|Year : 2022 | Volume
| Issue : 3 | Page : 113-120
The impact of administering intraoperative dexamethasone versus placebo on major complications and mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis
Ashish Madkaiker1, Tania Mehta2, Pratik Manek1, Chirag Doshi3, Pratik Shah4, Sanjay Patel4
1 Department of Cardiovascular and Thoracic Surgery, U. N. Mehta Institute of Cardiology and Research Center, Ahmedabad, Gujarat, India
2 Department of Cardiovascular and Thoracic Surgery, Leeds Teaching Hospital, Leeds, UK
3 Department of Cardiovascular and Thoracic Surgery, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, Gujarat, India
4 Research, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, Gujarat, India
|Date of Submission||10-Sep-2022|
|Date of Decision||19-Oct-2022|
|Date of Acceptance||31-Oct-2022|
|Date of Web Publication||14-Dec-2022|
Department of Cardio Vascular and Thoracic Surgery, U. N. Mehta Institute of Cardiology and Research Center, Ahmadabad, Gujarat
Source of Support: None, Conflict of Interest: None
Background: Inflammations resulting from cardiac surgical procedures have traditionally been controlled with corticosteroids such as dexamethasone. However, the use of these medications to attenuate the inflammatory responses from cardiac surgery remains contentious. The aim of this systematic review and meta-analysis was to evaluate the effect of administering dexamethasone intraoperatively on major complications and mortality compared to placebo interventions.
Study Design: This was a systematic review and meta-analysis.
Methods: The research was conducted on online databases such as PubMed, Google Scholar, EMBASE, and the Cochrane Central Register of Control Trials until August 5, 2022. The studies in the online databases were written between January 1, 2000, and August 1, 2022. The studies that were selected were scanned and analyzed based on an established eligibility criteria for the study.
Results: Ten randomized and controlled trials were included in this systematic review and meta-analysis. The incidence of mortality was 2.2% (154 out of 7007 patients) in the dexamethasone group and 2.3% (164 out of 7038 patients) in the placebo group (odds ratio [OR],0.94; 95% confidence interval [CI], 0.75–1.01; P = 0.73; I2 = 0%). Myocardial infarction incidence was 1.88% (88 out of 4685 patients) in the dexamethasone group and 2.12% (100 out of 4708 patients) in the placebo group (OR, 0.88; 95% CI, 0.66–1.18; P = 0.39; I2 = 9%). The incidence of stroke for the dexamethasone group was 1.56% (70 out of 4488 patients) and 1.82% (82 out of 4511 patients) in the placebo group (OR, 0.86; 95%CI, 0.62–1.18; P = 0.34; I2 = 0%). The prevalence of new onset atrial fibrillation was 32.3% (797 out of 2469 patients) for dexamethasone and 34.7% (859 out of 2478 patients) for placebo (OR, 0.90; 95%CI, 0.80–1.01; P = 0.08; I2 = 0%). The incidence of renal failure was slightly higher in the placebo group with 1.58% (108 out of 6857 patients) compared to the dexamethasone group 0.97% (66 out of 6823 patients) (OR, 0.61; 95% CI, 0.45–0.83; P = 0.002; I2 = 0%).
Conclusion: According to this review, dexamethasone does not result in a significant decrease in incidences of mortality, myocardial infarction and stroke. However, the medication was associated with decreased incidences of renal failure and atrial fibrillation in a majority of the studies.
Keywords: Atrial fibrillation, cardiac surgery, corticosteroids, dexamethasone, mortality, myocardial infarction, renal failure, stroke
|How to cite this article:|
Madkaiker A, Mehta T, Manek P, Doshi C, Shah P, Patel S. The impact of administering intraoperative dexamethasone versus placebo on major complications and mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis. Heart India 2022;10:113-20
|How to cite this URL:|
Madkaiker A, Mehta T, Manek P, Doshi C, Shah P, Patel S. The impact of administering intraoperative dexamethasone versus placebo on major complications and mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis. Heart India [serial online] 2022 [cited 2023 Feb 2];10:113-20. Available from: https://www.heartindia.net/text.asp?2022/10/3/113/363543
| Background|| |
Cardiac surgery poses a huge risk for developing postoperative complications affecting the respiratory, circulatory, and renal as well as the central neurologic system. Despite major advancements in surgical and anesthetic techniques that have significantly reduced mortality, these complications strongly influence the incidence of morbidity, death, the duration of hospitalization, and overall quality of life of the patients.
