Meta-Analysis: Shouldn’t Prophylactic Corticosteroids be Administered During Cardiac Surgery with Cardiopulmonary Bypass?

Abstract

Background:

Corticosteroids can effectively inhibit systemic inflammation induced by cardiopulmonary bypass. Recently clinical trials and meta-analyses and current guidelines for cardiac surgery do not support corticosteroids prophylaxis during cardiac surgery because of an increase in myocardial infarction and no benefit for patients. The aim of this study is to determine whether specific corticosteroids dose ranges might provide clinical benefits without increasing myocardial infarction.

Methods:

The PubMed, Web of Science, Embase, Clinical Trials, and Cochrane databases were searched for randomized controlled trials (RCTs) published before August 1, 2021.

Results:

88 RCTs with 18,416 patients (17,067 adults and 1,349 children) were identified. Relative to placebo and high-dose corticosteroids, low-dose corticosteroids (≤20 mg/kg hydrocortisone) during adult cardiac surgery did not increase the risks of myocardial infarction (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.43–2.17; p = 0.93). However, low-dose corticosteroids were associated with lower risks of atrial fibrillation (OR: 0.58, 95% CI: 0.44–0.76; p < 0.0001) and kidney injury (OR: 0.29, 95% CI: 0.09–0.96; p = 0.04). Furthermore, low-dose corticosteroids significantly shortened the mechanical ventilation times (mean difference [MD]: −2.74 h, 95% CI: −4.14, −1.33; p = 0.0001), intensive care unit (ICU) stay (MD: −1.48 days, 95% CI: −2.73, −0.22; p = 0.02), and hospital stay (MD: −2.29 days, 95% CI: −4.51, −0.07; p = 0.04).

Conclusion:

Low-dose corticosteroids prophylaxis during cardiac surgery provided significant benefits for adult patients, without increasing the risks of myocardial infarction and other complications.

Introduction

Cardiopulmonary bypass (CPB) is used during most cardiac surgeries, although CPB often induces systemic inflammatory response syndrome (SIRS) (1). The development of SIRS involves activation of complement, platelets, neutrophils, monocytes, macrophages, and cascade reactions, which leads to increased endothelial permeability, blood vessel damage, and parenchymal cell damage (2–4). These events are associated with single and multiple organ dysfunction, myocardial injury and infarction, respiratory failure, and ultimately death (5–7).

Corticosteroids are inexpensive drugs that can effectively inhibit inflammation, limit systemic capillary leak syndrome, and reduce organ damage, which provides a theoretical basis for their use during CPB (8–10). However, corticosteroids can cause side effects, including hyperglycemia, which is associated with immunosuppression and poor wound healing (11, 12). In addition, high-dose corticosteroids are associated with an increased risk of gastrointestinal bleeding and myocardial infarction (11, 12). Thus, the benefits of corticosteroids treatment are controversial for patients undergoing cardiac surgery with CPB (13–15).

Three meta-analyses of small RCTs revealed that prophylactic corticosteroids could reduce the risk of atrial fibrillation after adult cardiac surgery, also caused some side effects (5–7). Two large multi-center RCTs subsequently revealed that corticosteroids therapy provided no benefits and increased the risk of myocardial infarction in adult patients (13, 14). Thus, the adult cardiac surgery guidelines do not recommend routine prophylactic use of corticosteroids during cardiac surgery (16), although there are no specific guidelines regarding corticosteroids use during pediatric cardiac surgery. We hypothesized that the specific corticosteroids dose range might influence the risks and benefits during cardiac surgery with CPB. Therefore, this systematic review and meta-analysis aimed to evaluate the dose-dependent benefits and risks of prophylactic corticosteroids for adults and children undergoing cardiac surgery with CPB.

Methods

Ethical Statement

This study was a meta-analysis of the results of published randomized controlled trials, and ethical approval and informed consent of patients were not required.

Search Strategy and Selection Criteria

Two authors (XJY and MYT) searched the PubMed, Web of Science, Embase, ClinicalTrials, and Cochrane Central Register of Controlled Trials databases for relevant RCTs that were published in any language before August 1, 2021. The reference lists of relevant articles were also manually checked. The study protocol followed the PRISMA-P guidelines (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193658). The search terms were: (“corticosteroids” OR “dexamethasone” OR “prednisolone” OR “prednisone” OR “methylprednisolone” OR “hydrocortisone”) AND (“cardiopulmonary bypass” OR “cardiac surgery”) AND (“randomized controlled trials”) (Supplementary Table S1).

