Stephen J. Roth

Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES In a randomized, single-center trial, we compared perioperative outcomes in infants undergoing cardiac operations after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS Admission criteria included reparative cardiac surgery, age less than 9 months, birth weight 2.25 kg or more, and absence of associated congenital or acquired extracardiac disorders. RESULTS Among the 182 infants in the study, diagnoses included D-transposition of the great arteries (n = 92), tetralogy of Fallot (n = 50), tetralogy of Fallot with pulmonary atresia (n = 6), ventricular septal defect (n = 20), truncus arteriosus (n = 8), complete atrioventricular canal (n = 4), and total anomalous pulmonary venous return (n = 2). Ninety patients were assigned to alpha-stat and 92 to pH-stat strategy. Early death occurred in four infants (2%), all in the alpha-stat group (p = 0.058). Postoperative electroencephalographic seizures occurred in five of 57 patients (9%) assigned to alpha-stat and one of 59 patients (2%) assigned to pH-stat strategy (p = 0.11). Clinical seizures occurred in four infants in the alpha-stat group (4%) and two infants in the pH-stat group (2%) (p = 0.44). First electroencephalographic activity returned sooner among infants randomized to pH-stat strategy (p = 0.03). Within the homogeneous D-transposition subgroup, those assigned to pH-stat tended to have a higher cardiac index despite a lower requirement for inotropic agents; less frequent postoperative acidosis (p = 0.02) and hypotension (p = 0.05); and shorter duration of mechanical ventilation (p = 0.01) and intensive care unit stay (p = 0.01). CONCLUSIONS Use of the pH-stat strategy in infants undergoing deep hypothermic cardiopulmonary bypass was associated with lower postoperative morbidity, shorter recovery time to first electroencephalographic activity, and, in patients with D-transposition, shorter duration of intubation and intensive care unit stay. These data challenge the notion that alpha-stat management is a superior strategy for organ protection during reparative operations in infants using deep hypothermic cardiopulmonary bypass.

Ten-Year Institutional Experience With Palliative Surgery for Hypoplastic Left Heart Syndrome Risk Factors Related to Stage I Mortality

BACKGROUND We reviewed 212 consecutive patients who underwent stage I palliative surgery for hypoplastic left heart syndrome (HLHS) at our institution between January 1983 and June 1993. METHODS AND RESULTS Six surgeons participated in the care of these patients. Follow-up is 97% complete. Preoperative anatomic and physiological factors and procedural features of the stage I operation were analyzed for impact on stage I mortality, survival to stage II palliation, and actuarial survival. Hospital mortality was not significantly lower during the second half of the study period (P = .242). Operative mortality was 46.2%. Multivariate analysis revealed improved stage I operative survival in patients with mitral stenosis (MS) and aortic stenosis (AS; P = .006). Additional risk factors for stage I mortality were a lower immediately pre-stage I pH (P = .034) and weight < 3 kg (P = .015). Overall first-year actuarial survival for MS/AS was 59%, and it was 33% for all others (P = .001). Among stage I survivors, patients with MS/AS were more likely to survive to stage II palliation (P = .031). Analysis of actuarial survival of stage I survivors showed that a smaller ascending aorta (P < .001), aortic atresia (P < .001), and mitral atresia (P = .002) were all risk factors for intermediate death. CONCLUSIONS Preoperative anatomic and physiological state are predictors of stage I mortality. HLHS anatomic subtype also influences intermediate outcome, most notably pre-stage II attrition. These data may be useful in choosing initial management for patients with HLHS.

Aortic Valve Endothelial Cells Undergo Transforming Growth Factor-β-Mediated and Non-Transforming Growth Factor-β-Mediated Transdifferentiation in Vitro

Cardiac valves arise from endocardial cushions, specialized regions of the developing heart that are formed by an endothelial-to-mesenchymal cell transdifferentiation. Whether and to what extent this transdifferentiation is retained in mature heart valves is unknown. Herein we show that endothelial cells from mature valves can transdifferentiate to a mesenchymal phenotype. Using induction of α-smooth muscle actin (α-SMA), an established marker for this process, two distinct pathways of transdifferentiation were identified in clonally derived endothelial cell populations isolated from ovine aortic valve leaflets. α-SMA expression was induced by culturing clonal endothelial cells in medium containing either transforming growth factor-β or low levels of serum and no basic fibroblast growth factor. Cells induced to express α-SMA exhibited markedly increased migration in response to platelet-derived growth factor-BB, consistent with a mesenchymal phenotype. A population of the differentiated cells co-expressed CD31, an endothelial marker, along with α-SMA, as seen by double-label immunofluorescence. Similarly, this co-expression of endothelial markers and α-SMA was detected in a subpopulation of cells in frozen sections of aortic valves, suggesting the transdifferentiation may occur in vivo. Hence, the clonal populations of valvular endothelial cells described here provide a powerful in vitro model for dissecting molecular events that regulate valvular endothelium.

Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery

OBJECTIVES We previously reported that postoperative hemodynamics and developmental outcomes were better among infants randomized to a higher hematocrit value during hypothermic cardiopulmonary bypass. However, worse outcomes were concentrated in patients with hematocrit values of 20% or below, and the benefits of hematocrit values higher than 25% were uncertain. METHODS We compared perioperative hemodynamics and, at 1 year, developmental outcome and brain magnetic resonance imaging in a single-center, randomized trial of hemodilution to a hematocrit value of 25% versus 35% during hypothermic radiopulmonary bypass for reparative heart surgery in infants undergoing 2-ventricle repairs without aortic arch obstruction. RESULTS Among 124 subjects, 56 were assigned to the lower-hematocrit strategy (24.8% +/- 3.1%, mean +/- SD) and 68 to the higher-hematocrit strategy (32.6% +/- 3.5%). Infants randomized to the 25% strategy, compared with the 35% strategy, had a more positive intraoperative fluid balance (P = .007) and lower regional cerebral oxygen saturation at 10 minutes after cooling (P = .04) and onset of low flow (P = .03). Infants with dextro-transposition of the great arteries in the 25% group had significantly longer hospital stay. Other postoperative outcomes, blood product usage, and adverse events were similar in the treatment groups. At age 1 year (n = 106), the treatment groups had similar scores on the Psychomotor and Mental Development Indexes of the Bayley Scales; both groups scored significantly worse than population norms. CONCLUSIONS Hemodilution to hematocrit levels of 35% compared with those of 25% had no major benefits or risks overall among infants undergoing 2-ventricle repair. Developmental outcomes at age 1 year in both randomized groups were below those in the normative population.

Cardiac catheterization of patients supported by extracorporeal membrane oxygenation

OBJECTIVES The goal of this study was to describe the clinical outcomes of patients undergoing cardiac catheterization while supported with extracorporeal membrane oxygenation (ECMO). BACKGROUND Extracorporeal membrane oxygenation is an important mechanical support for the failing circulation. There are diagnostic and therapeutic indications for cardiac catheterization in patients on ECMO, but no large series has been reported. METHODS We performed a retrospective review of the indications and outcomes of patients catheterized on ECMO from a single, large pediatric tertiary care center. RESULTS At our institution, 192 patients with cardiac disease have undergone a total of 216 courses of ECMO; 60 catheterizations were performed on 54 patients (28%). Indications for catheterization included assessment of surgical repair (21 patients), left heart decompression (12 patients), myocarditis/cardiomyopathy assessment (10 patients), non-post-operative hemodynamic assessment (8 patients), planned catheter-based interventions (6 patients), and arrhythmia ablation (3 patients). An intervention was undertaken either during or after 50 of the catheterizations (83%); 29 occurred at catheterization, 17 in the operating room (OR), and 4 both during catheterization and in the OR. Complications during catheterization were two myocardial perforations that were treated with pericardial drains (3%). Overall outcomes included successful decannulation of 39 patients, survival to hospital discharge of 26 (48%) patients, and longer-term survival of 23 (43%) patients (median follow-up, 35 months; range, 1 to 180 months). Fifteen patients were withdrawn from ECMO support due to severe neurologic impairment or lack of myocardial recovery. CONCLUSIONS Cardiac catheterization can be performed safely on patients supported with ECMO. Catheterization during ECMO enables the diagnosis of residual lesions and can facilitate important therapeutic interventions.

