Prophylactic corticosteroids for pediatric open heart surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review is to assess the beneficial and harmful effects, in relation to hospital morbidity and mortality, of the administration of corticosteroids during either the pre, peri or postoperative period of CPB in pediatric open‐heart surgery.
Background
Description of the Condition and Intervention
Systemic inflammatory response syndrome (SIRS) that ensues after cardiopulmonary bypass (CPB), can be a major cause of morbidity and mortality. The physiological pathway that leads to this syndrome is complex and multifaceted. When left uncontrolled, it has been implicated in clinical deterioration of numerous body systems such as the neurological, cardiac, renal, pulmonary, vascular as well as haematological systems (ElBarbary 2002). The reported incidence of overall complications ranges from 4% to 44% (Johnson 1999; Kimmel 1991). In the pediatric patient, major neurological complications have been reported as high as 6%. In addition age has been demonstrated to be a significant determinant of the level of immunological response (Duval 1998). For this reason, conscientious effort on the clinicians behalf needs to be made to intervene in this downward cascade of events. This would include the use of various pharmacological agents, such as steroids, aimed at improving the postoperative care and survival of the pediatric cardiac surgical patient. To this end, we will systematically evaluate the evidence that exists to date in relation to the use of steroids in the setting of CPB for the pediatric patient.
The hallmark of SIRS is the creation of a pro inflammatory state that can cause tachycardia, tachypnea/hyperpnea, hypotension, hypoperfusion, oliguria, leukocytosis/leukopenia, pyrexia/hypothermia, and the need for volume infusion. Metabolic acidosis is a frequent accompaniment to SIRS, and is driven principally from lactate production (Kaplan 2004). The pathophysiology of SIRS in the setting of CPB is multifaceted and complex but essentially involves the body's reaction to the contact of the CPB apparatus, resulting in the activation of various blood cells, endothelial, leukocyte, platelets, visceral proteins plus activation of complements and the subsequent initiation of coagulation, fibrinolytic and kallikrein cascades (Casey 1993; Drusin 1965; Kaplan 2004; Tarnok 2001). In addition, circulating endotoxins and cytokines may be elevated resulting in increasing endothelial cell permeability (Casey 1993; Niazi 1979). White blood cells migrate across the 'leaky' blood vessel walls into other tissues and various serum proteases and neutrophil elastase are released that in turn exaggerate both vascular and cellular damage (Tarnok 2001). It is known that the neonate, infant and adult myocardium each have a distinct systemic response to CPB (Friedrich 2003; Lequier 2000; Schroeder 2003). The younger the patient, the greater the immune response will be to CPB (Duval 1998). The type of operation performed in the child with congenital heart disease coupled with the pre‐operative oxidative stress of the congenital anomaly all present fundamental physiological differences that cannot be extrapolated to the adult population. Compared to the adult patient, the child with a congenital heart defect is seen to be at an increased risk for endotoxemia pre and peri‐operatively due to the low perfusion of the intestine and bowel or the relatively normal intestinal perfusion with cyanotic arterial blood (Lequier 2000).
Why it is important to do this review
The clinical benefits and harms of corticosteroid treatment following CPB in the pediatric patient is not clear (Mayumi 1997; Morton 1976; Seghaye 1993). While much has been written about the favourable use of steroids, other studies refute this claim on the basis that steroids alone may not be adequate to arrest the multi‐faceted, complex and dynamic nature of SIRS (Maharaj 2004). Additionally, inconsistency exists in the choice of agent (glucocorticoid or mineralocorticoid), preferred dosage regimen and complications associated with its administration (Clapp 1998; Niazi 1979; Wakabayashi 1999; Wilson1994). It is therefore prudent to systematically review the existing research to assist the clinician in their decision making toward minimizing the deleterious effects of CPB on the pediatric population.
Objectives
The primary objective of this review is to assess the beneficial and harmful effects, in relation to hospital morbidity and mortality, of the administration of corticosteroids during either the pre, peri or postoperative period of CPB in pediatric open‐heart surgery.
Methods
Criteria for considering studies for this review
Types of studies
All randomised and quasi‐randomised clinical trials will be included irrespective of blinding, publication status, or language.
Types of participants
Male or female patients, aged between 31 days and 18 years, from any ethnic origin, who have undergone open heart surgery with cardiopulmonary bypass for a congenital cardiac anomaly. In particular, all trials where they have defined their population/ sample as pediatric will be included. Neonates and patients undergoing heart transplantation will be excluded.
