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Original Articles: Pediatric Cardiac

Blood Transfusion After Pediatric Cardiac Surgery Is Associated With Prolonged Hospital Stay

^a Department of Cardiology, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
^b Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Hospital, Rome, Italy
^c Department of Cardiovascular Surgery, Children's Hospital Boston, and Department of Surgery, Harvard Medical School, Boston, Massachusetts
^d Department of Anesthesia, Children's Hospital Boston, and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts

Accepted for publication July 9, 2010.

^_* Address correspondence to Dr Salvin, Department of Cardiology, Cardiac ICU Office, Bader 600, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115 (Email: joshua.salvin{at}cardio.chboston.org).

	Abstract

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Background: Red blood cell transfusion is associated with morbidity and mortality among adults undergoing cardiac surgery. We aimed to evaluate the association of transfusion with morbidity among pediatric cardiac surgical patients.

Methods: Patients discharged after cardiac surgery in 2003 were retrospectively reviewed. The red blood cell volume administered during the first 48 postoperative hours was used to classify patients into nonexposure, low exposure (15 mL/kg), or high exposure (>15 mL/kg) groups. Cox proportional hazards modeling was used to evaluate the association of red blood cell exposure to length of hospital stay (LOS).

Results: Of 802 discharges, 371 patients (46.2%) required blood transfusion. Demographic differences between the transfusion exposure groups included age, weight, prematurity, and noncardiac structural abnormalities (all p < 0.001). Distribution of Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1) categories, intraoperative support times, and postoperative Pediatric Risk of Mortality Score, Version III (PRISM-III) scores varied among the exposure groups (p < 0.001). Median duration of mechanical ventilation (34 hours [0 to 493] versus 27 hours [0 to 621] versus 16 hours [0 to 375]), incidence of infection (21 [14%] versus 29 [13%] versus 17 [4%]), and acute kidney injury (25 [17%] versus 29 [13%] versus 34 [8%]) were highest in the high transfusion exposure group when compared with the low or nontransfusion groups (all p < 0.001). In a multivariable Cox proportional hazards model, both the low transfusion group (adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI]: 0.66 to 0.97, p = 0.02) and high transfusion group (adjusted HR 0.66, 95% CI: 0.53 to 0.82, p < 0.001) were associated with increased LOS. In subgroup analyses, both low transfusion (adjusted HR 0.81, 95% CI: 0.65 to 1.00, p = 0.05) and high transfusion (adjusted HR 0.65, 95% CI: 0.49 to 0.87, p = 0.004) in the biventricular group but not in the single ventricle group was associated with increased LOS.

Conclusions: Blood transfusion is associated with prolonged hospitalization of children after cardiac surgery, with biventricular patients at highest risk for increased LOS. Future studies are necessary to explore this association and refine transfusion practices.

	Introduction

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Red blood cell (RBC) transfusion may benefit a subset of patients in whom a low hemoglobin concentration contributes to a state of oxygen-supply dependency. The RBC transfusion is not without risk, and recent data suggest an association between transfusion and poor outcome in critically ill adults [1-4]. The use of leukocyte-reduced product may limit the activation of the inflammatory cascade during RBC transfusion, and thus reduce morbidity associated with transfusion of whole blood [5]. However, transfusion of even leukocyte-reduced RBCs in adult cardiac surgical patients remains associated with infection, postoperative morbidity, mortality, prolonged hospital length of stay (LOS), and increased hospital costs [6].

Because the majority of these patients underwent coronary artery bypass graft surgery, generalization of this information to children undergoing cardiac surgery is limited. Lacroix and coworkers [7] recently demonstrated the safety of a restrictive transfusion strategy compared with a liberal strategy in a randomized prospective noninferiority trial of general pediatric intensive care unit patients. While not powered to determine equivalence, a subgroup analysis of noncyanotic postoperative cardiac surgical patients from this cohort suggested that a restrictive transfusion strategy was not associated with organ dysfunction [8]. Children undergoing cardiac surgery are frequently exposed to blood products, and recent data support RBC transfusion associations with morbidity and poor outcome [9–11].

The primary aim of this study was to examine the relationship of RBC transfusion upon hospital LOS in a large, single center and heterogeneous pediatric cardiac surgical cohort. We hypothesized that patients requiring early postoperative blood transfusion would have longer LOS after adjusting for variables known to influence duration of hospitalization. The secondary aims were to compare the demographic, anatomic, and physiologic characteristics of patients who received RBC transfusion with those of patients who did not, and to identify a subset of patients who may warrant future study of a restrictive transfusion strategy.

