Jill M. Cholette

Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial.

Objectives: Children undergoing cardiac surgery with cardiopulmonary bypass are susceptible to additional inflammatory and immunogenic insults from blood transfusions. We hypothesize that washing red blood cells and platelets transfused to these patients will reduce postoperative transfusion-related immune modulation and inflammation. Design: Prospective, randomized, controlled clinical trial. Setting: University hospital pediatric cardiac intensive care unit. Patients: Children from birth to 17 yrs undergoing cardiac surgery with cardiopulmonary bypass. Interventions: Children were randomized to an unwashed or washed red blood cells and platelet transfusion protocol for their surgery and postoperative care. All blood was leuko-reduced, irradiated, and ABO identical. Plasma was obtained for laboratory analysis preoperatively, immediately, and 6 and 12 hrs after cardiopulmonary bypass. Primary outcome was the 12-hr postcardiopulmonary bypass interleukin-6-to-interleukin-10 ratio. Secondary measures were interleukin levels, C-reactive protein, and clinical outcomes. Measurements and Main Results: One hundred sixty-two subjects were studied, 81 per group. Thirty-four subjects (17 per group) did not receive any blood transfusions. Storage duration of blood products was similar between groups. Among transfused subjects, the 12-hr interleukin ratio was significantly lower in the washed group (3.8 vs. 4.8; p = .04) secondary to lower interleukin-6 levels (after cardiopulmonary bypass: 65 vs.100 pg/mL, p = .06; 6 hrs: 89 vs.152 pg/mL, p = .02; 12 hrs: 84 vs.122 pg/mL, p = .09). Postoperative C-reactive protein was lower in subjects receiving washed blood (38 vs. 43 mg/L; p = .03). There was a numerical, but not statistically significant, decrease in total blood product transfusions (203 vs. 260) and mortality (2 vs. 6 deaths) in the washed group compared to the unwashed group. Conclusions: Washed blood transfusions in cardiac surgery reduced inflammatory biomarkers, number of transfusions, donor exposures, and were associated with a nonsignificant trend toward reduced mortality. A larger study powered to test for clinical outcomes is needed to determine whether these laboratory findings are clinically significant.

Children with single-ventricle physiology do not benefit from higher hemoglobin levels post cavopulmonary connection: results of a prospective, randomized, controlled trial of a restrictive versus liberal red-cell transfusion strategy.

Objective: To examine the impact of a restrictive vs. liberal transfusion strategy on arterial lactate and oxygen content differences in children with single-ventricle physiology post cavopulmonary connection. Children with single-ventricle physiology are routinely transfused postoperatively to increase systemic oxygen delivery, and transfusion thresholds in this population have not been studied. Design: Prospective, randomized, controlled, clinical trial. Setting: Pediatric cardiac intensive care unit in a teaching hospital. Patients: Infants and children (n = 60) with variations of single-ventricle physiology presenting for cavopulmonary connection. Interventions: Subjects were randomized to a restrictive (hemoglobin of <9.0 g/dL), or liberal (hemoglobin of ≥13.0 g/dL) transfusion strategy for 48 hrs post operation. Primary outcome measures were mean and peak arterial lactate. Secondary end points were arteriovenous (C(a-v)o2) and arteriocerebral oxygen content (C(a-c)o2) differences and clinical outcomes. Measurements and Main Results: A total of 30 children were in each group. There were no significant preoperative differences. Mean hemoglobin in the restrictive and liberal groups were 11 ± 1.3 g/dL and 13.9 ± 0.5 g/dL, respectively (p < .01). No differences in mean (1.4 ± 0.5 mmol/L [Restrictive] vs. 1.4 ± 0.4 mmol/L [Liberal]) or peak (3.1 ± 1.5 mmol/L [Restrictive] vs. 3.2 ± 1.3 mmol/L [Liberal]) lactate between groups were found. Mean number of red blood cell transfusions were 0.43 ± 0.6 and 2.1 ± 1.2 (p < .01), and donor exposure was 1.2 ± 0.7 and 2.4 ± 1.1 to (p < .01), for each group, respectively. No differences were found in C(a-v)o2, C(a-c)o2, or clinical outcome measures. Conclusion: Children with single-ventricle physiology do not benefit from a liberal transfusion strategy after cavopulmonary connection. A restrictive red blood cell transfusion strategy decreases the number of transfusions, donor exposures, and potential risks in these children. Larger studies with clinical outcome measures are needed to determine the transfusion threshold for children post cardiac repair or palliation for congenital heart disease.

Transfusion‐related immunomodulation: review of the literature and implications for pediatric critical illness

Transfusion‐related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions.