The meta-analysis only included RCTs that compared corticosteroids with a placebo used before or at the beginning of CPB. Patients undergoing surgery with CPB for heart and/or valvular diseases were included. And the studies were excluded if they used different concomitant medications or evaluated corticosteroids during off-pump heart surgery.

Two authors (TCC and XHZ) independently determined whether the identified articles fulfilled the inclusion criteria. The two authors also independently used pre-designed data extraction forms to record information regarding trial characteristics, clinical outcomes, randomization methods, application of blinding, allocation concealment, inclusion criteria, and exclusion criteria. There were no instances of disagreement regarding the extracted data.

Data Analysis

Study characteristics included first author, publication date, country, study size, study design, randomization, blinding, follow-up duration, patient withdrawals, and study duration. Patient characteristics included age, sex, surgery type, blood pressure, history of diabetes, history of smoking, renal status, and fulfillment of the inclusion criteria. The interventions included the corticosteroids type, dose, timing, and route of administration during CPB.

The primary outcomes included myocardial infarction, insulin use, mortality, new atrial fibrillation, lengths of ICU and hospital stays, acute kidney injury, mechanical ventilation time. The secondary outcomes included postoperative bleeding, re-intubation, duration of CPB and procedure, pulmonary complications (pulmonary edema), postoperative infection, neurological complications (stroke), delirium, gastrointestinal bleeding, extracorporeal membrane oxygenation (ECMO) use, vasoactive medication use, re-thoracotomy, inotropic score, blood transfusion, and and blood concentrations of glucose, lactate, C-reactive protein (CRP), tumor necrosis factor-α(TNF-α), interleukin (IL)-6, IL-8, and IL-10 at 24 h after CPB.

The Cochrane Handbook for Systematic Reviews of Interventions and Jadad score were used to assess the risk of bias for each trial (17, 18). The data were synthesized using Review Manager version 5.3 and Stata software version 16 (StataCorp, College Station, TX, USA). Inter-study heterogeneity was assessed using the chi-squared test and I² statistic, with the random effects model used for data with high heterogeneity (p < 0.1 or I² > 50%) and the fixed effects model used for data with less heterogeneity. The Mantel-Haenszel method was used to pool binary data and the results were reported as ORs with 95% CIs. An inverse variance analysis method was used to pool continuous data and the results were reported as MDs with 95% CIs. The GRADEpro GDT (https://www.gradepro.org/) was used to classify the certainty of evidence.

Results

This study identified 88 RCTs from 27 countries that included 18,416 patients (Figure 1). The trials considered adult patients (73 trials and 17,067 patients) or pediatric patients (15 trials and 1,349 patients). The corticosteroids treatments included dexamethasone, betamethasone, methylprednisolone, hydrocortisone, and prednisolone, with a broad range of total doses (1–900 mg/kg hydrocortisone equivalent). Table 1 shows the characteristics of the included studies, Table 2 shows the GRADE summary of the findings and Table 3 summarizes the impact of corticosteroids on adults and pediatric.

Figure 1

During adult cardiac surgery with CPB, corticosteroids prophylaxis was associated with increased risks of myocardial infarction (OR: 1.19, 95% CI: 1.05–1.35; p = 0.008, I²= 0%) (Figure 2) and insulin infusion (OR: 1.91, 95% CI: 1.18–3.11; p = 0.009, I²= 46%) (Supplementary Figure S1), with no obvious improvement in mortality (OR: 0.86, 95% CI: 0.71–1.03; p = 0.10, I²= 0%) (Figure 3).

Figure 2

Figure 3

However, corticosteroids prophylaxis reduced the risk of postoperative atrial fibrillation (OR: 0.68, 95% CI: 0.57–0.82; p < 0.0001, I²= 48%) (Figure 4), shortened the ICU stay (MD: −0.27 days, 95% CI: −0.34, −0.19 days; p < 0.001, I²= 93%), and shortened the hospital stay (MD: −0.66 days, 95% CI: −1.03, −0.30 days; p = 0.0003, I² = 95%) (Supplementary Figures S2, S3). In addition, corticosteroids prophylaxis was associated with reduced postoperative bleeding and a reduced risk of re-intubation (Table 3 and Supplementary Figures S4, S5).