Characterization of transendothelial chemotaxis of T lymphocytes

We have adapted a chemotaxis assay using human umbilical vein endothelial cell (HUVEC) monolayers on microporous membranes for studying lymphocyte transendothelial chemotaxis in vitro. Supernatants of peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA) were identified as an excellent source of lymphocyte chemoattractant activity. The activity in PHA supernatant typically caused 2-6% of peripheral blood lymphocytes (PBL) to transmigrate compared to 0.1-0.3% to media control. Checkerboard analysis demonstrated that transmigration was directional and not attributable to random locomotion. Purified T lymphocytes also underwent transendothelial chemotaxis to PHA supernatant. Using monoclonal antibodies to several human adhesion receptors, we found that the interaction between LFA-1 and ICAM-1/ICAM-2 was more important for transendothelial lymphocyte chemotaxis than the interaction between VLA-4 and VCAM-1. A monoclonal antibody to the beta 1 integrin subunit inhibited chemotaxis more than antibodies to the VLA alpha 2, alpha 3, alpha 4, or alpha 5 subunits. The transendothelial assay was used to guide purification of the lymphocyte chemoattractant activity, which we reported previously to be monocyte chemoattractant protein-1 (MCP-1) (Carr et al., Proc. Natl. Acad. Sci. USA (1994) 91, 3652). The adhesion molecules required for chemotaxis to MCP-1 were similar to those with PHA supernatant. The use of HUVEC in the assay enhances the signal-to-background ratio of chemotaxis and provides a model that is physiologically relevant to lymphocyte emigration from the bloodstream into sites of inflammation.

Transendothelial chemotaxis of human αβ and γδ T lymphocytes to chemokines

Two subpopulations of human T lymphocytes expressing different antigen receptors, α / β and γ / δ, emigrate into inflamed tissues in distinctive patterns. We compared the transmigration of α / β and γ / δ T cells to C‐C and C‐X‐C chemokines using an in vitro transendothelial chemotaxis assay. The C‐C chemokines monocyte chemoattractant protein (MCP)‐1, RANTES, macrophage inflammatory protein (MIP)‐1α and MIP‐1β stimulated similar, dose‐dependent chemotaxis of purified γ / δ T cells, whereas MCP‐1, RANTES, and MIP‐1α pro duced greater chemotaxis of purified α / β T cells than MIP‐1β. In contrast, the C‐X‐C chemokines interleukin (IL)‐8 and interferon‐γ inducible protein‐10 (IP‐10) did not promote chemotaxis of either α / β or γ / δ T cells. Three γ / δ T cell clones with differing CD4 and CD8 phenotypes also migrated exclusively to C‐C chemokines. Phenotypic analysis of mononuclear cells that transmigrated from an input population of unfractionated peripheral blood mono nuclear cells confirmed the results with purified γ / δ T cells. Our data demonstrate that human peripheral blood α / β and γ / δ T cells can transmigrate to MCP‐1, RANTES, MIP‐1α, and MIP‐1β, and suggest that both T lymphocyte subpopulations share the capacity to emigrate in response to C‐C chemokines during inflammation.

A continuous heparin infusion does not prevent catheter-related thrombosis in infants after cardiac surgery.

Objective: To determine whether a continuous infusion of heparin reduces the rate of catheter-related thrombosis in neonates and infants post cardiac surgery. Central venous and intracardiac catheters are used routinely in postoperative pediatric cardiac patients. Catheter-related thrombosis occurs in 8% to 45% of pediatric patients with central venous catheters. Design: Single-center, randomized, placebo-controlled, double-blinded trial. Setting: Cardiovascular intensive care unit, university-affiliated childrens hospital. Patients: Children <1 yr of age recovering from cardiac surgery. Interventions: Patients were randomized to receive either continuous heparin at 10 units/kg/hr or placebo. The primary end point was catheter-related thrombosis as assessed by serial ultrasonography. Results: Study enrollment was discontinued early based on results from an interim futility analysis. Ninety subjects were enrolled and received the study drug (heparin, 53; placebo, 37). The catheter-related thrombosis rate in the heparin group, compared with the placebo group, was 15% vs. 16% (p = .89). Subjects in the heparin group had a higher mean partial thromboplastin time (52 secs vs. 42 secs, p = .001), and this difference was greater for those aged <30 days (64 secs vs. 43 secs, p = .008). Catheters in place ≥7 days had both a greater risk of thrombus formation (odds ratio, 4.3; p = .02) and catheter malfunction (odds ratio, 11.2; p = .008). We observed no significant differences in other outcome measures or in the frequency of adverse events. Conclusions: A continuous infusion of heparin at 10 units/kg/hr was safe but did not reduce catheter-related thrombus formation. Heparin at this dose caused an increase in partial thromboplastin time values, which, unexpectedly, was more pronounced in neonates.

