Cardiac operations with the use of cardiopulmonary bypass (CPB) induce an intense generalized inflammatory system activation that could affect clinical outcomes (1–4).
Blood contact with artificial surfaces of the circuits, hypothermia, ischemia-reperfusion injury, hemodilution, continuous blood flow and flow turbulences, hemolysis, and air and solid embolism are some of the factors that, together with surgical trauma, contribute to the systemic inflammatory response syndrome (SIRS) development (5).
Many strategies should be adopted to reduce inflammatory system activation, but the most common pharmacological treatment is perioperative steroid administration.
Perioperative steroid administration reduces early inflammatory processes, such as increased capillary permeability, subsequent edema formation, and leukocyte migration.
The anti-inflammatory effects of glucocorticoid therapy after CPB have been demonstrated (6).
Synthetic steroid molecules decrease pro/anti-inflammatory interleukins ratio, thus limiting the deleterious effects of massive inflammation activation induced by CPB (7), but benefits on clinical outcome are doubtful, probably related to the highly variable administration practices (8–20).
Limits for the use of steroids were related to their possible adverse effects: concern arise for infections due to immunosuppression despite steroids prophylaxis did not affect wound infections incidence in adult patients (21). So far only a nonrandomized observational analysis evidenced that steroid administration was associated with greater infection rate and greater insulin use in pediatric patients (13).
Few studies have prospectively evaluated the effects of steroid administration in pediatric patients undergoing CPB surgery, but the results of these studies are inconclusive due to limited number of patients.
We performed a systematic review of the literature and conducted a meta-analysis restricted to randomized controlled trials (RCTs) to determine the effects of steroid treatment on mortality and outcomes (acute kidney injury [AKI], length of stay in ICU, and duration of mechanical ventilation) in pediatric cardiac surgery patients.
MATERIALS AND METHODS
We screened PubMed and Cochrane databases until August 2013. The search strategies were restricted for human randomized clinical trials and English language.
The number 1 search was “cardiac surgery,” “valve surgery,” “coronary surgery,” OR “cardiopulmonary bypass OR extracorporeal circulation” (PubMed, 5,587 citations; Cochrane, 4,313 citations).
The number 2 search was “glucocorticoid OR steroid OR hydrocortisone OR dexamethasone OR methylprednisolone” (PubMed, 51,952 citations; Cochrane, 18,943 citations).
The number 3 search was “infant OR congenital OR pediatric OR pediatric OR children OR neonatal” (PubMed, 95,195 citations; Cochrane, 82,989 citations).
The last searches combined number 1 and number 2 and number 3 (PubMed, 48 citations; Cochrane, 32 citations).
Criteria for Considering Studies for This Review
RCTs published in English language involving pediatric patients undergoing elective or emergency cardiac surgery operations were included.
Titles and abstracts of all electronic citations were independently screened by three trained researchers (G.S., C.R., D.P.), and they were retrieved for full-text review if considered relevant. Furthermore, a manual screening of reference lists of the selected articles and pertinent reviews was performed to identify other possible studies.
Study Eligibility and Selection
Studies in which steroids were administered preoperatively were considered eligible.
Exclusion criteria were 1) lack of any data regarding mortality, 2) for subanalysis a lack of any data regarding the renal endpoints (renal function assessed by serum creatinine or creatinine clearance/glomerular filtration rate, data about AKI development, or renal replacement therapy (RRT) reported in tables or in the Results section) and duration of mechanical ventilation and ICU stay, 3) combination of other confounding treatments, 4) a lack of a placebo group, and 5) a lack of a randomized design.
Renal outcomes were collected regardless of whether they were considered outcomes of the studies. Comparison was with placebo group or with standard of care of each institution.
Mortality was intended as hospital mortality. AKI definitions (if defined) were not uniform, and criteria for RRT initiation were not reported or standardized across all studies.
Figure 1 depicts the flow chart of this selection process performed according to Quality of Reporting of Meta-analyses standards (22).
Three authors (G.S., D.P., C.R.) assessed the quality of the trials using the Jadad score (23). Jadad score ranges from 0 to 5 and a score of 5 corresponds to “best” quality.
