Faculty Bibliography

An established echocardiographic (echo) standard for assessing the newborn right ventricle (RV) for hypertrophy has not been thoroughly developed. This is partially due to the RV's complex architecture, which makes quantification of RV mass by echo difficult. Here, we retrospectively evaluate the thickness of the inferior RV wall (iRVWT) by echo in neonates and infants with normal cardiopulmonary physiology. Inferior RVWT was defined at the medial portion of the inferior wall of the RV at the mid-ventricular level, collected from a subxiphoid, short axis view. iRVWT was indexed to body surface area (BSA) to the 0.5 power and normalized to iLVWT to explore the best normalization method. Ninety-eight neonates and 32 infants were included in the final analysis. Mean age for neonates and infants was 2 days and 59 days, respectively. Mean ± SD for neonate and infant end-diastole iRVWT was 2.17 ± 0.35 mm and 1.79 ± 0.28 mm, respectively. There was no residual relationship between the index iRVWT and BSA (r = 0.03, p = NS). In the infant cohort, the iRVWT was significantly lower and iLVWT was significantly higher compared to neonate, consistent with known physiologic changes of RV and LV mass. Thus, iRVWT may serve as a reliable and accurate proxy for RV mass and the parameter warrants further evaluation.

BACKGROUND:Antiretroviral options for neonates (< 28 days of life) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the '4-in-1' fixed-dose paediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates. METHODS:The PETITE study is an ongoing phase I/II, open-label, single arm, two-stage trial conducted in South Africa. In Stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine +/- zidovudine) received single dose(s) of the 4-in-1 formulation followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn following an observed dose at 1, 2, 4, 8- and 12-hours post-dose. Here, we report the planned interim pharmacokinetic and safety analysis after completion of the single dose administration. RESULTS:Sixteen neonates, median (range) birth weight 3130 (2790-3590) g, completed 24 pharmacokinetic visits. The 4-in-1 imposed relatively high mg/kg doses of abacavir 8.6 (6.6-11.4) and lamivudine 4.3 (3.3-5.7), but lower lopinavir doses of 11.5 (8.8-15.2). Geometric mean (GM, 90% CI) AUC0-12 of abacavir, lamivudine and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83) and 3.49 (2.13-5.72) µg.hr/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.hr/mL) and ritonavir concentrations were only detectable in 4/120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1. CONCLUSION/CONCLUSIONS:The high mg/kg abacavir and lamivudine doses and AUCs were safe, and the formulation well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates. Alternative paediatric solid antiretroviral formulations must be studied in neonates.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

BACKGROUND:Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS:Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. RESULTS:Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were <2 years of age, and 8 (9%) were HIV-positive. The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16 kg child. Stunting and HIV infection increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥ 500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (inter-individual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. CONCLUSIONS:Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when co-administered with other QT-prolonging agents.

Objective/UNASSIGNED:Although the right ventricle (RV) to pulmonary artery conduit in stage 1 Norwood operation results in improved interstage survival, the long-term effects of the ventriculotomy used in the traditional technique remain a concern. The periscopic technique (PT) of RV to pulmonary artery conduit placement has been described as an alternative technique to minimize RV injury. A retrospective study was performed to compare the effects of traditional technique and PT on ventricular function following Norwood operation. Methods/UNASSIGNED:A retrospective study of all patients who underwent Norwood operation from 2012 to 2019 was performed. Patients with baseline RV dysfunction and significant tricuspid valve regurgitation were excluded. Prestage 2 echocardiograms were reviewed by a blinded experienced imager for quantification of RV function (sinus and infundibular RV fractional area change) as well as for regional conduit site wall dysfunction (normal or abnormal, including hypokinesia, akinesia, or dyskinesia). Wilcoxon rank-sum tests were used to assess differences in RV infundibular and RV sinus ejection fraction and the Fisher exact test was used to assess differences in regional wall dysfunction. Results/UNASSIGNED: = .002). Conclusions/UNASSIGNED:The PT for RV to pulmonary artery conduit in Norwood operation results in better preservation of early RV global and regional systolic function. Whether or not this benefit translates to improved clinical outcome still needs to be studied.

Intrapericardial teratomas are rare, predominantly benign tumors that warrant surgical resection in the neonatal period because of their potential detrimental effects on the cardiorespiratory system. Surgical resection can be a challenge when the tumor encases and obscures a coronary artery. Adherence to certain operative principles is necessary to achieve successful outcomes.

Diagnosis of anomalous origin of the right subclavian artery (AORSA) from the right pulmonary artery (RPA) is usually made using CT, MRI, or invasive angiography. We report a patient diagnosed using transthoracic echocardiography (TTE). A newborn girl prenatally known to have d-TGA presented with cyanosis sparing the right hemithorax and arm. Oxygen saturations on the right hand were persistently higher than on the right ear and other extremities. Repeat TTE using a modified echocardiographic imaging plane allowed for full visualization of the entire subclavian artery course, revealing AORSA from RPA. We discuss further the approach to echocardiographic diagnosis and surgical implications.

Quantification of left ventricular (LV) mass by echocardiography has not been validated against the gold standard of cardiac magnetic resonance imaging (CMR) in the pediatric population. The purpose of this study was to compare LV mass by two-dimensional and conventional M-mode echocardiography versus CMR in children. Consecutive CMR studies were paired with echocardiograms and retrospectively analyzed in children age ≤ 16 years (3 days old to 16 years old). Studies performed > 3 months between modalities and single ventricle anatomy were excluded. Unindexed LV mass was calculated using M-mode, area-length (AL), and truncated ellipsoid (TE) methods via echocardiography, and compared to cine stack CMR images. There were 46 patients included in the study (both MRI and echocardiography). Good correlations were observed for LV mass measured by CMR and all echocardiographic methods: M-mode (R = 0.965), AL (R = 0.975), and TE (R = 0.975). There was a significant overestimation using TE echocardiography, by a mean of 10.5 g (95% confidence interval 5.7-15.2 g, p < 0.05). There was no significant over- or underestimation of LV mass observed by M-mode or AL echocardiographic measurements, with tight limits of agreement when compared to CMR (95% confidence interval - 5.2 to 4.4 g and - 1.5 to 6.7 g, respectively). Interobserver agreement was good for each of the echocardiographic measurements, but inferior with M-mode (ICC, 0.89) compared to two-dimensional methods (ICC, 0.97). Echocardiographic estimates of LV mass have good correlation with CMR in children. Performance comparison showed AL echocardiographic method provides the most accurate measurement of LV mass with the best reproducibility compared to other methods.