Michael E. Mitchell

Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18.

OBJECTIVE We sought to evaluate performance of a noninvasive prenatal test for fetal trisomy 21 (T21) and trisomy 18 (T18). STUDY DESIGN A multicenter cohort study was performed whereby cell-free DNA from maternal plasma was analyzed. Chromosome-selective sequencing on chromosomes 21 and 18 was performed with reporting of an aneuploidy risk (High Risk or Low Risk) for each subject. RESULTS Of the 81 T21 cases, all were classified as High Risk for T21 and there was 1 false-positive result among the 2888 normal cases, for a sensitivity of 100% (95% confidence interval [CI], 95.5-100%) and a false-positive rate of 0.03% (95% CI, 0.002-0.20%). Of the 38 T18 cases, 37 were classified as High Risk and there were 2 false-positive results among the 2888 normal cases, for a sensitivity of 97.4% (95% CI, 86.5-99.9%) and a false-positive rate of 0.07% (95% CI, 0.02-0.25%). CONCLUSION Chromosome-selective sequencing of cell-free DNA and application of an individualized risk algorithm is effective in the detection of fetal T21 and T18.

Near-infrared spectroscopy in neonates before palliation of hypoplastic left heart syndrome.

BACKGROUND Neonates with hypoplastic left heart syndrome have circulatory vulnerability that results in shock and high risk of mortality without intervention. High arterial saturation (SaO(2)) is often used as a proxy for inadequate systemic oxygen delivery and triggers the use of invasive therapies to restore circulatory balance. We hypothesized that preoperative use of near-infrared spectroscopy (NIRS) would reduce the need for invasive therapies, including controlled ventilation and inspired gas manipulation. METHODS A Human Research Review Board-approved retrospective review of patients who had stage 1 palliation from January 2000 to January 2006 was conducted. Preoperative patient characteristics, cardiorespiratory support, and monitored data were collected for all patients. Cerebral and somatic tissue oxyhemoglobin saturations were recorded for patients with preoperative NIRS monitoring. RESULTS The studied cohort included 92 patients, 47 without and 45 with preoperative NIRS. Patient characteristics were similar between groups. Differences were observed in preoperative respiratory support. Controlled ventilation was less common in the NIRS group (51% versus 79%, p = 0.005) as was the use of inspired nitrogen (16% versus 70%, p = 0.001). The NIRS patients had higher mean SaO(2) (92% versus 88%, p = 0.001). Age at surgery was similar between groups (5.7 +/- 3.2 versus 6.5 +/- 5.2 days, p = 0.3). Early survival was 96% in each group. CONCLUSIONS Near-infrared spectroscopy monitoring of patients with hypoplastic left heart syndrome awaiting palliation provides noninvasive assessment of oxygen delivery and simplified management, with reduced use of controlled ventilation and inspired gas. Higher SaO(2) in the NIRS group was not associated with impaired systemic oxygen delivery, and did not lead to earlier palliation or postoperative mortality.

Perioperative monitoring in high-risk infants after stage 1 palliation of univentricular congenital heart disease

OBJECTIVE Survival of high-risk patients with univentricular heart disease after Norwood palliation is reduced. We hypothesized that early goal-directed monitoring with venous oximetry and near-infrared spectroscopy would offset their increased vulnerability and improve survival. METHODS A prospective database of patients undergoing stage 1 palliation was used to assess differences in outcomes across risk groups in the setting of a comprehensive, goal-directed monitoring program. High-risk criteria included gestational age 35 weeks or less, birth weight less than 2.5 kg, and additional cardiac or extracardiac anomalies. Outcomes included survival to defined end points and measures of postoperative support. RESULTS From September 2000 to September 2008, 162 patients underwent stage 1 palliation: 28% (45/162) high-risk and 72% (117/162) standard-risk patients. Lesions other than hypoplastic left heart syndrome were more common among high-risk patients (38%, 17/45, vs 15%, 18/117, P = .003). Operative survival was not statistically different(87%, 39/45, high risk vs 95%, 111/117, standard risk, P = .1). High-risk patients were more likely to receive inpatient treatment until stage 2 palliation (24%, 11/45, vs 10%, 12/117, P = .001) and had lower 1-year survival (78% vs 93%, P = .01) and survival to date (71% vs 92%, P = .001). CONCLUSIONS Intensive monitoring partially offset biologic vulnerability of high-risk patients, helping attain comparable early outcomes. Vulnerability persisted throughout the interstage period, however, and increased mortality beyond cavopulmonary shunt was seen only among high-risk patients. Although enhanced monitoring reduced early mortality, high resource use and attrition after stage 2 palliation suggest an ongoing need to evaluate our current palliative strategy for this subset of patients.