The primary outcome was all-cause in-hospital mortality, and it was evaluated on all identified RCT. The secondary outcomes were duration of mechanical ventilation, ICU length-of-stay duration, and AKI (as defined and reported in each study by the authors using one of the definitions for AKI). Considering the heterogeneous AKI definitions (renal failure, acute renal failure, acute kidney disease, and renal complications) and the lack of description of criteria for RRT, renal outcomes have been unified as worsening renal function (WRF).
Two authors (G.S., C.R.) independently extracted in duplicate the following data from full-text articles: year of publication, country of origin, study design, type of surgery, patient characteristics (sex, mean age, weight, and height), type and timing of interventions, aortic cross-clamp and CPB time, ICU length of stay, duration of mechanical ventilation, outcomes for creatinine, creatinine clearance/glomerular filtration rate, prevalence of AKI, RRT, and mortality. Disagreements were resolved through consensus.
Odds ratio (OR) was used to estimate the treatment effects. Individual study ORs with 95% CIs were calculated. Overall summary ORs were obtained by random-effects modeling of the binary data from the multiple 2 × 2 tables by using the metan module in STATA software, version 12 (StataCorp, College Station, TX). Forest plots were used to visualize heterogeneity among studies. We evaluated I2 as test for heterogeneity across studies. Continuous variables were compared using analysis of variance given the mean, SD, and number of subjects in each study group. p value of less than 0.05 was considered statistically significant.
A total of 80 citations (PubMed, 48 citations; Cochrane, 32 citations) were identified, of which 14 articles were analyzed in depth, and after screening, six articles fulfilled eligibility criteria and reported mortality data (232 patients) (9, 10, 14, 18–20). Only two articles (49 patients) reported data for renal outcomes (18, 20) and two studies evaluated mechanical ventilation time and ICU length of stay (60 patients) (10, 18). Table 1 summarizes the main characteristics of the studies.
In 40 patients randomized in two groups, IV methylprednisolone administration (30 mg/kg) significantly favorably modified pro/anti-inflammatory balance, but blood glucose levels were significantly higher in treatment group. Despite a significant limitation of inflammatory response, clinical or outcome measurements were similar in both groups (10).
Heying et al (14) reported that in 20 neonates, pretreatment with dexamethasone (1 mg/kg) generated a down-regulation of proinflammatory and up-regulation of anti-inflammatory cytokines, but no differences were appreciated for mortality or other outcomes.
In 20 neonates undergoing complete biventricular repair assigned to receive hydrocortisone or placebo, Ando et al (18) reported no mortality in both groups and a shorter duration of mechanical ventilation (83.5 ± 42.1 vs 138.2 ± 89.7 hr; p = 0.098) in the hydrocortisone group. Peritoneal dialysis was used in six patients in placebo group and in one patient in treatment group (p = 0.019), and urinary output was higher in hydrocortisone group.
Checchia et al (19) reported significantly lower mean cardiac troponin I levels at 24 hours in dexamethasone-treated patients suggesting a possible cardioprotective effect. They reported no differences for adverse effects, such as wound infection, reoperation for bleeding, or gastrointestinal bleeding.
Bronicki et al (20) reported that dexamethasone administration (1 mg/kg) reduced inflammatory response in 30 children. One patient in dexamethasone group and seven patients in control group had an increase in creatinine levels compared with baseline levels. Besides a lower alveolar-arterial oxygen gradients during the first 24 hours, shorter mechanical ventilation duration (3 d vs 5 d; p = 0.02) and ICU length of stay (4 d vs 7 d; p =0.01) were reported in treated patients.
Repeated methylprednisolone (30 mg/kg) dose administration was evaluated by Toledo-Pereyra et al (9), reporting no hemodynamic or biochemical differences but an improvement in survival.
A small number of patients characterizes all studies, but one was designed to evaluate circulating biomarkers, and none of them reported information about the adequacy of the sample size.
None of the studies included in the analysis (9, 10, 14, 18–20) had a Jadad score lower than 2.