	Patients and Methods

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Study Design
We performed a retrospective review of all patients admitted to the cardiac intensive care unit (CICU) at Children's Hospital Boston after cardiac surgery between January 1 and December 31, 2003. The Institutional Review Board at the hospital approved the review of patient records for this study. A comprehensive database including demographic, anatomic, and preoperative, intraoperative, and postoperative physiologic data for all patients was created. Patients requiring extracorporeal membrane oxygenation (ECMO) were necessarily exposed to RBC, and were thereby excluded in an attempt to eliminate selection bias. Patients who died were also excluded, as the majority of nonsurvivors required ECMO before death. The final study population therefore included all patients admitted to the CICU after cardiac surgery who survived to discharge without the need for ECMO.

Demographic and anatomic data were collected from the electronic medical record. Cardiac surgical procedures were categorized using the Risk Adjusted Classification for Congenital Heart Surgery, Version 1 (RACHS-1) method [12]. Patients were classified as either single ventricle circulation (including shunted single ventricle physiology and all cavopulmonary connections) or biventricular circulation based upon their physiology at the time of postoperative admission to the CICU. Intraoperative variables including cardiopulmonary bypass time (CPB [minutes]), aortic cross-clamp time (minutes), and use of deep hypothermic circulatory arrest were collected. Operative lactate (mmol/L) was defined as the peak reported value in the operating room after cardiopulmonary bypass. Vital signs and laboratory values obtained during the first 24 hours after admission to the CICU were used to calculate the postoperative Pediatric Risk of Mortality, Version III (PRISM-III) score [13, 14]. Peak CICU lactate (mmol/L), defined as the highest lactate value within the first 24 hours after CICU admission, was also collected. Reoperation was defined as the need for surgical revision of the original cardiac repair before hospital discharge. Acute kidney injury was defined as either a 50% rise in serum creatinine compared with admission baseline, or an absolute rise in serum creatinine of 0.3 mg/dL [15] during the CICU stay for all age groups. Infection was defined as a positive blood or endotracheal tube aspirate culture per the Center for Disease Control and Prevention's National Healthcare Safety Network surveillance criteria in use during the study time period [16]. Duration of mechanical ventilation was defined as the number of hours from admission to the CICU from the operating room until the date and time of the first attempted trial of extubation. Inotropic score for the first 48 postoperative hours was calculated using a previously described formula: (dopamine + dobutamine + [milrinone*10] + [epinephrine*100]), using peak infusion rates measured in micrograms per kilogram per minute [17, 18]. The need for temporary pacing was recorded for any patient requiring an external pacing device for longer than 24 hours after surgery. Weight, CPB time, aortic cross-clamp time, PRISM-III score, and inotrope scores were divided by interquartile range to facilitate interpretation of regression modeling.

Irradiated, leukocyte-reduced RBCs were administered to all patients per institutional blood bank protocol. The CICU patients were transfused with the oldest available matched unit of RBC per institutional protocol. The RBC transfusion was given with the goal of improving oxygen delivery or blood volume at the discretion of the bedside CICU physician or cardiac surgeon. Early postoperative RBC transfusion volume was defined as the total volume of RBCs (mL/kg) administered in the CICU during the initial 48 hours after cardiac surgery (postoperative day [POD] 1 or 2). The RBC transfusion volume administered in the operating room was excluded from this analysis because indications for RBC transfusion were considered different when compared with the CICU. Additionally, electronic recording of intraoperative RBC transfusion during the study period was inconsistent and precluded accurate data collection.

Three exposure groups were defined based on the volume of RBC administered in the CICU during the first 48 postoperative hours. Patients requiring no blood on POD 1 or 2 were categorized as the nontransfusion group. The low transfusion group contained transfused patients receiving a total of 15 mL/kg or less RBC, while the high transfusion group contained transfused patients receiving a total of more than 15 mL/kg RBC on POD 1 or 2. Nadir hemoglobin in the low and high transfusion groups was defined as the lowest hemoglobin concentration before first transfusion on POD 1 or 2. In the nontransfused cohort, nadir hemoglobin was defined as the lowest hemoglobin concentration on POD 1 or 2.

Hospital LOS was chosen as the primary outcome variable as it incorporated the cumulative effect of postoperative morbidities previously associated with RBC transfusion in the literature [6, 19–21], including time of mechanical ventilation, renal failure, infection, and end-organ injury.

Statistical Analysis
Continuous variables were summarized as median (range) or mean (SD) as appropriate. The ² test, and when appropriate, Fisher's exact test were used to test for differences in proportions between the exposure groups. Normally distributed continuous variables were compared by analysis of variance techniques, while nonnormally distributed continuous variables were compared using the Mann-Whitney U nonparametric method.