Figure 4

Corticosteroids prophylaxis also reduced the blood concentrations of some inflammatory markers in adult patients, which included IL-6, TNF-α, and IL-8 (Table 3 and Supplementary Figures S6–S8). Among children, corticosteroids prophylaxis was associated with a significantly lower peak CRP concentration, a significantly lower IL-6 concentration, and a significantly higher IL-10 concentration (Table 3 and Supplementary Figures S9–S11).

Relative to the placebo group, corticosteroids prophylaxis was not associated with significant improvements in terms of kidney injury, pulmonary complications, stroke, gastrointestinal bleeding, postoperative infection or mechanical ventilation time (Table 3 and Figure 5, Supplementary Figures S12–S17).

Figure 5

Figure 6

Subgroup analysis that the benefits were largely attributable to the prophylactic use of low-dose corticosteroids (≤20 mg/kg hydrocortisone), and these benefits were not observed at higher corticosteroids doses (Table 2). Low-dose corticosteroids prophylaxis was associated with a significantly reduced mechanical ventilation time (MD: −2.74 h, 95% CI: −4.14, −1.33 h; p = 0.0001, I²= 92%) (Figure 5), without increased risks of myocardial infarction (OR: 0.96, 95% CI: 0.43–2.17; p = 0.93, I²= 0%) (Figure 2) or insulin infusion (OR: 1.72, 95% CI: 0.83–3.55; p = 0.15, I²= 36%) (Supplementary Figure S7). Pooled analysis with meta-regression revealed that corticosteroids dose was significantly related to the variation in the mechanical ventilation time (exp: 1.004, 95% CI: 1.002–1.006; p < 0.0001), but not the variation in the other clinical outcomes (Supplementary Figures S18–S26). Funnel plots failed to reveal evidence of publication bias regarding mortality, myocardial infarction, pulmonary complications, kidney injury, postoperative infection, and neurological complications (stroke) (Supplementary Figures S27–S32). However, the funnel plots suggested that there might be some publication bias regarding new atrial fibrillation, mechanical ventilation time, and hyperglycemia requiring insulin infusion (Supplementary Figures S33–S35). Thus, we used the trim and fill method to adjust the analysis, which did not significantly alter the findings.

During pediatric cardiac surgery with CPB, corticosteroids prophylaxis was associated with a decreased CPB time (MD: −11.54 min, 95% CI: −14.32, −8.75 min; p < 0.001, I²= 5%) and an increased insulin infusion (OR: 3.68, 95% CI: 1.53–8.84; p = 0.004, I²= 48%), but did not significantly influence mortality, kidney injury, ECMO use, postoperative infection, mechanical ventilation time, and ICU length of stay [LOS] (Tables 2, 3 and Supplementary Figures S36–S43). Relative to placebo and higher dose corticosteroids (>50 mg/kg hydrocortisone), corticosteroids prophylaxis (≤50 mg/kg hydrocortisone) significantly reduced the risk of kidney injury (OR: 0.29, 95% CI: 0.09–0.96; p = 0.04, I²= 49%) (Table 2 and Supplementary Figure S39). Meta-regression revealed that corticosteroids dose was not related to the variations in mortality (exp: 0.998, 95% CI: 0.981–1.015; p = 0.734) or the duration of CPB (exp: 1.000, 95% CI: 0.993–1.008; p = 0.89) (Supplementary Figures S44, S45). The funnel plots failed to reveal evidence of publication bias regarding mortality, kidney injury, postoperative infection, and ICU LOS (Supplementary Figures S46–S49). However, the funnel plots suggested that there might be some publication bias regarding mechanical ventilation time and CPB duration (Supplementary Figures S50–S51). Thus, we used the trim and fill method to adjust the analysis, which did not significantly alter the findings.

