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. Author manuscript; available in PMC: 2015 Mar 1.
Published in final edited form as: J Thorac Cardiovasc Surg. 2013 Jul 16;147(3):902–908. doi: 10.1016/j.jtcvs.2013.06.010

Preoperative Steroid Treatment Does Not Improve Markers of Inflammation Following Cardiac Surgery in Neonates: Results from a Randomized Trial

Eric M Graham 1, Andrew M Atz 1, Kimberly E McHugh 1, Ryan J Butts 1, Nathaniel L Baker 1, Robert E Stroud 1, Scott T Reeves 1, Scott M Bradley 1, Francis X McGowan Jr 1, Francis G Spinale 1
PMCID: PMC3864609  NIHMSID: NIHMS506830  PMID: 23870160

Abstract

Objective

Neonatal cardiac surgery requiring cardiopulmonary bypass results in a heightened inflammatory response. Perioperative glucocorticoid administration is commonly utilized in attempt to reduce the inflammatory cascade, although characterization of the cytokine response to steroids in neonatal cardiac surgery remains elusive due to highly variable approaches in administration. This randomized trial was designed to prospectively evaluate the effect of specific glucocorticoid dosing protocols on inflammatory markers in neonatal cardiac surgery requiring cardiopulmonary bypass.

Methods

Neonates scheduled for cardiac surgery were randomly assigned to receive either two-dose (8 hours preoperatively and operatively, n=36) or single dose (operatively, n=32) methylprednisolone at 30mg/kg/dose in a prospective double-blind trial. The primary outcome was the effect of these steroid regimens on markers of inflammation. Secondary analyses evaluated the association of specific cytokine profiles with postoperative clinical outcomes.

Results

Patient demographics, perioperative variables and preoperative indices of inflammation were similar between the single and two-dose groups. Preoperative cytokine response after the two-dose methylprednisolone protocol was consistent with an anti-inflammatory effect, although this did not persist into the postoperative period. Pre-medication baseline levels of interleukin-6, interleukin-8, interleukin-10 and tumor necrosis factor alpha were predictive of postoperative intensive care unit and hospital length of stay. Only interleukin-8 demonstrated a postoperative response associated with duration of intensive care unit and hospital stay.

Conclusions

The addition of a preoperative dose of methylprednisolone to a standard intraoperative methylprednisolone dose does not improve markers of inflammation following neonatal cardiac surgery. The routine administration of preoperative glucocorticoids in neonatal cardiac surgery should be reconsidered.

This is the largest pediatric and only exclusively neonatal randomized trial examining the anti-inflammatory effect of two different methylprednisolone dosing regimens for neonates requiring cardiac surgery. The addition of a preoperative dose of methylprednisolone to a standard intraoperative methylprednisolone dose does not improve markers of inflammation following neonatal cardiac surgery.

Introduction

Cardiopulmonary bypass (CPB) is a complex pathophysiologic environment in which exposure to non-physiologic surfaces in the pump circuit, hemolysis and ischemia-reperfusion injury combine to initiate a complex cascade that includes pro-inflammatory cytokines, anti-inflammatory cytokines and products of neutrophil activation.1-3 The inflammatory consequences from CPB culminate in a systemic inflammatory response syndrome (SIRS). The SIRS is further exacerbated in neonates due to morbidity factors of smaller patient size, greater hemodilution, hypothermia, and longer CPB times, resulting in a postoperative recovery period that is longer and more complex than similar operations performed in older infants and children.4-6

Clinical appreciation of this post-CPB inflammatory response has resulted in a number of interventions directed toward its reduction.7-9 Glucocorticoid administration is among the most common methods to attenuate the clinical and biochemical features of the post-CPB inflammatory response, although the technique of steroid administration in neonatal cardiac surgery is highly variable.8,9 To further confound matters, the limited number of studies investigating clinical outcomes associated with the use of corticosteroids in children requiring CPB yield contradictory results.10-13

Given the intertwined and redundant inflammatory cascade and the highly variable clinical practices in neonatal preoperative and intraoperative care, characterizing the anti-inflammatory response of steroids in neonatal cardiac surgery has remained elusive. Accordingly, this randomized trial was designed to prospectively evaluate the effect of uniform and specific glucocorticoid dosing protocols on inflammatory markers in the context of neonatal cardiac surgery requiring CPB.

