding the effect of corticosteroids on oxygen exchange and tracheal intubation time. Although some investigators have found a reduced intubation time in methylprednisolone-treated patients compared with historical controls [2] and improved oxygenation [8], others have found no effect on intrapulmonary shunt fraction [9], and still others have shown an increased intubation time as well as shunting [7]. In the latter study, the methylprednisolone-treated group received a significantly larger dose of midazolam intraoperatively, and a larger (although not statistically significant) dose of midazolam postoperatively. This may have contributed to the longer intubation time in the steroid-treated group. Dexamethasone increased the percentage of patients extubated early (< 6 hours); however, the trend toward a lower mean intubation time approached, but did not reach, statistical significance. This may represent a type II statistical error resulting from a small sample size, but it also may be the result of the presence (in both groups) of a few outliers with very long intubation time, as indicated by the large standard deviation. The reduced intubation time that we observed in the DEX group may reflect a direct effect of the drug, but is more likely due to the fact that shivering was less common in this group. Shivering was associated with delayed tracheal extubation, possibly because of the sedation and neuromuscular blockade required to treat it. We found that dexamethasone did not affect the ratio of arterial to inspired oxygen at ICU admission. Impaired oxygenation after cardiac surgery has been attributed to activation of the inflammatory response, pulmonary sequestration of neutrophils, and oxidative stress [5, 10, 11]. The inflammatory response to CPB can be modulated not only by corticosteroids but also by other factors such as the temperature used during CPB [12, 13]. The temperature maintained during CPB in our study was higher than in other reports [7], explaining in part the difference in results.

The reduced incidence of fever that we observed in the immediate postoperative period in dexamethasone-treated patients has been previously described. It has been attributed to inhibition of the release of pyrogenic cytokines by corticosteroids [5]. This corticosteroid-mediated effect is advantageous in the cardiac surgery patient, as oxygen consumption is directly related to temperature [14].

The association of dexamethasone treatment with a decreased incidence of new- onset atrial fibrillation in the first 3 days postsurgery is intriguing. Atrial fibrillation affects 20% to 30% of cardiac surgery patients, with the peak incidence on day 2 or 3 after surgery [15]. It may be associated with serious complications including strokes, decreased cardiac output, and impaired oxygen exchange, and it usually necessitates an increase in hospital length of stay [16]. Our results suggest a possible link between new-onset atrial fibrillation and the post-CPB inflammatory response; however, the mechanism of such an association is unclear.

The excessive systemic inflammatory response syndrome that is seen in some cardiac surgical patients may result in postoperative failure of major organs. Corticosteroids are thought to improve outcome through inhibition of the systemic inflammatory response syndrome [17, 18]. Our results show that dexamethasone has no impact on operative morbidity and mortality. Such findings could imply that a single dose of dexamethasone had no impact on such outcome measurements. However, it is possible that because these complications are rare, the sample size was not adequate to allow detection of such a difference. Our data on serious postoperative complications are potentially incomplete, as we did not follow-up patients after their hospital discharge. It is therefore possible that some patients received treatment for such complications in another facility. Cardiopulmonary bypass suppresses delayed immunity, particularly in older patients [19], and methylprednisolone suppresses T-cell–mediated function synergistically with CPB [20]. The hyperglycemia and increased need for insulin that we observed in patients receiving dexamethasone have previously been described [5]. The combination of dexamethasone-induced suppression of the immune response and hyperglycemia raises concerns about a greater susceptibility to infection [21] and strokes [22] in this group, and emphasizes the need to monitor and control blood glucose, particularly in patients receiving dexamethasone.

Contrary to other reports, we did not find a significant increase in cardiac index or a decrease in the use of inotropic agents in patients treated with dexamethasone [5, 23]. The metabolic acidemia observed in the DEX group upon ICU admission is of concern, although it was mild.

When compared with historical controls, patients receiving corticosteroids as part of an accelerated recovery protocol have been shown to have a shorter hospital length of stay [2]. In other cases a nonsignificant decrease in ICU length of stay in patients receiving dexamethasone has been reported [5]. The lack of difference in ICU and postoperative hospital length of stay between groups in our study might be due to the fact that we used smaller doses of steroids than in other studies, or it might indicate that dexamethasone had no effect on length of stay. However, it is more likely a reflection of the fact that, for all study patients, we used accelerated recovery protocols and hospital-specific management decisions, independent of study design.

In conclusion, this post hoc study shows that, in addition to the reduced incidence of postoperative shivering that we demonstrated previously, dexamethasone facilitates early tracheal extubation, reduces the incidence of early postoperative fever, and is associated with a lower incidence of new-onset atrial fibrillation. Except for decreased glucose tolerance and a mild metabolic acidemia on ICU admission, no adverse effect could be attributed to dexamethasone treatment with respect to mortality and morbidity. However, because such complications are rare, a larger sample size is needed to confirm these findings. An important limitation of this study is that we did not measure inflammatory mediators released in response to CPB and the study drug. Further research is needed to correlate clinical observations with biochemical markers of inflammation, and to determine whether inhibition of the inflammatory response by a different dose of dexamethasone is advantageous. The increased severity of hyperglycemia in dexamethasone-treated patients raises concerns about potential associated adverse effects, and suggests that patients should be monitored and treated effectively to prevent hyperglycemia.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yared, J.-P. Articles by Rosenberger, T. E. Search for Related Content PubMed PubMed Citation Articles by Yared, J.-P. Articles by Rosenberger, T. E.