Cardiopulmonary bypass (CPB) surgery, in particular, is linked to an acute inflammatory response throughout the body due to exposure of blood to foreign substances during the procedure. This inevitably leads to complement activation, the onset of coagulation, kallikrein, and fibrinolysis cascades. Consequent immunoregulatory cell activation triggers a significant production of both pro-inflammatory and anti-inflammatory cytokines. This cytokine storm is associated with postoperative morbidity and is linked to organ malfunction or failure., Moreover, the systemic inflammatory response may cause perioperative coagulation complications that frequently happen after heart surgery by simultaneously activating the coagulation cascade through tissue factor as well as necrosis factor-kB. Typically administered in a high dose, corticosteroids can be given during cardiac surgery to suppress systemic inflammatory activities.
Humans have hundreds of distinct steroid types, some of which are known to have anti-inflammatory properties. Synthetic glucocorticoids have been created, utilized, and studied for their ability to reduce inflammation in a variety of medical circumstances, from infectious disorders to palliative care. At the molecular level, corticosteroids are made up of a steroid base and a number of side-chain variations that can alter the molecule's action. Drug producers use these altered side chains to change the various features of corticosteroids. Since corticosteroids can easily pass through cell walls due to their fat soluble nature, they can attach to their receptors within the target cell. They enter the cell nucleus after binding to their receptor where they operate as a transcription factor to alter the translation of certain cellular proteins. Cardiac surgery patients may be given either synthetic or naturally occurring corticosteroids before, during or after the procedure.
Inflammation has traditionally been controlled with the help of corticosteroids. They work to inhibit both early signs of inflammation such as enhanced capillary permeability, edema development, and leukocyte migration as well as late signs such as later signs such as capillary proliferation and collagen deposition. Examples of corticosteroids given during cardiac surgery are dexamethasone, methylprednisolone, prednisolone, hydrocortisone, and prednisone. Numerous studies that demonstrated reduction of the systemic inflammatory response during CPB provided support to the rationale of administering corticosteroids to individuals undergoing cardiac surgery. Reduced levels of pro-inflammatory cytokine were associated with improved myocardial protection, reduced need for inotropes, and fluids as well as increased maintenance of lung function following surgery.
According to Asehnoune et al., dexamethasone may reduce the risk of serious complications following surgery in two different ways. First, its strong anti-inflammatory actions may lessen the exaggerated postoperative inflammatory reaction that causes organ failure and immunological cell death. This is characterized by the lower levels of C-reactive proteins (CRP). Second, dexamethasone may help in restoring immune functions that are impaired in people admitted to hospitals putting them at risk for secondary infections. When given during a systemic inflammatory response, anti-inflammatory cytokine concentrations in the blood drop, interferon-gamma and interleukin (IL)-12 concentrations rise, and neutrophil phagocytic activity increase.
The use of corticosteroids during cardiac surgery is still debatable. This is due to concerns regarding possible their possible negative effects such as insufficient serum glucose control, risk of infections, and inadequate wound healing as well as gastrointestinal bleeding. Dexamethasone also has a significant hyperglycemic impact on patients undergoing cardiac surgery impairing glucose regulation., The purpose of this systematic review and meta-analysis is to therefore examine the impact of administering intraoperative dexamethasone on mortality and other major adverse effects compared to placebo on cardiac surgery patients.
| Methods|| |
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A preliminary search was carried out on online e-databases such as PubMed, Google Scholar, EMBASE, and the Cochrane Central Register of Control Trials using the key words. All studies and articles applicable to the research topic were identified. A subsequent search was conducted on the reference lists of the studies found in the initial search. Related articles recommended by the aforementioned digital libraries were also included as results of the second literature search. The keywords used in the research included dexamethasone, corticosteroids, cardiac surgery, mortality, myocardial infarction, atrial fibrillation, ischemic stroke, renal failure, surgical outcomes, and surgical complications. The search strategy was modified to cater for each of the included online e-database, atrial fibrillation, cardiac surgery, corticosteroids, ischemic stroke, mortality, myocardial infarction, renal failure, surgical outcomes, taking into account all identified keywords, and index terms. The [Table 1] shows a description of the search strategy:
The research was conducted from inception to August 2022. The included articles were published between January 1, 2000, and August 1, 2022.
Guidelines and selection criteria
The following criteria were included in the study:
- The use of any given dose of dexamethasone during cardiac surgery procedure
- Studies that compared patients that received intra operative dexamethasone with those
- who did not
- Studies with reported figures on the occurrence of the anticipated postoperative clinical outcomes such as myocardial infarction, ischemic stroke, renal failure, atrial fibrillation and mortality. Primary author's definitions of all clinical endpoints were accepted
- Randomized controlled trials (RCTs)
- Studies published in English language
- Full text studies.