The association of preoperative and intraoperative factors with the need for RBC transfusion was assessed in a univariate logistic regression model. All covariates reaching statistical significance in univariate modeling were entered into a forward selection multivariable logistic regression model designed to assess the independent association of preoperative and intraoperative factors with the need for transfusion.

An independent association of transfusion group to the primary outcome variable (LOS) was assessed using a Cox proportional hazards survival model owing to the nonnormal distribution for LOS. Each candidate covariate for inclusion in the Cox multivariable model was chosen from univariate regression of the variable with LOS. Covariates independently associated with the need for transfusion were also included in final multivariable analysis. Eligible covariates were entered into a forward selection multivariable Cox proportional hazards model. The multivariable Cox proportional hazard analysis modeled an instantaneous risk of discharge from the hospital. Thus, a hazard ratio (HR) of less than 1 predicted a lower probability of discharge and implied longer LOS. Secondary subgroup analysis of the relationship between transfusion and LOS was performed in an identical fashion for both the biventricular and single ventricle cohorts.

All statistical tests were two-sided, and type I error was controlled at 0.05. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC) and SPSS version 16.0.2 for Macintosh (SPSS, Chicago, IL).

	Results

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Demographics
Eight hundred and thirty-three patients were admitted to the CICU after cardiac surgery. Twenty-three patients (3%) required postoperative ECMO, and 20 patients (2%) died in the postoperative period (including 12 patients who died after ECMO) and were therefore excluded from analysis. Thus, the final study cohort contained 802 postoperative admissions to the CICU. When characterized by age, there were 147 neonates (18%), 276 patients (34%) aged 1 month to 1 year, and 379 (47%) more than 1 year of age. Thirty-eight infants (5%) were born prematurely (36 weeks' gestation), and 57 (7%) had noncardiac structural abnormalities. The most common cardiac diagnoses were atrial septal defect (n = 104), hypoplastic left heart syndrome (n = 83), tetralogy of Fallot with pulmonary stenosis (n = 69), D-transposition of the great arteries (n = 51), complete common atrioventricular canal (n = 46), ventricular septal defect (n = 45), and coarctation of the aorta (n = 45). There were 173 patients (22%) who had single ventricle physiology at the time of postoperative admission.

Transfusion Exposure Groups
Four hundred and nineteen patients (52%) were exposed to blood while in the CICU. Figure 1 demonstrates the proportion of patients who received transfusion for each POD. Within the transfused group, 371 patients (89%) were exposed on POD 1 or 2, the median volume administered was 14.7 mL/kg, and the mean admission hemoglobin concentration was 14.6 ± 2.3 g/dL. There were 222 patients in the low transfusion volume group (15 mL/kg) and 149 patients in the high transfusion volume group (>15 mL/kg). Characteristics of the nontransfusion, low transfusion, and high transfusion groups are compared in Table 1. There was significant variation in age, weight, single ventricle physiology, and RACHS-1 and PRISM-III scores across the transfusion groups. There was no significant difference in sex, prematurity, or the presence major noncardiac structural abnormality among the transfusion exposure groups.

View larger version (6K): [in this window] [in a new window]   Fig 1. This graph demonstrates the proportion of all patients exposed to a red blood cell transfusion (black bars) on each postoperative day. Among patients requiring red blood cells, the majority (89%) received their first transfusion within the first 48 postoperative hours. (Gray bars = no transfusion.)

View larger version (3K): [in this window] [in a new window]   Fig 2. This box plot demonstrates the median hospital length of stay (LOS) for patients across the red blood cell transfusion exposure groups. Patients in the high transfusion group had longer median length of stay than did patients in the low transfusion group or nontransfusion group (Mann-Whitney U p < 0.001).

	Comment

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In this study of 802 postoperative admissions to the CICU, we found that 46% received RBC transfusion within the first 48 postoperative hours. Patients requiring RBC transfusion were younger, more likely to have single ventricle physiology, required more complicated cardiac surgery, and were more acutely ill than those in the low transfusion or nontransfusion groups. In a multivariable model adjusting for univariate associations, RBC transfusion was associated with longer hospital LOS, and the strongest association was found in the high transfusion group. Single ventricle patients were more likely to require RBC transfusion, and were transfused at a higher hemoglobin concentration. In contrast to a transfused single ventricle patient, low or high RBC transfusion requirement in the biventricular circulation patient was associated with a longer hospital LOS.

