Study Population
Patient files were reviewed of all patients that underwent a surgical procedure between January 2010 and December 2014 in the CAHAL center for CHD Amsterdam-Leiden, The Netherlands for the presence of crPE. CrPE was defined as PE that results in an alteration of the usual course of postoperative management, such as when additional echocardiographs were made, diuretics were initiated or continued, corticosteroid therapy was initiated or when pericardial drainage was required.
The CAHAL consists of three academic hospitals (Leiden University Medical Center, Academic Medical Center, and Free University Medical Center). All procedures took place in the department of cardiothoracic surgery of the Leiden University Medical Center. Patients were eligible for study inclusion when they were 18 years of age or younger at the time of surgery and when they underwent thoracic surgery of the heart and/or the great vessels.
Data Collection
The EZIS patient information system (Chipsoft, Amsterdam, The Netherlands) and the HiX system (Chipsoft, Amsterdam, The Netherlands) were used to examine all files available in the LUMC. These files included all correspondence letters of the department of pediatric cardiology of the Leiden University Medical Center and of the intensive care department of the Leiden University Medical Center, as well as the letters of the collaborating hospitals. Intensive care information was thoroughly examined by means of the PDMS intensive care program (MetaVision iMDsoft, Düsselforf, Germany). Since 80% of patients develop PE within 1 month [
5], 1 month of follow-up was collected for all patients. When patients were referred to the Academic Medical Center, the Free University Medical Center or the Juliana Pediatric Hospital, The Hague, The Netherlands within this month and letters of that period were not available in the EZIS system, patient files were examined at that location. When patients were referred to a different hospital, it was assumed they did not develop crPE, since patients with crPE would have been referred back to one of the hospitals of the CAHAL, because no specialized pediatric cardiologists are available in those centers.
Patients were examined in eligible surgical episodes. An eligible surgical episode was defined as the time interval between an eligible procedure, i.e., thoracic surgery of the heart and/or the great vessels, and 1 month of follow-up. Some patients underwent multiple procedures. When these procedures were performed within the period of 1 month, the follow-up was extended to 1 month after the last procedure. When procedures were performed more than 1 month apart, they were analyzed as separate episodes.
Routine echocardiographs were made at discharge from the intensive care unit (ICU), discharge from hospital and at least once during the second to fourth week after operation. Additional echocardiographies were made either during ICU stay or in between echocardiographies when a patient developed symptoms for which an echocardiograph was indicated. All echocardiography reports were examined to find out whether a patient developed PE during the episode and whether this PE was clinically relevant. For this, the echo-reports were searched for the mention of PE. When presence or absence of PE was not mentioned or if uncertainties existed within the report, a senior pediatric cardiologist (AAWR) reviewed the echocardiography. Patients were considered to have developed PE when there was echocardiographic evidence of effusion at least once during follow-up. As stated above, crPE was defined as PE that results in an alteration of the usual course of postoperative management, such as when additional echocardiographs were made, diuretics were initiated or continued, corticosteroid therapy was initiated or when pericardial drainage was required. The need for therapy initiation or adjustment was determined according to physicians’ discretion and distracted from the medical records. In these instances, the patients were considered to have developed crPE. Perioperative and postoperative patient data were collected until the moment that crPE was diagnosed.
Potential Risk Factors for CrPE
Preoperative characteristics such as age at the time of procedure, gender, weight, length, and primary diagnosis were collected for all patients. Body surface area was calculated according to the formula of Dubois. Next, the primary diagnosis was classified as being simple, moderate, or severe in complexity according to the classification described by Hoffman and Kaplan [
1]. This classification was used because it is a patient characteristic that conveys disease severity and because PE is known to occur more frequently in patients with specific congenital heart defects, such as tetralogy of Fallot, ventricular septal defect with additional defects, and isolated septal defects. Furthermore, for perioperative risk factors, we chose risk factors known from literature [
9]: CPB use and duration and clamp time, clamp time. Therefore, we did not include classifications that focus more on difficulty of the performed operation, such as the STAT classification [
10]. It was also noted whether the patient had a right-sided heart defect. These heart defects included atrial septal defect type 2, tricuspid valve disease, Ebstein tricuspid valve disease, tricuspid valve stenosis, tricuspid valve hypoplasia, sinus venosus atrial septal defect, double outlet right ventricle, and tetralogy of Fallot. An overview of the diagnoses included in this study with their severity and whether they were analyzed as being right-sided is given in Table S1.