Methods

Patient Selection, Enrollment and Randomization

The study was approved by the Institutional Review Board and informed written consent was obtained from the parent or legal guardian in accordance with all policies and regulations regarding obtaining informed consent of a minor. The study was part of a clinical outcomes trial and the design details and clinical outcomes have been published (ClinicalTrials.gov Identifier: NCT00934843).10 In brief, inclusion criteria consisted of all inpatient neonates (aged ≤ 30 days) scheduled to undergo a cardiac operation requiring CPB. Exclusion criteria included prematurity (defined as ≤36 weeks postmenstrual age) at the time of surgery, treatment with steroids in the 2 weeks prior to surgery, suspected infection that would contraindicate steroid use (eg, herpes), known hypersensitivity to methylprednisolone (MP) or other contraindication to steroid therapy (eg, gastrointestinal bleeding). Subjects were randomly assigned to either preoperative placebo (∼8 hours preoperatively) and intraoperative MP at 30 mg/kg of body weight (Single Dose group) or preoperative and intraoperative MP (Two Dose group) within strata according to planned corrective or palliative operation. All investigation and clinical site personnel were blinded to the treatment allocation until the close of the study.

Outcome Variables

The primary outcome was markers of inflammation following administration of specific glucocorticoid dosing protocols. The correspondence of cytokine profiles with clinical outcomes such as low cardiac output syndrome (LCOS), intensive care unit (ICU) and hospital stay were investigated in secondary analyses. The presence of LCOS was defined by the clinicial signs and symptoms of low cardiac output (eg, tachycardia, oliguria, cold extremities, cardiac arrest) that require 1 or more of the following inte: mechanical circulatory support, the escalation of exisiting pharmacologic circulatory support to more than 100% over baseline, or the inititation of new pharmacologic circulatory support.14 The determination of LCOS was made by 2 independent reviewers and then agreed on between both reviewers before unblinding. Markers of inflammation were compared between treatment groups which included the plasma levels of the pro-inflammatory cytokines interleukin (IL)-2, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) and the anti-inflammatory cytokine IL-10. The rationale for the selection of these cytokines was to survey both pro and anti-inflammatory markers. Samples were collected at 6 timepoints: 1) “Baseline” prior to preoperative placebo/MP treatment (∼8 hours preoperatively), 2) immediately prior to skin incision, 3) upon completion of modified ultrafiltration, and at 4) 4 hours, 5) 12 hours and 6) 24 hours postoperatively. Whole blood samples of 1 mL were collected in EDTA tubes at each of the 6 timepoints. Plasma was isolated by centrifugation, decanted into aliquots and stored at -80°C until processed for immunoassays.

Plasma Levels of cytokines were determined by multiplex suspension array using commercially available and validated kits (R&D Systems, Minneapolis, MN).3 Plasma values were corrected for hemodilution using hematocrit values. All samples were batched and run simultaenously to avoid potential laboratory assay variance. Patients enrolled in the parent study were included in this analysis if they had an adequate volume of plasma at each of the 6 time points to analyze all inflammatory markers. Plasma free hemoglobin, as a measurement of hemolysis, was obtained postoperatively on arrival to the ICU.

Statistical Analysis

Standard descriptive statistics were used to summarize the general demographic and clinical data. Continuous demographic characteristics are listed as means and associated standard deviations and were compared between groups using a T-test. Categorical characteristics are expressed as the number and percentage of subjects and were compared using a normal Pearson's chi-square test statistic. Due to their skewed distributions, baseline measures of inflammatory markers are expressed as the median and interquartile range and are compared across steroid groups using a Wilcoxon rank sums test statistic. Preoperative indices of inflammation were measured at “baseline” prior to administration of the preoperative steroids (or placebo) and again prior to surgery (pre-incision). To appraise the pharmacologic effect of preoperative MP steroid dose on cytokine levels, an ANOVA model was used fitting the preoperative steroid levels while controlling for the baseline premedication levels.

In order to assess the effect of steroid treatment on the cytokine profiles following surgery, a linear mixed effect model was used. Restricted maximum likelihood (REML) methods were used to estimate the fixed effects and variance components in the presence of unbalanced data.15 Baseline cytokine values (pre-med), randomized treatment assignment and aprotinin use status were used as covariates in a regression model and estimate statements were used to construct group level mean tests across steroid treatment groups at each time point. All cytokine post-hoc pairwise comparison results are adjusted using the Bonferonni method. Due to the highly skewed and non-normal distributions of the markers of inflammation, the values were log10 transformed prior to model analysis.