Transfusion of cell saver salvaged blood in neonates and infants undergoing open heart surgery significantly reduces RBC and coagulant product transfusions and donor exposures: results of a prospective, randomized, clinical trial

Objective: To evaluate whether transfusion of cell saver salvaged, stored at the bedside for up to 24 hrs, would decrease the number of postoperative allogeneic RBC transfusions and donor exposures, and possibly improve clinical outcomes. Design: Prospective, randomized, controlled, clinical trial. Setting: Pediatric cardiac intensive care unit. Patients: Infants weighing less than 20 kg (n = 106) presenting for cardiac surgery with cardiopulmonary bypass. Interventions: Subjects were randomized to a cell saver transfusion group where cell saver blood was available for transfusion up to 24 hrs after collection, or to a control group. Cell saver subjects received cell saver blood for volume replacement and/or RBC transfusions. Control subjects received crystalloid or albumin for volume replacement and RBCs for anemia. Blood product transfusions, donor exposures, and clinical outcomes were compared between groups. Measurements and Main Results: Children randomized to the cell saver group had significantly fewer RBC transfusions (cell saver: 0.19 ± 0.44 vs. control: 0.75 ± 1.2; p = 0.003) and coagulant product transfusions in the first 48 hrs post-op (cell saver: 0.09 ± 0.45 vs. control: 0.62 ± 1.4; p = 0.013), and significantly fewer donor exposures (cell saver: 0.60 ± 1.4 vs. control: 2.3 ± 4.8; p = 0.019). This difference persisted over the first week post-op, but did not reach statistical significance (cell saver: 0.64 ± 1.24 vs. control: 1.1 ± 1.4; p = 0.07). There were no significant clinical outcome differences. Conclusion: Cell saver blood can be safely stored at the bedside for immediate transfusion for 24 hrs after collection. Administration of cell saver blood significantly reduces the number of RBC and coagulant product transfusions and donor exposures in the immediate postoperative period. Reduction of blood product transfusions has the potential to reduce transfusion-associated complications and decrease postoperative morbidity. Larger studies are needed to determine whether this transfusion strategy will improve clinical outcomes.

Decreased Incidence of Supravalvar Pulmonary Stenosis After Arterial Switch Operation

Background— Supravalvar pulmonary stenosis (SVPS) is frequently observed after arterial switch. Traditionally the coronary arteries are removed from the neopulmonic root by excising the entire sinus of Valsalva. As a result, reconstruction of the neopulmonic root requires a pericardial patch encompassing two-thirds of the anastomosis between the neopulmonic root and pulmonary artery. We present a technique where the coronary arteries are removed as limited buttons of sinus tissue, leaving the transected edge of the neopulmonic root intact. We hypothesize that maintaining native arterial tissue in the anastomosis between the neopulmonic root and the pulmonary artery bifurcation reduces postoperative SVPS. Methods and Results— We performed a retrospective review of neonates with D-transposition of the great arteries undergoing arterial switch procedure from 1996 to 2009. Charts were reviewed, and clinical outcomes recorded for each patient. Most recent echocardiograms were evaluated for right ventricular outflow tract obstruction. A total of 120 patients received arterial switch using this technique. There was 99% survival and no injuries to the coronary arteries regardless of anatomy. Total follow-up was 564 patient-years. Mean follow-up at last clinical visit was 66±46 months. Evaluation of the most recent outpatient echocardiogram revealed an average peak instantaneous gradient across the neopulmonic root of 22.5±5 mm Hg. Only 7 (5%) patients required reintervention (balloon dilation, n=5; surgery, n=2). Conclusions— Our technique of removing the coronary arteries as limited buttons, and anastomosis of the pulmonary artery using only native arterial tissue provides excellent midterm results with minimal SVPS.

Longer RBC storage duration is associated with increased postoperative infections in pediatric cardiac surgery.

Objectives: Infants and children undergoing open heart surgery routinely require multiple RBC transfusions. Children receiving greater numbers of RBC transfusions have increased postoperative complications and mortality. Longer RBC storage age is also associated with increased morbidity and mortality in critically ill children. Whether the association of increased transfusions and worse outcomes can be ameliorated by use of fresh RBCs in pediatric cardiac surgery for congenital heart disease is unknown. Interventions: One hundred and twenty-eight consecutively transfused children undergoing repair or palliation of congenital heart disease with cardiopulmonary bypass who were participating in a randomized trial of washed versus standard RBC transfusions were evaluated for an association of RBC storage age and clinical outcomes. To avoid confounding with dose of transfusions and timing of infection versus timing of transfusion, a subgroup analysis of patients only transfused 1–2 units on the day of surgery was performed. Measurements and Main Results: Mortality was low (4.9%) with no association between RBC storage duration and survival. The postoperative infection rate was significantly higher in children receiving the oldest blood (25–38 d) compared with those receiving the freshest RBCs (7–15 d) (34% vs 7%; p = 0.004). Subgroup analysis of subjects receiving only 1–2 RBC transfusions on the day of surgery (n = 74) also demonstrates a greater prevalence of infections in subjects receiving the oldest RBC units (0/33 [0%] with 7- to 15-day storage; 1/21 [5%] with 16- to 24-day storage; and 4/20 [20%] with 25- to 38-day storage; p = 0.01). In multivariate analysis, RBC storage age and corticosteroid administration were the only predictors of postoperative infection. Washing the oldest RBCs (> 27 d) was associated with a higher infection rate and increased morbidity compared with unwashed RBCs. Discussion: Longer RBC storage duration was associated with increased postoperative nosocomial infections. This association may be secondary in part, to the large doses of stored RBCs transfused, from single-donor units. Washing the oldest RBCs was associated with increased morbidity, possibly from increased destruction of older, more fragile erythrocytes incurred by washing procedures. Additional studies examining the effect of RBC storage age on postoperative infection rate in pediatric cardiac surgery are warranted.