Types of interventions
All studies including one or more of the following will be considered for inclusion in this review:
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Any type of corticosteroid, at any dose or administration regime;
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Corticosteroids compared with no intervention, placebo, supportive therapy, or conventional therapy;
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Trials of corticosteroids plus supportive therapy versus supportive therapy alone will also be included. Co‐interventions will be allowed as long as all arms of the randomised allocation received the same co‐interventions.
Types of outcome measures
The primary outcome measure sought at the end of treatment and at maximal follow‐up after end of treatment will be:
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composite end‐point of all cause mortality and cardiac/circulatory complications.
The secondary outcome measures will include all other complications:
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temperature >38 C or <36 C;
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heart rate for age limit;
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respiratory rate > 40 breaths/min;
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acidosis (elevated lactate levels or reduced pH);
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sepsis: WBC >12,000 cells/mm3 , >4000 cells/mm3 or, >10% immature (band) forms;
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prolonged Length of Stay (LOS);
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haemodynamic instability;
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inotrope requirements > 10 μg/kg/min for greater than 48 hrs.
These adverse events will be classified into two principle groups:
1. Serious
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death;
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life‐threatening;
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required hospitalisation or prolongation of hospitalisation;
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resulted in persistent or significant disability;
2. Non serious
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any event that may jeopardise the patient and require intervention to prevent one of the former serious adverse events from occurring;
Search methods for identification of studies
Electronic searches
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Chinese Biomedical CD Database will be searched from their date of inception onwards. In addition to the terms below, filters will be used to identify RCTs on MEDLINE and EMBASE using the Cochrane Collaboration's recommended highly sensitive search strategies (Alderson 2004). No language restrictions will be applied.
Details of the search strategy for CENTRAL on the Cochrane Library will include the following:
[Terms in capitals are exploded MeSH terms and those in lower case are
textword searches.]
#1 CARDIAC SURGICAL PROCEDURES
#2 (cardiac next surger*)
#3 (heart next surger*)
#4 cardiosurgery
#5 CARDIOPULMONARY BYPASS
#6 EXTRACORPOREAL CIRCULATION
#7 (cardiopulmonary next bypass*)
#8 ( #1 or #2 or #3 or #4 or #5 or #6 or #7)
#9 ANTI‐INFLAMMATORY AGENTS
#10 IMMUNOSUPPRESSIVE AGENTS
#11 ADRENAL CORTEX HORMONES
#12 steroid*
#13 corticostero*
#14 immunosuppress*
#15 GLUCOCORTICOIDS
#16 MINERALOCORTICOIDS
#17 predniso*
#18 dexamethason*
#19 hydrocortiso*
#20 methylprednison*
#21 budesonide*
#22 cortiso*
#23 fludrocortiso*
#24 betamethasone
#25 (#9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17)
#26 (#18 or #19 or #20 or #21 or #22 or #23 or #24)
#27 (#25 or #26)
#28 (#8 and #27)
#29 child*
#30 adolescen*
#31 pediatric*
#32 paediatric*
#33 infant*
#34 (#29 or #30 or #31 or #32 or #33)
#35 (#28 and #34)
Handsearches
Arabic publications, publications from the Middle Eastern region not included on MEDLINE plus the EMRO (Eastern Mediterranean Regional Office) database of WHO will be handsearched. The reference lists of identified clinical trials and review articles will be checked in order to find randomised trials not identified by the electronic searches or handsearches. Conference proceedings relevant to this topic will also be handsearched.
Additional searches
Ongoing trials will be searched through the National Research Register and the website (www.controlled‐trials.com) and grey literature through the database of SIGLE (system for Information on Grey Literature in Europe). Authors and experts in this field will also be contacted to ask if they know any other trials.
Data collection and analysis
Selection of trials for inclusion
Two reviewers (SR and ME) will independently select the trials through reading titles and abstracts of the citations. Any potential eligible studies will be retrieved for further identification according to pre‐specified selection criteria. Any disagreement will be resolved by discussion with the third party (BA).