To test whether baseline or peak cytokine levels are associated with clinical postoperative outcomes (ICU length of stay and hospital length of stay), regression models were developed that adjusted for study design variables (randomized steroid treatment group and aprotinin administration). Independent associations were present between gender and surgery type (corrective vs. palliative) with both ICU and hospital length of stay. Thus, all regression models were additionally adjusted for both characteristics. To test whether increases in baseline or peak cytokine levels are associated with higher odds to develop post-operative LCOS, similarly adjusted logistic regression models were developed. Statistical analyses were performed with SAS (version 9.2; SAS Institute, Inc, Cary, NC).

Results

Preoperative Demographics and Intraoperative Variables

Enrollment and outcomes have been previously reported.10 Briefly, 97 patients were screened for enrollment, 78 met all inclusion/exclusion criteria and were randomized. Two subjects did not receive interventions utilizing CPB and were excluded post randomization. The remaining 76 randomized patients were assigned to the preoperative placebo and intra-operative MP (Single Dose, n=37) or preoperative and intraoperative MP (Two Dose, n=39) protocol. Of the 76 subjects in the parent study, 68 patients had inflammatory markers measured at all 6 time points and were included in this analysis (Single Dose, n=32; Two Dose, n=36). Patient demographics, cardiac diagnoses, clinical characteristics, operative and immediate post-operative procedures were similar between groups (Table 1). Similarly, overall CPB times, cross-clamp times, the use of deep hypothermic circulatory arrest and immediate postoperative procedures were similar between the groups and have been previously reported.10 Mean plasma free hemoglobin levels upon arrival to the ICU was 71±36 mg/dl in the Single Dose group and 75±40 mg/dl in the Two Dose group, p=0.69.

Table 1.

Preoperative demographics and clinical characteristics in neonatal patients undergoing cardiac surgery; randomized to either a single or 2-dose methylprednisolone strategy.

Baseline demographic and clinical characteristics MP Single Dose n = 32 MP 2-Dose n = 36 P Value
Demographics
 Gestational age at birth (wks) 38.4 ± 1.4 38.9 ± 1.2 0.21
 Gestational age at surgery (wks) 39.5 ± 1.4 40.1 ± 1.5 0.08
 Age at surgery (days) 7.7 ± 4.3 8.7 ± 5.3 0.27
 Age ≤ 7 days, n (%) 25 (78) 22 (61) 0.13
 Weight at surgery (kg) 3.1 ± 0.5 3.3 ± 0.5 0.37
 Prenatal diagnosis, n (%) 14 (44) 18 (50) 0.61
 Male, n (%) 16 (50) 20 (56) 0.65
Markers of Inflammation
 IL-2 (pg/mL) 1.1 (0.9, 1.3) 1.2 (1.0, 1.3) 0.15
 IL-6 (pg/mL) 6.7 (3.5, 9.4) 8.8 (3.7, 21.2) 0.33
 IL-8 (pg/mL) 22 (17, 42) 31 (19, 47) 0.25
 IL-10 (pg/mL) 1.2 (0.8, 2.1) 1.4 (0.9-2.4) 0.45
 TNF-α (pg/mL) 6.8 (4.1, 8.7) 5.9 (4.2, 8.2) 0.56
 IFN-γ (pg/mL) 0.10 (0.09, 0.12) 0.11 (0.10, 0.13) 0.19
Diagnosis
 Corrective Procedure 17 (53) 19 (53) 0.97
 Aortic arch hypoplasia with VSD 3 5
 Tetralogy of Fallot 2 2
 Transposition of the great arteries 9 9
 Truncus arteriosis 1 2
 Other biventricular repair 2 1
 Palliative Procedure 15 (47) 17 (47)
 Hypoplastic left heart syndrome 5 8
 Other single ventricle lesions 8 7
 Pulmonary atresia with intact 0 2
 ventricular septum
 Tetralogy of Fallot with pulmonary atresia 2 0
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VSD, Ventricular septal defect; MP, methylprednisolone. Data are reported as mean ± standard deviation, number (%) or median (interquartile range) as appropriate.