Aspirin resistance following pediatric cardiac surgery

INTRODUCTION Aspirin is often used to prevent thrombosis in pediatric cardiac surgery. The primary study aim was to assess aspirin resistance in this context. Secondary aims were to evaluate (1) the relationship between elevated inflammatory markers and thrombosis and (2) aspirins effect on these levels. MATERIALS AND METHODS This was a prospective observational study of children undergoing cardiac surgery managed with and without aspirin. Aspirin response was assessed using the VerifyNow system and urinary 11-dehydrothromboxane B2 (uTxB2) measurements. Laboratory studies of inflammation were also obtained. RESULTS 101 subjects were studied; 50 received aspirin. Six subjects (5.9%), 5 aspirin-treated, experienced symptomatic thrombosis. When measured by VerifyNow resistance was 43% after aspirin suppositories and 14% after additional days of oral aspirin. There was no correlation with thrombosis. Upper quartile post-operative day (POD) #5 uTxB2 was correlated with thrombosis in aspirin treated subjects (p<0.01). High risk aspirin-treated subjects who experienced thrombosis had higher POD#5 uTxB2. This finding did not reach statistical significance (p=0.07). Elevated pre-operative C-reactive protein (CRP) was independently associated with thrombosis (p<0.02) in all subjects and in high risk subjects (p=0.01). Inflammatory markers were not affected by aspirin. CONCLUSIONS Aspirin inhibited ex-vivo platelet function with a low incidence of resistance. Elevated POD#5 uTxB2 and pre-operative CRP were correlated with thrombosis in aspirin treated subjects. Further studies are needed to determine whether children with high levels of uTxB2 despite aspirin therapy and/or those with elevated preoperative CRP are at increased risk for thrombosis.

Pharmacokinetics of ε-aminocaproic acid in neonates undergoing cardiac surgery with cardiopulmonary bypass

Background: Antifibrinolytic medications such as &egr;-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Methods: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). Results: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70)0.75. Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg−1 · h−1, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. Conclusions: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Surgical Strategy for Aortic Coarctation Repair Resulting in Physiologic Arm and Leg Blood Pressures

OBJECTIVE The goal of aortic coarctation repair is laminar aortic blood flow resulting in a negative or absent arm:leg blood pressure (BP) gradient. Despite satisfactory relief of coarctation, associated arch hypoplasia can result in residual obstruction and postoperative upper body hypertension. INTERVENTION We devised a surgical strategy to create a tension-free anastomosis with a diameter as large as both the adjacent proximal and distal aorta using a radically extended end-to-end anastomosis via sternotomy and/or thoracotomy. Sternotomy is chosen when there is significant transverse arch hypoplasia defined as a distal transverse arch ≤ diameter of the left carotid artery, presence of a common brachiocephalic trunk, or coexisting intracardiac lesion requiring repair. Thoracotomy is used in all other cases. RESULTS From 2000 to 2008, 95 consecutive patients were repaired using this approach, 35 with sternotomy and 60 with thoracotomy. At a mean follow-up of 50 ± 23 months, mean systolic BP was 94 ± 10 mm Hg, and 84% of patients had no residual arm:leg BP gradient. Mean arm:leg BP gradient was not statistically different between groups (-8.5 ± 15 sternotomy and -7.0 ± 10 mm Hg thoracotomy, P= .7). With Doppler echocardiography, 96% of patients demonstrated normal early diastolic reversal of blood flow in the descending thoracic aorta. CONCLUSIONS For aortic coarctation repair in infancy, a strategy designed to directly address aortic arch hypoplasia results in excellent intermediate-term results with normal BP, physiologic arm:leg BP relationship, and near normal descending aortic blood flow velocities by Doppler.

Modified repair of truncus arteriosus to maintain pulmonary artery architecture.

Neonatal surgical repair for truncus arteriosus historically involves removing the pulmonary arteries from the truncal root, closing the ventricular septal defect, and creating right ventricular to pulmonary artery continuity. Unfortunately, early reintervention is frequently required for conduit failure and proximal branch pulmonary artery stenosis. We present a technique that preserves the pulmonary artery architecture, keeping the pulmonary arteries in their native position. This technique has been applied to 16 patients and appears to decrease proximal branch pulmonary artery stenosis, thereby extending conduit longevity and increasing the freedom from early reintervention.