The test for heterogeneity of effects for steroid treatment, although size and quality score of the studies differed considerably, was not significant (I2, 23%; p =0.273) (Fig. 2).
Meta-Analysis of the Effects of Treatment on Mortality, ICU Length of Stay, Mechanical Ventilation Time, and Renal Function
No differences were reported for postoperative mortality. Steroid administration (11 [4.7%] vs 4 [1.7%] patients; OR, 0.41; 95% CI, 0.14–1.15; p = 0.089) had no effects on mortality rates (Fig. 2).
Steroid administration had no effects on duration of mechanical ventilation (117.4 ± 95.9 hr vs 137.3 ± 102.4 hr; p = 0.43) and ICU length of stay (9.6 ± 4.6 d vs 9.9 ± 5.9 d; p = 0.8) in treated versus control patients, respectively.
Perioperative administration of steroids in pediatric cardiac surgery patients reduces WRF prevalence (13 [54.2%] vs 2 [8%] patients; OR, 0.07; 95% CI, 0.01–0.38; p = 0.002).
The present systematic literature review suggests that in pediatric cardiac surgery patients, there is large variability of information about clinical effects of steroid administration.
In its biochemical aspects, perioperative steroid administration significantly attenuates CPB-induced systemic inflammatory response (5, 10, 14).
The intense and unregulated response, associated to coagulation system activation, leads to microcirculation abnormalities and possible multiple end-organ dysfunctions that can influence postoperative complications rate (1–4, 24).
Steroid administration had no significant effects on mortality rate, although a trend of reduced mortality was observed in steroid-treated patients. Our data call for an adequately designed prospective clinical trial to ascertain the real short- and medium-term benefits and risks of steroid administration in pediatric cardiac surgery patients. The trial should confirm that the reduction of the systemic and pulmonary inflammatory response might protect patients from prolonged need of mechanical ventilation and ICU stay.
Several confounding factors such as the use of different drugs and different administration protocols reduce the accuracy of many little studies. It should be desirable and worthwhile in an adequately powered RCT to focus the attention not to a long-lasting compound as dexamethasone, considering the usually short-lived inflammatory response to cardiac surgery, but to a low-dose medium acting drug as methylprednisolone, considering the proven benefits and lower side effects of low-dose corticosteroid when compared with higher dose (25). A subsequent comparison of two different drugs might be useful to better define the best immune-modulatory strategy.
Respiratory dysfunction after pediatric cardiac surgery is a common complication that negatively influences postoperative morbidity. In addition to cardiac performance alterations, fluids overload, inadequate intraoperative left heart decompression, neuromuscular weakness, bronchial secretions atelectasis, diaphragmatic paralysis, and SIRS due to CPB use play an important role in respiratory dysfunction. In fact, lungs, representing a large vascular bed, are susceptible to endothelial dysfunction related to inflammatory injuries, and it had been demonstrated that endothelial dysfunction increases vascular permeability and extravascular lung water, leading to interstitial and alveolar edema and impaired surfactant function (26).
Probably preserving microvascular structural integrity, steroid administration decreases pulmonary and systemic capillary leak improving arterial oxygenation with better respiratory gas exchange or less mechanical ventilation time (20, 27), but these encouraging results had to be confirmed in a large population of patients.
Our meta-analysis shows that steroids prophylaxis effectively reduces WRF. Although the small number of studies retained in our meta-analysis, and different compounds used makes it difficult to affirm the effectiveness of steroid administration on AKI, a possible role of steroid administration should be considered.
In general PICUs the reported incidence of AKI is approximately 58%, while after pediatric cardiac operations surgery the incidence varies from 5% to 33%, an event that increases patients’ mortality risk (28, 29).
In AKI development, a key role is played by local inflammatory activation, but during CPB, systemic activation is also important. In fact, a renal insult (ischemic, toxic agent, etc.) generates morphological and functional changes in vascular endothelial cells and in tubular epithelium: an acute ischemic insult promotes the activation of endothelial renal cells, with a contribution to the inflammatory reaction and loss of vascular blood flow self-regulation (30) and endothelial continuity, increased vascular permeability, and expression of adhesion molecules (31, 32).