Discussion

This meta-analysis revealed that corticosteroids prophylaxis during cardiac surgery with CPB was associated with significantly decreased blood inflammatory factor concentrations of CRP, TNF-α, IL-6, and IL-8. During adult cardiac surgery, corticosteroids prophylaxis reduced the risks of postoperative atrial fibrillation and re-intubation, shortened the ICU and hospital LOSs, and reduced postoperative bleeding, although it was associated with increased risks of myocardial infarction and hyperglycemia requiring insulin infusion. Interestingly, the benefits among adult patients were largely attributable to low-dose corticosteroids use (≤20 mg/kg hydrocortisone), as the benefits were not observed among patients who received higher corticosteroids doses. In addition, low-dose corticosteroids significantly reduced the mechanical ventilation time without increasing the risks of myocardial infarction and insulin infusion, while high-dose corticosteroids were associated with increased risks of myocardial infarction and prolonged mechanical ventilation. During pediatric cardiac surgery, corticosteroids prophylaxis was associated with a shortened CPB time, an increased risk of insulin infusion, and no substantial changes in terms of mortality, ECMO use, postoperative infection, mechanical ventilation time, and ICU LOS. Moreover, corticosteroids prophylaxis (≤50 mg/kg hydrocortisone) significantly reduced the risk of kidney injury in pediatric patients.

The SIRS plays a vital role in the development of complications after cardiac surgery with CPB (1). Corticosteroids can effectively inhibit SIRS and reduce inflammatory factor concentrations, which provides a theoretical basis for prophylactic administration during cardiac surgery with CPB (2–10). However, several RCTs have indicated that corticosteroids prophylaxis did not provide significant benefits to patients undergoing cardiac surgery with CPB, and was instead associated with an increased risk of myocardial infarction and prolonged mechanical ventilation (10, 13, 14, 19). Thus, the adult cardiac surgery guidelines, as well as routine practice for adult and pediatric cardiac surgery with CPB, involve limited or no prophylactic corticosteroids (16). However, corticosteroids exert dose-dependent anti-inflammatory effects and clinical side effects (3, 4, 7). Thus, we hypothesized that an appropriate dosage range might effectively inhibit SIRS and provide clinical benefits without major side effects, as the optimal corticosteroids dose would protect cardiomyocytes rather than damage them.

Our results revealed that corticosteroids prophylaxis reduced the blood concentrations of various inflammatory markers after cardiac surgery, including CRP, TNF-α, IL-6, and IL-8. These findings support the prophylactic administration of corticosteroids to prevent SIRS after cardiac surgery with CPB (8–10). However, we did not detect any significant change in mortality, which is consistent with the results of previous studies (5–7, 13, 14, 19). This may be related to advanced cardiac surgery management and active treatment of complications in the current era.

The SIRS trial and Ho et al.’s meta-analysis of 50 small RCTs revealed that corticosteroids prophylaxis in adults significantly increased the risks of myocardial infarction and hyperglycemia requiring insulin infusion (6, 14). In this context, high doses of corticosteroids can rapidly and significantly induce insulin resistance, reduce cellular utilization of glucose, and cause hyperglycemia (20). Hyperglycemia downregulates glyoxalase 1 and glyoxalase 2, which inhibits the post-injury repair of cardiomyocytes (21). This may be the main mechanism through which high-dose corticosteroids induce myocardial infarction. We found that corticosteroids (>20 mg/kg hydrocortisone), but not low-dose corticosteroids, increased the risk of myocardial infarction and hyperglycemia requiring insulin infusion in adults. This may be because low-dose corticosteroids inhibit SIRS and protect cardiomyocytes, without substantially impairing glucose utilization. We did not observe a substantial change in this relationship when we re-analyzed data from 18 high-quality RCTs (Jadad score of ≥4, 18/25 trials), which all adopted the general definition of myocardial infarction and used cardiac biomarkers to predict its occurrence. In children, corticosteroids increased the use of insulin but did not significantly influence the risk of myocardial infarction, which may be related to neonatal cardiomyocytes having increased glucose uptake and utilization (22).