Significant variability in blood transfusion practice exists among adult intensive care units [22, 23]. Recent studies support the notion that RBC transfusion does not improve outcome in critically ill adults, and may be an independent risk factor for increased morbidity and mortality [1–4]. A randomized controlled trial of more than 800 adult intensive care unit patients established that a restrictive RBC transfusion strategy is safe, and may be superior to liberal transfusion practices [24]. In subgroup analysis of this trial, Hebert and colleagues [25] demonstrated this restrictive strategy was safe in all patients with cardiovascular disease except those with acute myocardial infarction. Analyses of adults undergoing coronary artery bypass surgery have identified transfusion as an important independent risk factor for mortality, renal failure, infection, prolonged ventilation, neurologic events, and hospital costs, with each unit of blood incrementally increasing the risk of poor outcome [6, 20, 21]. In patients requiring large-volume transfusion, leukocyte depletion has been shown to reduce postoperative mortality, suggesting that exposure to donor white blood cells may a mechanism for increased mortality [26].

Transfusion occurs in nearly half of pediatric intensive care unit patients [19]. Children with cardiac disease are more likely to require RBC transfusion when compared with noncardiac pediatric intensive care unit patients [27]. In analyses of primarily noncardiac pediatric intensive care unit patients, RBC transfusion in the critically ill child was independently associated with increased mortality, prolonged duration of mechanical ventilation, and inotrope requirements [19, 28]. Our findings in children recovering from cardiac surgery are consistent with these data. In the only randomly controlled pediatric trial of transfusion practice, the Transfusion Requirements in Pediatric ICUs (TRIPICU) group reported the safety of a restrictive compared with a liberal strategy [7]. This study contained a minority of cardiac patients (20%) admitted after cardiac surgery, and there was no secondary analysis of this subset reported.

In the operating room under the low-flow conditions of CPB, a recent study from our institution found that a hematocrit of 35% compared with 25% did not impact postoperative hemodynamics or short-term neurologic outcome [29]. After cardiopulmonary bypass, patients admitted to the CICU present a unique challenge in terms of blood transfusion strategy. The RBC transfusion improves oxygen-carrying capacity and thus oxygen delivery; however, this benefit may be countered by the risk of transfusion-associated lung injury, immune modulation, cellular hypoxia, and other unknown factors. Prolonged LOS may serve as composite outcome that incorporates the cumulative effects of these morbidities, consistent with reported poor outcomes in adult cardiac surgical patients receiving RBC transfusion. Furthermore, our findings are consistent with the reported increased mortality and morbidity in transfused noncardiac surgical pediatric patients [1]. The retrospective nature of our study precluded evaluation of the mechanisms related to RBC transfusion that may lead to morbidity in children undergoing cardiac surgery. However, we hypothesize that these potential effects may in part underlie the independent association between volume of RBC transfusion and prolonged LOS.

We found that the association of blood transfusion and LOS was limited to patients with a biventricular circulation. The mechanism for this observation is uncertain. Improving oxygen delivery in single ventricle physiology increases the mixed venous oxygen saturation, and therefore, the systemic arterial saturation. That, in turn, may create a more favorable oxygen balance at the cellular level. We speculate that this physiologic advantage may mitigate the potentially harmful effects of transfusion and its association with LOS. In contrast, we suspect that increasing oxygen carrying capacity above a critical level in a biventricular circulation is less likely to improve the ratio of oxygen consumption to delivery; thus, there may be less therapeutic benefit and more negative effects of transfusion on patient outcomes.

This analysis has several limitations, many related to the retrospective nature of the study design. The associations we found between RBC transfusion and longer LOS do not prove causality. Variables influencing LOS, and hence our conclusions, may not have been collected for adjustment in the multivariable model. While only a small, experienced group of cardiac surgeons and intensivists cared for all 802 patients, transfusion practice and patient management in our CICU were not specifically standardized. The retrospective nature of the data collection also precluded accurate assessment of the indication for blood transfusion, which could influence the interpretation of our data. Longer duration of red cell storage has been associated with greater postoperative morbidity and mortality [21, 30]; however, data regarding the age of transfused RBCs were not available for use in this study. Despite these limitations, our results are consistent with other published information in both children and adults describing the association of poor outcomes with RBC transfusion. The information presented here may serve as important preliminary data in the planning of future studies to evaluate the influence of RBC transfusion on patient outcomes.

In conclusion, we show that the volume of RBC transfusion is associated with increased length of hospitalization for children undergoing cardiac surgery, particularly for children with biventricular circulation. Further prospective studies are required to confirm this association and optimize transfusion practice.

	Acknowledgments

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The Rochelle E. Rose Research Fund of the Cardiac Intensive Care Unit at the Children's Hospital Boston supported this study.

	References

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