To examine perioperative and postoperative characteristics, a case–control study was performed within the cohort. Therefore, all patients that developed crPE were selected and matched with patients that did not develop crPE in a ratio of one-to-one. Matching criteria were age, gender, and diagnosis severity. Matching was done in a two-step procedure. In the first step, a maximum age difference of 3 months was allowed. In the second step, cases that did not yet have a matched control were matched again with a maximum age difference of 12 months.
The perioperative characteristics that were investigated are shown in Table
4. If clamp time was not recorded, asystole duration as registered in the PDMS intensive care program was used instead. To justify this, clamp time was internally compared with asystole time in patients in whom clamp time and asystole time were both available. The maximum difference was 2 min, which was thought sufficiently small to justify the use of asystole time when clamp time was absent.
The postoperative characteristics that are investigated are also shown in Table
4. Inotropic use was assessed using a maximum inotropic score [
11]. For respiratory ventilation, a distinction was made between bilevel positive airway pressure and/or assisted spontaneous breathing ventilation and continuous positive airway pressure ventilation. For corticosteroids use, perioperative use and the maximum dosage during ICU stay were recorded. Postoperative dexamethasone was only provided in case of stridor. However, due to few patients receiving corticosteroids, it was decided only to implement the use of peri- and postoperative corticosteroids in the statistical analysis. For diuretics, anticoagulation medication, antihypertensives, and non-steroidal anti-inflammatory drugs, it was only documented whether this type of medication was given and not the dose.
To prevent distortion of our results by outlying values, it was decided to categorize variables in which these outlying values could be expected. These variables were age, ICU duration, duration of bilevel positive airway pressure and/or assisted spontaneous breathing, and duration of continuous positive airway pressure ventilation. Clinically relevant cut-off values were chosen. Age was categorized into neonatal (0–1 month), 1–6 months, 6 months–1 year, and 1–18 years. ICU duration was categorized into ≤ 1 day, 1–5 days, 5–10 days, and > 10 days. Bilevel positive airway pressure and/or assisted spontaneous breathing ventilation was categorized into 0–1 h, 1–12 h, 12–24 h, and > 24 h. Continuous positive airway pressure ventilation was categorized into no continuous positive airway pressure usage, 0–1 h usage, 1–12 h, and > 12 h.
Statistical Analysis
Preoperative patient characteristics were examined in the complete study cohort and perioperative and postoperative characteristics were assessed in the case–control sub-cohort. Continuous variables are shown as medians with interquartile ranges. Nominal variables are shown as frequencies and percentages. In the complete study cohort, patients with and without crPE were compared by means of independent sample student T tests for continuous variables and χ2 tests for dichotomous variables. Odds ratios were calculated by means of logistic regression analysis, with robust standard errors to account for clustered measurements within a child. The effect of perioperative and postoperative characteristics was assessed by comparing the patients with crPE to their matched controls, using paired t tests and McNemar tests. Conditional logistic regression was used to calculate odds ratios. Statistical significance was defined as p < 0.05.
The multivariate regression analysis was conducted in two steps. First the most predictive preoperative variables were selected. Therefore, the preoperative variables that were univariately associated with crPE (
p value < 0.10) were entered in a logistic model. In the second step, the additional value of the peri- and postoperative variables was assessed using the case–control data. Unconditional logistic regression was used in which the regression coefficients for the preoperative variables were hold fixed at the values of the complete cohort analysis [
12]. The peri- and postoperative variables that were univariately associated with crPE (
p value < 0.10) were subsequently entered in the analysis. To account for missing data values, multiple imputation was used.
All analyses were conducted using SPSS statistics version 22.0 for Mac and STATA version 14 for Windows.