Preoperative Indices of Inflammation

Prior to study drug administration, baseline cytokine levels were similar between groups (Table 1). Immediately prior to skin incision the pro-inflammatory cytokines IL-6 and TNF-α values fell by 40% or more (p<0.01, Figure 1A and 1D) and the anti-inflammatory cytokine IL-10 increased nearly 5 fold in the Two Dose group (p<0.01, Figure 1C), consistent with a pharmacologic effect of the preoperative MP dose. A pharmacologic response to preoperative MP occurred in the majority of patients in the Two Dose group, as evident by 92% (33/36) had a drop in IL-6 levels between these preoperative time points. Although absolute IL-8 values prior to skin incision were similar between groups, when adjusted for baseline values there was a significant effect of preoperative MP administration (p<0.01, Figure 1B). IL-2 and IFN-γ were low at baseline (Table 1) and not affected by preoperative MP administration.

Figure 1.

Figure 1

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Cytokine profile at baseline (at meds) and response to MP or placebo before CPB (pre-incision) and after CPB (0, 4, 12, and 24 hours following surgery) compared between treatment groups for logarithm transformed values of IL-6, IL-8, IL-10, and TNF-α. * p<0.05 (Bonferonni Adjusted).

Postoperative Indices of Inflammation

Dynamic changes in cytokine levels occurred in the post-operative period, indicative of altered inflammatory response in neonatal cardiac surgery. Robust increases in the pro-inflammatory responses of IL-6 and IL-8 occurred in the early postoperative period in both groups (p<0.01). These increases were similar between the Single and Two Dose group (Figure 1). Immediately following modified ultrafiltration, IL-6 levels in the Single Dose group remained numerically, but not significantly, higher than in the two dose group (p=0.054). The anti-inflammatory molecule IL-10 also had a significant increase in the postoperative period in both groups (p<0.01) and was higher in the Two Dose group immediately following modified ultrafiltration (p=0.001; Figure 1c), but was similar to the Single Dose group at all other postoperative time points. The pleotropic molecule TNF-α was higher in the Single Dose group immediately prior to CBP but failed to maintain this difference for the duration of the postoperative follow up.

Preoperative Indices of Inflammation and Outcomes

Baseline indices of a heightened inflammatory state were associated with clinical postoperative outcomes of interest. Of the 68 study participants, 29 (43%) experienced LCOS. For the entire cohort, mean ICU length of stay was 11.3 days (SD=16.5) and hospital stay was 23.5 days (SD=21.1), with no difference in these clinical outcomes between treatment groups. Higher levels of IL-6, IL-8 and IL-10 at baseline were significantly associated with increased post-operative ICU and hospital length of stay (all p<0.04, Table 2). Increased levels of TNF-α at baseline were modestly associated with ICU (p=0.057) and hospital (p=0.044) length of stay. None of the baseline cytokine measures were associated with LCOS following surgery (all p>0.15).

Table 2. Association Between Baseline and Peak Measures of Inflammation with Postoperative Outcomes.

Postoperative Outcomes
Measures of Inflammation ICU Length of Stay Hospital Length of Stay Low Cardiac O Syndrome output
(β ± SE P value (β ± SE P value OR (95% CI) P value
Baseline Levels
 Log10 IL-6 0.14 ± 0.06 0.039 0.18 ± 0.05 <0.001 0.49 (0.18-1.34) 0.162
 Log10 IL-8 0.28 ± 0.09 0.002 0.19 ± 0.07 0.012 1.54 (0.43-5.52) 0.510
 Log10 IL-10 0.23 ± 0.09 0.017 0.20 ± 0.08 0.013 0.55 (0.14-2.17) 0.395
 Log10 TNF-α 0.33 ± 0.17 0.057 0.29 ± 0.14 0.044 3.81 (0.33-43.8) 0.293
Postoperative Levels
 Log10 IL-6 0.08 ± 0.09 0.364 0.06 ± 0.08 0.414 1.15 (0.33-4.04) 0.822
 Log10 IL-8 0.33 ± 0.09 <0.001 0.26 ± 0.08 <0.001 2.39 (0.61-9.38) 0.213
 Log10 IL-10 0.02 ± 0.07 0.792 0.03 ± 0.06 0.585 1.24 (0.47-3.29) 0.664
 Log10 TNF-α 0.11 ± 0.12 0.371 0.16 ± 0.10 0.119 0.61 (0.12-3.26) 0.564
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Preoperative levels of inflammation measured prior to administration of study medication. Postoperative levels include the peak results measured after surgery. All analysis results shown are adjusted for study design variables (steroid treatment assignment and aprotinin administration), gender and surgery type. Both ICU and hospital length of stay were highly skewed and were also log10 transformed prior to analysis. Beta (β) estimates from mixed effects linear models are shown as β ± SE and logistic regression results are shown as Odds Ratio (OR) (95 % CI).