The following criteria were excluded from the study:
- Studies that focused on other intraoperative interventions other than dexamethasone
- Articles focusing on other surgical procedures
- Studies without a control group made up of individuals from an identical population
- Clinical trials that reported exclusively on different adverse clinical outcomes
- Animal studies
- Case reports, review articles, editorials, unpublished literature, and articles that had only abstracts without full texts
- Articles written in any other language apart from English
- Duplicate articles.
The titles and abstracts of the selected articles were examined to ascertain their relevance to this analysis and to determine if they met the preset eligibility criteria for the study. The studies that met the outlined eligibility criteria were then fully read and examined to assess their relevance and contribution toward fulfilling the purpose of this systematic review. All disagreements that arose were settled through discussion and consensus.
Data extraction, quality assessment and synthesis
The information extracted from the articles included author's name, year of publication, number of participants, study design, participants' characteristics including their mean age, sex, and type of cardiac surgery. Other information extracted included the dosage of dexamethasone given and the postoperative outcomes measured during the follow-up period. The Cochrane RevMan Software was used to conduct a meta-analysis of the various subgroup data.
The PEDRO tool and the Sackett scales were used to assess the risk of bias. The 11-item PEDRO-P scale assesses a trial's internal validity and determines whether it has enough statistical data to facilitate its interpretation. The first criterion, which addresses external validity, is not included in the overall quality score out of 10. The second through to ninth criteria assess the study's internal validity and address pretreatment, performance, and data analysis biases. The 10th and 11th criteria evaluate the variability measurements, in-between subgroup statistical comparisons, and presentation of point estimates to determine the interpretability of the results. The Cochrane tool was used to assess the risk of bias and gauge the credibility and transparency of the results. The authors resolved all discrepancies relating to any aspects of the chosen articles during the data collection process.
| Results|| |
One hundred and forty-eight studies were found through searches in the online e-databases using the aforementioned keywords. One hundred and four studies remained after elimination of duplicates. The titles and abstracts of the 104 studies were examined to determine their applicability to the systematic review. Fifty-eight studies were excluded as they were not relevant to this systematic review leaving only 42 studies. The 42 studies were then assessed against the eligibility criteria for the systematic review. Thirty-two studies did not meet the eligibility criteria and were therefore excluded from the study. The 10 studies that were chosen for inclusion in this systematic review and meta-analysis were those that fulfilled the study's preset eligibility criteria. [Table 2] summarizes the study characteristics of included studies. The PRISMA diagram for the selection process is shown in [Figure 1].
|Figure 1: PRISMA Flow Diagram for impact of Administering Intra-operative Dexamethasone versus Placebo on Major complications and Mortality in Patients Undergoing Cardiac Surgery. PRISMA-referred Reporting Items for Systematic Reviews and Meta-Analyses|
Click here to view
Forest plot for mortality
The incidence of mortality was 2.2% (154 out of 7007 patients) in the dexamethasone group and 2.3% (164 out of 7038 patients) in the placebo group (odds ratio [OR],0.94; 95% confidence interval [CI], 0.75–1.01; P = 0.73; I2 = 0%) [Figure 2].
Forest plot for myocardial infarction
Myocardial infarction incidence was 1.88% (88 out of 4685 patients) in the dexamethasone group and 2.12% (100 out of 4708 patients) in the placebo group (OR, 0.88; 95% CI, 0.66–1.18; P = 0.39; I2 = 9%) [Figure 3].
Forest plot for stroke
The incidence of stroke for the dexamethasone group was 1.56% (70 out of 4488 patients) and 1.82% (82 out of 4511 patients) in the placebo group (OR, 0.86; 95%CI, 0.62–1.18; P = 0.34; I2 = 0%) [Figure 4].
Forest plot for atrial fibrillation
The prevalence of new onset atrial fibrillation was 32.3% (797 out of 2469 patients) for dexamethasone and 34.7% (859 out of 2478 patients) for placebo (OR, 0.90; 95% CI, 0.80–1.01; P = 0.08; I2 = 0%) [Figure 5].
Forest plot for renal failure
The incidence of renal failure was slightly higher in the placebo group with 1.58% (108 out of 6857 patients) compared to the dexamethasone group 0.97% (66 out of 6823 patients) (OR, 0.61; 95% CI, 0.45–0.83; P = 0.002; I2 = 0%) [Figure 6].