Data extraction
The data will be extracted independently by two reviewers (SR and ME) Table 1. The methodological rigour and clinical significance of each trial will be assessed independently by each reviewer using the established quality assessment methods described in the Cochrane Handbook (Alderson 2004). This pays particular attention to the randomisation procedure (especially allocation concealment) and gives studies a rating of A (adequate), B (unclear) or C (inadequate). In addition, other aspects of quality such as whether the trial was of a double blind design and reporting of withdrawals and dropouts will be described. If the above data are not available in the trial reports, further information will be sought by correspondence with the principal investigator(s). Differences in data extraction will be resolved by discussion. In situations where no consensus is reached between the two reviewers, a third reviewer (BA) will make the final decision.
| Questions | Answers |
| AUTHORS | |
| PUBLICATION ID | |
| YEAR OF PUBLICATION | |
| LANGUAGE | |
| TYPE OF STUDY | |
| COMMENTS ON STUDY DESIGN | |
| Inclusion and exclusion criteria were clearly defined in the text? | |
| Outcomes of patients who withdrew or were excluded after allocation | |
| Outcome of patients who withdrew or were excluded after allocation were | |
| Treatment and control groups were adequately described at entry (a minimum of 4 admission details were described (age, sex, weight, allergies) | |
| Treatment and control groups were NOT adequately described at entry | |
| The text stated that the care programmes other than the trial options were identical | |
| Outcome measures were clearly defined in the text | |
| Outcome assessors were blind to the allocation of patients | |
| The timing of outcome measures was appropriate | Yes No Unclear |
| METHODS: | Yes No Unclear |
| PARTICIPANTS: | |
| Were groups similar at entry | Yes No Unclear |
| INTERVENTION | Yes No Unclear |
| COMMENT ON TREATMENT | |
| OUTCOMES: (mean values for continuous data) | |
| Authors contacted regarding unreported outcome data | Yes No Unclear |
| COMMENTS ON OUTCOMES |
Data synthesis
Dichotomous data will be presented as odds ratio (OR) and continuous outcomes as weighted mean difference (WMD), both with 95% confidence intervals (CI). All additional analyses will be performed by intention‐to‐treat where possible. For dichotomous outcomes, trials with incomplete or missing data will be included in a sensitivity analysis by counting them as treatment failures to explore the possible effect of loss to follow‐up on the findings (worst‐case scenario). All statistical analysis will be dual entered and performed on the RevMan Manager software (RevMan 4.2).
Meta‐analysis will be performed only with comparisons where individual trials compared the same experimental intervention versus the same control intervention. Tests for homogeneity will be undertaken using the models available in RevMan 4.2. (RevMan) Causes of heterogeneity between trials will be explored and explained. A sensitivity analysis will be conducted to determine if removing suspected trials improves the homogeneity. A random effects model will be used if statistical heterogeneity is found.
Comparisons will be displayed as :
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corticosteroids versus no intervention or placebo;
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types of corticosteroids versus other types;
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dose of corticosteroids versus other doses;
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regimens of corticosteroids versus other regimens;
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optimal corticosteroids versus supportive intervention.
Sub‐group analyses will be performed when appropriate (by age, dose of corticosteroid and trial methodology).
Publication bias
A funnel plot analysis will be undertaken using the model provided in RevMan 4.2 to determine the degree of publication bias (Egger 1997).
| Questions | Answers |
| AUTHORS | |
| PUBLICATION ID | |
| YEAR OF PUBLICATION | |
| LANGUAGE | |
| TYPE OF STUDY | |
| COMMENTS ON STUDY DESIGN | |
| Inclusion and exclusion criteria were clearly defined in the text? | |
| Outcomes of patients who withdrew or were excluded after allocation | |
| Outcome of patients who withdrew or were excluded after allocation were | |
| Treatment and control groups were adequately described at entry (a minimum of 4 admission details were described (age, sex, weight, allergies) | |
| Treatment and control groups were NOT adequately described at entry | |
| The text stated that the care programmes other than the trial options were identical | |
| Outcome measures were clearly defined in the text | |
| Outcome assessors were blind to the allocation of patients | |
| The timing of outcome measures was appropriate | Yes No Unclear |
| METHODS: | Yes No Unclear |
| PARTICIPANTS: | |
| Were groups similar at entry | Yes No Unclear |
| INTERVENTION | Yes No Unclear |
| COMMENT ON TREATMENT | |
| OUTCOMES: (mean values for continuous data) | |
| Authors contacted regarding unreported outcome data | Yes No Unclear |
| COMMENTS ON OUTCOMES |