Postoperative Indices of Inflammation and Outcomes

Despite the association of baseline levels of cytokines with clinical outcomes, a similar association for most postoperative values was not found to be statistically significant. The postoperative response of the pro-inflammatory cytokine IL-8 was predictive of ICU and hospital stay (β=0.33 and β=0.26, respectively p<0.001, Table 2). None of the other postoperative measured cytokines were predictive of outcomes. Additionally, no peak cytokine response was predictive of LCOS.

Discussion

This prospective, randomized study utilizing two different MP dosing strategies yielded a balanced set of patients in each treatment arm and thereby provided control for a number of potentially confounding variables. The unique findings are 3-fold. First, while the Two Dose MP protocol reduced preoperative pro-inflammatory cytokines and increased anti-inflammatory cytokine levels, consistent with an anti-inflammatory effect, this effect did not persist into the postoperative period. Second, premedication baseline levels of IL-6, IL-8, IL-10 and TNF-α were associated with increased postoperative ICU and hospital lengths of stay. Third, while the baseline levels of several cytokines were predictive of postoperative outcomes, only the postoperative response of the pro-inflammatory cytokine IL-8 was associated with an increased duration of ICU and hospital stay. None of the other cytokines measured were associated with LCOS, ICU or hospital stay. The results from this randomized MP dosing protocol indicate that preoperative glucocorticoid treatment does not improve early postoperative markers of inflammation in neonatal cardiac surgery when compared to a single intraoperative dose. These observations suggest that a more critical evaluation of the widespread use of glucocorticoids in these high risk cardiac surgery patients would be appropriate.

Glucocorticoid Dosing Strategies and Inflammatory Mediators - Past Studies

Glucocorticoids exert their anti-inflammatory effects through a complex series of both genomic and non-genomic effects. The classic genomic mechanism of glucocorticoids is activated via the cytosolic glucocorticoid receptor, resulting in both increased expression of anti-inflammatory regulatory proteins and decreased production of pro-inflammatory proteins.16 The modification of gene expression requires hours to days for clinical effects, founding the hypothesis for steroid administration 8-12 hours prior to CPB.17 Some rapid clinical effects occur too promptly to be explained by a genetic mode of action, and have been attributed to nongenomic mechanisms including specific interaction with the cytosolic glucocorticoid receptor, nonspecific interactions with cellular membranes and specific interactions with membrane-bound glucocorticoid receptors.18

Glucocorticoid administration has been associated with unclear benefits and potential detrimental effects in both adults and children undergoing cardiac surgery. Despite this, there is widespread use of perioperative glucocorticoid administration in pediatric cardiac surgery with 80-97% of centers employing some form of glucocorticoid therapy.8,9 Few controlled trials of glucocorticoids in the setting of CPB in pediatrics can be found. Bronicki and colleagues19 randomized 29 children (mean age of 28 months) to receive dexamethasone (1 mg/kg, n=15) or placebo (n=14) 1 hour prior to CPB. Similar to our findings, both groups demonstrated a significant elevation in IL-6 following CPB. However, dexamethasone-treated patients had a blunted IL-6 response when compared to placebo. The authors reported an increase in TNF-α 2 minutes after CPB in the placebo group. It remained more than 3 times higher 10 minutes after protamine administration in the placebo group, but this did not reach statistical significance. At 24 hours postoperatively the mean values were virtually identical. Complement component C3a and absolute neutrophil count were not affected by dexamethasone.

Lindberg and colleagues20 randomized 40 patients weighing > 10 kg (mean age of 52 months) to receive dexamethasone (1 mg/kg, n=20) or placebo (n=20) after the induction of anesthesia. C-reactive protein, as a marker of inflammation, was lower in the treatment group on the first postoperative day. In this cohort, we have previously reported similar levels of C-reactive protein at 36 hours postoperatively between the Single and Two Dose groups.10 Schroeder and associates21 randomized 29 children (mean age 4 months) to MP (30 mg/kg, n=15) or placebo (n=14) 4 hours before CPB. Similar to our study, MP (30 mg/kg) was administered in the pump prime in all patients. Serum IL-6 was lower immediately and 4 hours following CPB in the combined MP compared to the intraoperative-only group, but equally elevated in both groups by 24 hours. The anti-inflammatory cytokine IL-10 was elevated in the combined MP group at the end of CPB and returned to baseline in both groups by 24 hours, similar to this study. Interestingly, they measured RNA from atrial samples before and after CPB. Both groups had an increased expression of inflammatory mediators following CPB, however the combined steroid group had statistically significant reduction in the expression of RANTES, MCP-1, IL-6 and ICAM-1. Patients receiving preoperative steroids also had lower mRNA expression for MCP-1, IL-6 and ICAM-1 at bypass initiation, prior to myocardial ischemia.