Robertson-Malt et al (33) systematically reviewed the beneficial and harmful effects of the prophylactic administration of corticosteroids, compared with placebo, in pediatric open heart surgery but considering patients receiving corticosteroids preoperatively, perioperatively, or postoperatively. All-cause mortality was not assessed for incomplete data reports, but they found weak evidence in favor of prophylactic corticosteroid administration for reducing ICU stay and duration of ventilation.
A recent observational analysis of Pediatric Health Information System database conduced on 46,730 pediatric patients (0–18 yr) evidenced that steroid administration had no significant effects on mortality or duration of ventilation but was associated with longer length of stay, greater infection, and greater use of insulin. Besides, stratifying by Risk Adjustment in Congenital Heart Surgery Version 1 categories, no significant benefit was seen in any group, and the association of corticosteroid with increased morbidity was most prominent in the lower risk groups (13).
Clinical data from the Society of Thoracic Surgeons database were linked to medication data from the Pediatric Health Information Systems database for 3,180 neonates (< 30 d) undergoing heart surgery in 25 centers to evaluate outcomes across different methylprednisolone regimens versus no steroid administration. Multivariable analysis showed no significant mortality or length-of-stay benefit associated with any methylprednisolone regimen versus no steroids and no difference for postoperative infection, but a significant association of methylprednisolone with infection was detected in the lower-surgical-risk group (34).
In low-risk patients, the risk/benefit balance of corticosteroid therapy is shifted toward favoring relatively greater risk probably because low-risk operations are usually associated with shorter CPB times and attenuated inflammatory response compared with longer CPB times, thus reducing the potential expected benefits deriving from the immune-modulatory properties of corticosteroids. However, these speculations deserve specific prospective evaluations in RCTs.
Inflammatory system activation happens during pediatric cardiac surgery, and perioperative steroid administration reduces its intensity. This is the first meta-analysis evaluating only RCTs, but despite systematic literature review, the number of patients analyzed is limited. No significant effect on hospital mortality was demonstrated, but a significant reduction of renal function deterioration was associated with steroid treatment. The indisputable clinical benefit of steroid administration in pediatric patients should be explained by a large RCT such as the forthcoming SIRS trial (http://www.clinicaltrials.gov/ct2/show/NCT00427388) for adult cardiac surgery patients, in which methylprednisolone is compared with placebo with the aim to evaluate if drug administration reduces 30-day all-cause mortality in high-risk patients.
1. Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg. 1994;108:626–635
2. Gaudino M, Andreotti F, Zamparelli R, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108(Suppl 1):II195–199
3. Holmes JH 4th, Connolly NC, Paull DL, et al. Magnitude of the inflammatory response to cardiopulmonary bypass and its relation to adverse clinical outcomes. Inflamm Res. 2002;51:579–586
4. Jimenez JJ, Iribarren JL, Lorente L, et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: A case control study followed by a randomized double-blind controlled trial. Crit Care. 2007;11:R117
5. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: Pathophysiology and treatment. An update. Eur J Cardiothorac Surg. 2002;21:232–244
6. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: Pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg. 1997;85:766–782
7. Taniguchi T, Koido Y, Aiboshi J, et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med. 1999;27:1262–1264
8. Kawamura T, Inada K, Nara N, et al. Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med. 1999;27:545–548
9. Toledo-Pereyra LH, Lin CY, Kundler H, et al. Steroids in heart surgery: A clinical double-blind and randomized study. Am Surg. 1980;46:155–160