Safety and efficacy of prolonged dexmedetomidine use in critically ill children with heart disease

Objectives: To evaluate the safety and efficacy of prolonged dexmedetomidine administration (≥96 hrs) in critically ill children with heart disease. Design: Retrospective observational study. Setting: Cardiovascular intensive care unit in a single, tertiary care, academic children’s hospital. Interventions: None. Subjects: We conducted a retrospective review of the charts of all critically ill infants and children (up to 18 yrs of age) with congenital or acquired heart disease who received dexmedetomidine for ≥96 hrs in our pediatric cardiovascular intensive care unit between January 2009 and March 2010. Patients were divided into two groups for study purposes: the dexmedetomidine group (n = 52) included patients who received a dexmedetomidine infusion along with other conventional sedation agents, and the control group (n = 42) included patients who received conventional sedation agents without the use of dexmedetomidine. Clinical outcomes evaluated in our study included days of mechanical ventilation, cardiovascular intensive care unit length of stay, hospital length of stay, and mortality. To evaluate the safety of dexmedetomidine, we collected physiologic data, including heart rate, mean arterial pressure, respiratory rate, systemic oxygen saturation by pulse oximetry, and inotrope score. To assess the efficacy of dexmedetomidine, we examined the amount and duration of concomitant sedation and analgesic infusions over a period of 24 hrs in both dexmedetomidine and control groups. We also examined the number of rescue boluses for each category prior to the initiation of sedative infusion, during the sedative infusion, and after the termination of the sedative infusion. The potential side effects evaluated in our study included nausea, vomiting, abdominal distension, dysrhythmias, neurological abnormalities, seizures, and signs and symptoms of withdrawal. Measurements and Main Results: Patients’ baseline characteristics were similar in the two groups. Patient complexity as measured by Risk-Adjusted Classification for Congenital Heart Surgery-1 score, ventricular ejection fraction, and proportion of patients receiving mechanical ventilatory support at the time of initiation of sedative infusion was also similar. The duration and amount of continuous midazolam and morphine infusions were significantly lower in the dexmedetomidine group when compared to the control group. During dexmedetomidine infusion, there was no statistical difference in the heart rate and blood pressure between the two groups. Inotrope score was significantly lower in the dexmedetomidine group as compared to the control group in the last 6 hrs prior to termination of dexmedetomidine infusion (p < .001), and at 1 hr (p < .001) and 6 hrs (p < .001) after termination of dexmedetomidine infusion. There was no difference in duration of mechanical ventilation (p = .77), cardiovascular intensive care unit length of stay (p = .29), or hospital length of stay (p = .43) in the two groups. One patient experienced junctional rhythm at 130 beats/min requiring temporary pacing. No other significant side effects were noted. A higher proportion of patients in the dexmedetomidine group were administered clonidine when compared to the control group after termination of dexmedetomidine (31% vs. 7%, p = .005). Conclusions: Prolonged dexmedetomidine administration in children with heart disease appears to be safe and is associated with decreased opioid and benzodiazepine requirement and decreased inotropic support.

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-Defined Morbidity and Mortality Associated With Pediatric Ventricular Assist Device Support at a Single US Center The Stanford Experience

Background—The use of ventricular assist devices (VADs) to bridge pediatric patients to heart transplantation has increased dramatically over the last 15 years. In this report, we present the largest US single-center report of pediatric VAD use to date. We present detailed descriptions of morbidity and mortality associated with VAD support, using standard Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria for pediatrics to facilitate the comparison of these results to other studies. Methods and Results—We retrospectively identified 25 patients younger than 18 years with 27 episodes of mechanical circulatory support using VADs as bridge to heart transplantation from January 1998 to December 2007. Survival to transplant for the entire cohort was 74%. The most common major morbidities, as defined by INTERMACS criteria for a pediatric population, were respiratory failure, major localized infections, major bleeding events, hepatic dysfunction, and right heart failure. Major neurological events occurred in 48% of the study population. The median time to the first occurrence of an adverse event was less than 14 days for respiratory failure, right heart failure, major localized infection, and major bleeding. Patients who died before transplantation had significantly more adverse events per day of support than did those who were successfully transplanted. Episodes of major bleeding, tamponade, acute renal failure, respiratory failure, and right heart failure were all associated with increased risk of mortality. Conclusions—INTERMACS criteria can be successfully used to analyze pediatric VAD outcomes. These data serve as a baseline for future studies of VAD support in children and indicate good survival rates but considerable morbidity.