Use of a HeartWare Ventricular Assist Device in a Patient With Failed Fontan Circulation

We present a successful case of the use of a HeartWare ventricular assist device as a bridge to transplantation in an 11-year-old with a hypoplastic left heart and failed Fontan circulation.

Non-Invasive Prenatal Detection of Trisomy 21 Using Tandem Single Nucleotide Polymorphisms

Background Screening tests for Trisomy 21 (T21), also known as Down syndrome, are routinely performed for the majority of pregnant women. However, current tests rely on either evaluating non-specific markers, which lead to false negative and false positive results, or on invasive tests, which while highly accurate, are expensive and carry a risk of fetal loss. We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA. Methods and Findings Highly heterozygous tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 were analyzed using High-Fidelity PCR and Cycling Temperature Capillary Electrophoresis (CTCE). This approach was used to blindly analyze plasma DNA obtained from peripheral blood from 40 high risk pregnant women, in adherence to a Medical College of Wisconsin Institutional Review Board approved protocol. Tandem SNP sequences were informative when the mother was heterozygous and a third paternal haplotype was present, permitting a quantitative comparison between the maternally inherited haplotype and the paternally inherited haplotype to infer fetal chromosomal dosage by calculating a Haplotype Ratio (HR). 27 subjects were assessable; 13 subjects were not informative due to either low DNA yield or were not informative at the tandem SNP sequences examined. All results were confirmed by a procedure (amniocentesis/CVS) or at postnatal follow-up. Twenty subjects were identified as carrying a disomy 21 fetus (with two copies of chromosome 21) and seven subjects were identified as carrying a T21 fetus. The sensitivity and the specificity of the assay was 100% when HR values lying between 3/5 and 5/3 were used as a threshold for normal subjects. Conclusions In summary, a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma.

Outcomes of systemic to pulmonary artery shunts in patients weighing less than 3 kg: analysis of shunt type, size, and surgical approach.

OBJECTIVE To evaluate outcomes of systemic to pulmonary artery shunts (SPS) in patients weighing less than 3 kg with regard to shunt type, shunt size, and surgical approach. METHODS Patients weighing less than 3 kg who underwent modified Blalock-Taussig or central shunts with polytetrafluoroethylene grafts at our institution from January 1, 2000, to May 31, 2011, were reviewed. Patients who had undergone other major concomitant procedures were excluded from the analysis. Primary outcomes included mortality (discharge mortality and mortality before next planned palliative procedure or definitive repair), cardiac arrest and/or extracorporeal membrane oxygenation (ECMO), and shunt reintervention. RESULTS In this cohort of 80 patients, discharge survival was 96% (77/80). Postoperative cardiac arrest or ECMO occurred in 6/80 (7.5%), and shunt reintervention was required in 14/80 (17%). On univariate analysis, shunt reintervention was more common in patients with 3-mm shunts (11/30, 37%) compared with 3.5-mm (2/36, 6%) or 4-mm shunts (1/14, 7%) (P < .003). There were no statistically significant associations between shunt type, shunt size, or surgical approach and cardiac arrest/ECMO or mortality. Multiple logistic regression demonstrated that a shunt size of 3 mm (P = .019) and extracardiac anomaly (P = .047) were associated with shunt reintervention, whereas no variable was associated with cardiac arrest/ECMO or mortality. CONCLUSIONS In this high-risk group of neonates weighing less than 3 kg at the time of SPS, survival to discharge and the next planned surgical procedure was high. Outcomes were good with the 3.5- and 4-mm shunts; however, shunt reintervention was common with 3-mm shunts.

Coarctectomy combined with an interdigitating arch reconstruction results in a lower incidence of recurrent arch obstruction after the Norwood procedure than coarctectomy alone

OBJECTIVE Recurrent aortic arch obstruction after the Norwood procedure continues to be a source of morbidity. We sought to determine if a modified interdigitating technique for aortic arch reconstruction during the Norwood procedure decreased recurrent arch obstruction. METHODS A total of 142 consecutive infants undergoing the Norwood procedure were divided into groups according to surgical technique: Group 1 (n = 79, January 1999 to May 2003) underwent arch reconstruction with complete coarctectomy followed by anastomosis of the descending aorta to the transverse arch. Group 2 (n = 63, June 2003 to September 2006) underwent complete coarctectomy plus a modified interdigitating technique. Catheterization before stage 2 palliation was reviewed for hemodynamics and angiographic arch dimensions, and a coarctation index was calculated. RESULTS Reintervention for recurrent coarctation occurred in 28% (22/79) of group 1 patients compared with 2% (1/63) of group 2 patients (P = .001). Aortic pressures, gradients, dimensions, and coarctation index were consistently more favorable for group 2. CONCLUSIONS Coarctectomy plus an interdigitating arch anastomosis was superior to coarctectomy alone and resulted in a dramatically decreased incidence of recurrent arch obstruction.