The DECS trial (13) and the SIRS trial (14) revealed that corticosteroids prophylaxis did not reduce the risk of atrial fibrillation in adult patients after cardiac surgery. However, meta-analyses by Ho et al. (6) and Ng et al. (7) revealed that corticosteroids prophylaxis could significantly reduce the incidence of atrial fibrillation. Ho et al. (6) reported that both low-dose and high-dose corticosteroids could significantly reduce the risk of atrial fibrillation. Ng et al.’s meta-analysis included the DECS and SIRS trials, but did not include a stratified dose analysis (7). Interestingly, we found that only low-dose corticosteroids (≤20 mg/kg hydrocortisone) were effective for reducing the risk of atrial fibrillation, with no positive effects observed at a slightly higher dose (20–40 mg/kg hydrocortisone), a high dose (40–100 mg/kg hydrocortisone), or an ultra-high dose (>100 mg/kg hydrocortisone). These findings were not noticeably different when we re-analyzed 27 high-quality RCTs (27/33 RCTs), with low heterogeneity and no detectable publication bias. Unfortunately, the relevant molecular mechanisms are not clear, although the SIRS can induce atrial fibrillation (23). Thus, we speculate that low-dose corticosteroids might inhibition SIRS without increasing cardiomyocyte damage, which would reduce the incidence of atrial fibrillation. In contrast, high-dose corticosteroids might reduce SIRS but increase cardiomyocyte damage, which would not reduce the risk of atrial fibrillation.

The SIRS can cause systemic multi-organ damage, which often involves kidney damage (5–7). Prophylactic administration of corticosteroids protects the tissues and organs by inhibiting SIRS and thus reduces complications (8–10). We failed to identify significant effects of corticosteroids prophylaxis on the risks of pulmonary complications, neurological complications (stroke), gastrointestinal bleeding, and delirium, which might be related to the low incidences of those outcomes. However, prophylactic corticosteroids (≤50 mg/kg hydrocortisone) significantly reduced the risk of kidney injury in pediatric patients, and low-dose corticosteroids (≤20 mg/kg hydrocortisone) might reduce the risk of kidney injury in adult patients. While corticosteroids suppress the normal immune response and may increase the risk of postoperative infection (7), our results and those from previous studies suggest that corticosteroids prophylaxis did not influence the risk of postoperative infection (6, 13, 14). Ho et al. (6) reported that corticosteroids prophylaxis was closely associated with prolonged mechanical ventilation, and we found that low-dose corticosteroids (≤20 mg/kg hydrocortisone) significantly shortened the mechanical ventilation duration for adult patients, while high doses (>100 mg/kg hydrocortisone) significantly prolonged the mechanical ventilation duration. We also found that low-dose corticosteroids significantly reduced the ICU and hospital LOSs for adult patients, which might be related to accelerated recovery that was caused by suppression of the SIRS and reduced tissue and organ damage. Therefore, corticosteroids may be a cost-effective prophylactic treatment (generally <$5/patient) that can help reduce the burden on patients and hospitals by decreasing the risks of complications and shortening the ICU and hospital LOSs. Furthermore, the lower risk of complications may improve patients’ perioperative quality of life.

Our meta-analysis considered the dose-dependent benefits and risks of prophylactic corticosteroids during adult and pediatric cardiac surgery based on 29 clinical outcomes. Our findings conflict with the lack of support for corticosteroids prophylaxis during cardiac surgery in previous studies (5–7, 13, 14) and the guidelines for adult cardiac surgery (16). Our results suggest that low-dose corticosteroids (≤20 mg/kg hydrocortisone) were not associated with a significant reduction in mortality, but might substantially benefit adult patients by inhibiting SIRS and reducing complications. Therefore, we recommend prophylactic administration of low-dose corticosteroids (≤20 mg/kg hydrocortisone) during adult cardiac surgery. However, the optimal dose range for corticosteroids prophylaxis during pediatric cardiac surgery is unclear, as we only identified a small number of related RCTs. Nevertheless, our results indicate that high-dose glucocorticoids did not provide any benefits and significantly increased insulin use, which may increase the risk of hyperglycemia and related complications.

The evidence from our study was judged to be high based on the GRADE system. The low-dose subgroup for adult cardiac surgery (≤20 mg/kg hydrocortisone) only included 14 small RCTs, although 10 of these RCTs were considered high-quality based on the Jadad scores. Thus, large multi-center RCTs are needed as an additional source of evidence to clarify efficacy and optimal dose range for low-dose prophylactic corticosteroids during adult and pediatric cardiac surgery with CPB.

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