In a comparison of dosing strategies, Varan and colleagues22 randomized 30 children (mean age of 48 months) to receive either high dose (30 mg/kg) or low dose (2mg/kg) MP before the onset of CPB. Consistent with the findings of this study, plasma levels of IL-6, IL-8, C-reactive protein and polymorphonuclear leukocyte counts were all elevated postoperatively in both groups without a significant difference between groups.

Inflammatory Response and Clinical Outcomes

Few studies in neonates and infants can be found demonstrating a relationship between inflammatory mediators and postoperative recovery. Consistent with this study, Alcaraz et. al.6 investigated 8 neonates and 19 infants undergoing CPB and demonstrated significant increases in IL-6, IL-8 and TNF in both groups postoperatively. The magnitude of the inflammatory response was greater in the neonates, particularly for IL-8. Moreover the IL-8 response correlated with pulmonary dysfunction and longer ICU stay. In contrast, IL-6 and TNF response was not associated with clinical outcomes. In a larger study by Allan and colleagues4, the authors demonstrated in 93 infants ≤ 9 months of age undergoing low-to-moderate complexity cardiac surgery serum concentrations of IL-6 and IL-8 immediately following CPB and at 24 hours postoperatively were associated with ICU length of stay in multivariate analysis. However, despite reaching statistical significance the variability in outcomes accounted for by these inflammatory mediators was only of modest clinical significance (4% to 9% variability of a median ICU stay of 3 days). Furthermore, despite demonstrating a heightened preoperative inflammatory state in the neonatal population, this did not correlate with postoperative markers of inflammation or clinical outcomes. The authors concluded that in infants undergoing low-to-moderate complexity cardiac surgery, the contribution of inflammatory mediator production to postoperative morbidity is relatively limited.

In contrast, Appachi et al.23 demonstrated that neonates with hypoplastic left heart syndrome had higher preoperative and postoperative IL-6 levels than those with transposition of the great arteries, and postoperative IL-6 concentration was associated with mortality in neonates with hypoplastic left heart syndrome. This work suggests that the inflammatory response may have a greater significance in more complex operations. However, unique to the current study is the sole inclusion of neonates, resulting in the inclusion of complex corrective and palliative operations and the potential increased morbidity associated with them.

Study Limitations

Limitations of the current study include the lack of a completely placebo group. Therefore it remains unclear whether the dosing strategies utilized were equally effective or neither was effective. Thus recommendations for or against intraoperative MP can not be made. Given the theoretical benefits and the widespread use of intraoperative glucocorticoids, a completely placebo arm was thought to be inapproriate during the design of this study. Considered in total, the past and present studies, highlight the need for a recently initiated randomized controlled trial comparing intraoperative glucocorticoids to placebo in neonatal cardiac surgery (ClinicalTrials.gov identifier: NCT01579513). The results of our trial do not preclude the efficacy of other glucocorticoid regimens or the potential importance of other inflammatory pathways that were not directly examined in this study.

Conclusion

In conclusion, in the largest pediatric and only exclusively neonatal randomized trial comparing the efficacy of preoperative glucocorticoid therapy to intraoperative glucocorticoid therapy alone for neonates undergoing corrective and palliative cardiac operations requiring CPB, our data do not provide support for the addition of a preoperative dose of MP to a standard intraoperative dose alone. Although preoperative dosing was associated with an improvement in preoperative inflammatory markers, this did not persist in the postoperative period. In light of these findings, the routine use of preoperative glucocorticoids in neonatal cardiac surgery needs to be reconsidered. Alternative therapies, not necessarly directed at anti-inflammatory mediators, are needed.

Acknowledgments

Dr. Graham had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by a Career Development Award from the American College of Cardiology Foundation/Pfizer Scholarship (E.M.G.), NIH grants HL057952 and HL059165 (F.G.S.) and the Research Service of the Department of Veterans Affairs.

Footnotes

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