Effect of continuous and pulsatile flow left ventricular assist on pulsatility in a pediatric animal model of left ventricular dysfunction: pilot observations.

Pediatric ventricular assist devices are being developed that can produce pulsatile flow (PF) or continuous flow (CF). An important aspect of choosing between these two modes is understanding the consequences of each mode on pediatric vascular pulsatility. Differences in vascular pulsatility generated by PF and CF operation of the 3-inch pediatric cardiopulmonary assist system (pCAS, Ension, Inc., Pittsburgh, PA) were investigated while providing left atrium–to–aorta left ventricular assist (LVA), using an infant animal model of left ventricular dysfunction. Hemodynamic data were digitally recorded with the pCAS providing LVA at incremental flow rates while operating in continuous mode, pulsatile mode at 100 bpm, and pulsatile mode at 140 bpm. These data were used to calculate vascular input impedance (Zart), energy equivalent pressure, and surplus hemodynamic energy as indices of pulsatility for partial (50% of maximum) and maximum LVA flow. Both CF and PF LVA by the pCAS resulted in favorable hemodynamic rectification of left ventricular dysfunction while generating equivalent flows. PF LVA maintained a greater degree of pulsatility compared with CF, as evidenced by increasing energy equivalent pressure and a lesser drop in surplus hemodynamic energy with increasing pCAS flow. Differences in Zart modulus and phase were indiscernible. The selection of flow mode may have long-term consequences on Zart and end-organ perfusion affecting clinical outcomes in pediatric patients.

Thromboelastography in the assessment of bleeding following surgery for congenital heart disease.

Background: Perioperative bleeding is common in pediatric cardiac surgery patients. Traditional laboratory tests do not adequately characterize coagulation derangements in patients with bleeding. We sought to establish preoperative thromboelastography parameters in children prior to cardiopulmonary bypass, to compare thromboelastography assessment with standard coagulation parameters postoperatively, and to assess thromboelastography in children with significant hemorrhage. Methods: Sixty patients requiring cardiopulmonary bypass were enrolled in a prospective observational study of perioperative thromboelastography. Thromboelastography measures were obtained preoperatively, intraoperatively after protamine administration, upon admit to the intensive care unit, and when patients were treated for bleeding. Thromboelastography measures were not used for clinical care. Postoperative thromboelastography measurements were compared with the standard coagulation parameters. Intraoperative thromboelastography, postoperative thromboelastography, and clinical outcomes were compared among patients who did and did not have significant postoperative bleeding. Results: Preoperative thromboelastography parameters were similar to other published normal values for pediatric patients. Transfusion recommendations based on thromboelastography measurements were significantly different from those based on the standard coagulation testing. Thromboelastography measures after initial protamine administration were significantly different in patients with postoperative bleeding. This difference was not present upon arrival to the intensive care unit. Patients with significant bleeding tended to cease bleeding when clinical interventions were in agreement with recommendations based on thromboelastography. Conclusions: Pediatric patients with significant postoperative bleeding after surgery are more likely to have abnormal thromboelastography early after cessation of cardiopulmonary bypass. Thromboelastography illustrates derangements in the coagulation system and may aid in the treatment of postoperative bleeding.

Use of Cell-Free Fetal DNA in Maternal Plasma for Noninvasive Prenatal Screening

Noninvasive prenatal testing (NIPT) using cell-free fetal (cfDNA) offers potential as a screening tool for fetal anomalies. All pregnant women should be offered prenatal screening and diagnostic testing based on current guidelines. Adoption of NIPT in high-risk pregnancies suggests a change in the standard of care for genetic screening; there are advantages to an accurate test with results available early in pregnancy. This accuracy decreases the overall number of invasive tests needed for diagnosis, subjecting fewer pregnancies to the risks of invasive procedures. Women undergoing NIPT need informed consent before testing and accurate, sensitive counseling after results are available.