Given that all ten of the RCTs in the current systematic review and meta-analysis have a PEDRO score of at least 7, they can all be classified as having good quality according to the Sackett level of evidence scale (level 1a). As a result, the evidence level is high [Table 3].
| Discussion|| |
The results of this systematic review and meta-analysis show that the use of dexamethasone does not result in a significant reduction in the incidences of mortality (2.2% in dexamethasone vs. 2.3% in placebo) (OR, 0.86; 95% CI, 0.62–1.18; P = 0.34; I2 = 0%), myocardial infarction (1.88% for dexamethasone vs. 2.12% for placebo), (OR, 0.88; 95% CI, 0.66–1.18; P = 0.39; I2 = 9%) and stroke (1.56% in dexamethasone vs. 1.82% in placebo) (OR, 0.86; 95% CI, 0.62–1.18; P = 0.34; I2 = 0%). A slight decrease in myocardial infarction and stroke can be explained by the fact that dexamethasone eliminates pro-inflammatory responses involving tumor necrosis factor (TNF) alpha and IL-8, decreases IL-6 production while increasing anti-inflammatory IL-10 production. TNF alpha is a key mediator involved in the pathophysiology of myocardial ischemia-reperfusion damage. TNF-alpha also induces biventricular dilatation, hypotension, lower systemic vascular resistance, and a decrease in cardiac contractility and ejection fraction.
For atrial fibrillation, the results on difference between the dexamethasone and placebo group were slightly higher and statistically significant (OR, 0.90; 95% CI, 0.80–1.01; P = 0.08; I2 = 0%). An increased incidence of postoperative atrial fibrillation has been linked to preoperatively elevated CRP and postoperatively elevated complement C-4 as well as CRP. Recently, it was discovered that giving patients undergoing coronary artery bypass graft surgery methylprednisolone and dexamethasone together reduced the frequency of atrial fibrillation. Dexamethasone was able to alleviate the rise in pro-inflammatory cytokines similar to methylprednisolone. However, the authors were unable to demonstrate its efficacy in lowering atrial fibrillation incidence. A possible explanation to this is that the inflammatory reaction of dexamethasone on tissues of the atria is insufficient to combat other factors that cause atrial fibrillation., A systematic review by Yi et al. also concluded that dexamethasone did not decrease the incidence of atrial fibrillation and death after cardiac surgery.
The dexamethasone group had a lower incidence of kidney failure 0.97% compared to the placebo group with 1.58% (OR, 0.61; 95% CI, 0.45–0.83; P = 0.002; I2 = 0%). Corticosteroids may have renoprotective effects by reducing hemolysis or iron-mediated toxicity following cardiac surgery. Blood is subjected to nonphysiologic contacts and shear stresses during cardiac surgery which causes cell lysis and the liberation of free hemoglobin inti the bloodstream. The free hemoglobin is eliminated from the bloodstream by attaching to CD 163 which is a scavenger receptor that is activated by corticosteroids. Therefore, a biologically feasible method through which corticosteroids may reduce the incidence of renal failure is by increased elimination of unbound hemoglobin through increased levels of CD 163 on the cell surfaces of mononuclear cells.
Studies have also shown that dexamethasone has other benefits when administered intra operatively including decreasing postoperative nausea and emesis and increasing patients' appetite especially when combined with a receptor antagonist for 5-HT3., The anti-inflammatory properties of dexamethasone are also beneficial in reduction of cerebral edema and neural inflammation, better pulmonary gas exchange, and a decreased requirement for postoperative inotropic support.
| Conclusion|| |
The results of this systematic review and meta-analysis show that the administration of intraoperative dexamethasone does not result in a significant decrease in incidences of mortality, stroke, and myocardial infarction. It however played a role in the reduction of incidences of atrial fibrillation and renal failure.
The current systematic review and meta-analysis had several limitations. First, the reliability of our results is jeopardized extent of inter-trial variability in classifying and reporting clinical outcomes such as atrial fibrillation. Second, the studies that made up this systematic review concentrated on different dosages of dexamethasone and consisted of patients from a range of risk groups undergoing various surgical procedures. This adds methodological and clinical variation to our findings. Third, our ability to make conclusions regarding the impact of intraoperative dexamethasone on adverse outcomes is constrained by the low rates of these events and the small number of trials reporting on these complications. In addition, in some studies, the participants were either unblinded or single blinded.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Our study is Systematic Review and Meta-Analysis and hence Ethical Committee approval was not mandatory.
Dr. Ashish Madkaiker: Conceptualization ,Drafting, Design, Data analysis; Dr. Tania Mehta- Design, Aquisition, Analysis; Dr. Pratik Manek- Analysis, Interpretation, Drafting; Dr. Chirag Doshi,- Conceptualization, Design, Interpretation; Mr. Pratik Shah - Design, Data Analysis; Mr. Sanjay Patel-Data Analysis.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]