10. Keski-Nisula J, Pesonen E, Olkkola KT, et al. Methylprednisolone in neonatal cardiac surgery: Reduced inflammation without improved clinical outcome. Ann Thorac Surg. 2013;95:2126–2132
11. Graham EM, Atz AM, Butts RJ, et al. Standardized preoperative corticosteroid treatment in neonates undergoing cardiac surgery: Results from a randomized trial. J Thorac Cardiovasc Surg. 2011;142:1523–1529
12. Mastropietro CW, Barrett R, Davalos MC, et al. Cumulative corticosteroid exposure and infection risk after complex pediatric cardiac surgery. Ann Thorac Surg. 2013;95:2133–2139
13. Pasquali SK, Hall M, Li JS, et al. Corticosteroids and outcome in children undergoing congenital heart surgery: Analysis of the Pediatric Health Information Systems database. Circulation. 2010;122:2123–2130
14. Heying R, Wehage E, Schumacher K, et al. Dexamethasone pretreatment provides antiinflammatory and myocardial protection in neonatal arterial switch operation. Ann Thorac Surg. 2012;93:869–876
15. Gessler P, Hohl V, Carrel T, et al. Administration of steroids in pediatric cardiac surgery: Impact on clinical outcome and systemic inflammatory response. Pediatr Cardiol. 2005;26:595–600
16. Lindberg L, Forsell C, Jögi P, et al. Effects of dexamethasone on clinical course, C-reactive protein, S100B protein and von Willebrand factor antigen after paediatric cardiac surgery. Br J Anaesth. 2003;90:728–732
17. Checchia PA, Bronicki RA, Costello JM, et al. Steroid use before pediatric cardiac operations using cardiopulmonary bypass: An international survey of 36 centers. Pediatr Crit Care Med. 2005;6:441–444
18. Ando M, Park IS, Wada N, et al. Steroid supplementation: A legitimate pharmacotherapy after neonatal open heart surgery. Ann Thorac Surg. 2005;80:1672–1678
19. Checchia PA, Backer CL, Bronicki RA, et al. Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass. Crit Care Med. 2003;31:1742–1745
20. Bronicki RA, Backer CL, Baden HP, et al. Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2000;69:1490–1495
21. Cappabianca G, Rotunno C, de Luca Tupputi Schinosa L, et al. Protective effects of steroids in cardiac surgery: A meta-analysis of randomized double-blind trials. J Cardiothorac Vasc Anesth. 2011;25:156–165
22. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. QUOROM Group. Br J Surg. 2000;87:1448–1454
23. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:1–12
24. Boyle EM Jr, Pohlman TH, Johnson MC, et al. Endothelial cell injury in cardiovascular surgery: The systemic inflammatory response. Ann Thorac Surg. 1997;63:277–284
25. Ho KM, Tan JA. Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: A dose-response meta-analysis. Circulation. 2009;119:1853–1866
26. McGowan FX Jr, Ikegami M, del Nido PJ, et al. Cardiopulmonary bypass significantly reduces surfactant activity in children. J Thorac Cardiovasc Surg. 1993;106:968–977
27. Schroeder VA, Pearl JM, Schwartz SM, et al. Combined steroid treatment for congenital heart surgery improves oxygen delivery and reduces postbypass inflammatory mediator expression. Circulation. 2003;107:2823–2828
28. Plötz FB, Bouma AB, van Wijk JA, et al. Pediatric acute kidney injury in the ICU: An independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34:1713–1717
29. Pedersen KR, Povlsen JV, Christensen S, et al. Risk factors for acute renal failure requiring dialysis after surgery for congenital heart disease in children. Acta Anaesthesiol Scand. 2007;51:1344–1349
30. Molitoris BA, Sandoval R, Sutton TA. Endothelial injury and dysfunction in ischemic acute renal failure. Crit Care Med. 2002;30:S235–S240
31. Akcay A, Nguyen Q, Edelstein CL. Mediators of inflammation in acute kidney injury. Mediators Inflamm. 2009;2009:137072
32. Edelstein CL, Schrier RWSchrier RW. Pathophysiology of ischemic acute renal injury. Diseases of the Kidney and Urinary Tract. 2007Eighth Edition Philadelphia, PA R. Lippincott Williams & Wilkins:930–961 In
33. Robertson-Malt S, Afrane B, El Barbary M:. Prophylactic steroids for pediatric open heart surgery. Cochrane Database Syst Rev. 2007;;4:CD005550
34. Pasquali SK, Li JS, He X, et al. Perioperative methylprednisolone and outcome in neonates undergoing heart surgery. Pediatrics. 2012;129:e385–e391
cardiac surgical procedures; cardiopulmonary bypass; hospital mortality; inflammation; postoperative complications; steroids
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