Precision Medicine in Congenital Heart Disease*

Objective: Genetic syndromes (GS) are often linked to both congenital heart disease (CHD) and cardiomyopathy (CM). While GS are associated with prolonged recovery and increased morbidity and mortality following surgery for CHD, their effect on survival following pediatric heart transplantation (PHT) is not well described. We aim to compare outcomes following PHT between children with and without GS.

Methods: The United Network for Organ Sharing (UNOS) transplantation database was merged with the Pediatric Health Information System (PHIS) administrative database to identify children with major GS who received PHT from 2009-2019. Characteristics and outcomes were compared between the GS (n=225) and non-GS (n=2204) groups.

Results: Major GS were present in 225/2429 (9%) of PHT recipients. The most common syndromes were DiGeorge (n=28), muscular dystrophy (n=27), Down (n=26) and Turner (n=14). The incidence of CHD was higher in the GS compared to non-GS group, 54% vs. 38%, p<0.1. On the other hand, patient demographics, pulmonary artery pressure, incidence of renal and hepatic dysfunction, and requirement for dialysis, mechanical ventilation, ECMO and mechanical circulatory support on listing were not significantly different. [Table] The waitlist duration was also comparable between the GS (55 days, IQR 20-135) and non-GS (53 days, IQR 20-113) groups, p=0.4. The incidence of post-transplant complications were also similar including dialysis (8% vs. 5%, p=0.38), stroke (3% vs. 4%, p=0.34), primary graft dysfunction (2% vs. 2%, p=0.75), pacemaker need (1% vs. 1%, p=0.84) and rejection (3.4% vs. 3.4%, p=0.96). Post-transplant recovery parameters were likewise comparable. Survival at 10 years following PHT for GS and non-GS groups was 71% and 75%, respectively, p=0.59. This comparable survival was present in those with CM and those with CHD.

Conclusions: Children with major GS and end-stage CM or CHD are expected to have similar waitlist and post-transplant outcomes to those without GS. While early and late post-transplant care is individualized to each patient's characteristics including GS, the presence of GS should not be considered contraindication to PHT in well-selected children. 

Objective: Between 30-50% of children undergoing cardiac surgery develop cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI). Several human studies have associated nitric oxide (NO) administration via the CPB circuit with decreased incidence of AKI, although histopathologic and serologic evidence of NO efficacy for AKI attenuation are lacking.

Methods: Using a survival ovine CPB model, AKI was induced by implementing a low-flow CPB state (40 cc/kg; goal serum lactate 6 mmol/L) for two hours, followed by return to full-flow (80 cc/kg) for two hours. The experimental group (n=6) received NO via the oxygenator in the CPB circuit whereas the control group (n=5) did not receive NO. To study AKI incidence and progression, the animals were survived 72 hours post-CPB initiation before euthanasia and kidney harvest for histopathologic analyses. Serial serologic biomarkers (including LDH and creatinine) were obtained.

Results: The baseline characteristics and intraoperative hemodynamics of both groups were equivalent with regards to weight, CPB time, fluid administration, urine output (UOP, cc/kg/hr), heart rate, arterial pH, arterial pO2, and lactate (p>0.1 for all). Postoperatively, UOP, heart rate, respiratory rate, and SpO2 were comparable between groups (p>0.1 for all). As shown in the Figure (top panel), distinct serologic trends were seen in which post-CPB elevations in LDH and creatinine were much more pronounced in the control group compared to the NO group. Change in creatinine from baseline (pre-CPB) was significantly greater in the control group than NO at 16, 24, and 48 hours (p<0.05 for all). Upon histopathologic analysis, moderate/severe AKI occurred in 60% (3/5) control animals versus 0% (0/6) NO animals, with epithelial necrosis, tubular slough, cast formation, and glomerular edema occurring in the control but not NO group (Figure, bottom panel). Cortical tubular epithelial cilia lengthening (a sensitive sign of cellular injury) was significantly greater in the control group (all members) than the NO group (p=0.049).

Conclusions: In this survival ovine CPB model, NO administered via the CPB circuit demonstrated serologic and histopathologic evidence of protection from AKI. These results provide insight into one potential mechanism for CPB-associated AKI and supports the continued study of the use of NO via the CPB circuit for prevention of AKI. 

Objective: Volatile organic compounds (VOCs) are used in the sterilization and manufacture of medical equipment. VOCs have high vapor pressures and low water solubility and are emitted as gases from solids or liquids. VOCs can be mutagenic, neurotoxic, genotoxic, and/or carcinogenic. Safe limits of exposure for many VOCs are not known for neonates. This study examined determinants of VOC exposure in newborns undergoing cardiac surgery.

Methods: Nineteen metabolites of 16 VOCs (e.g., xylene, cyanide, acrolein, acrylonitrile, N, N-dimethylformamide, 1,3-butadiene, styrene, and benzene; see Table) were measured as metabolites in daily urine samples collected during the perioperative period from 10 neonates undergoing cardiac operations over 10 days (n=100 samples). VOC metabolites were quantified using reversed-phase ultra-high performance liquid chromatography and electrospray ionization tandem mass spectrometry. Repeated measures ANOVA was performed for each VOC and some commonly used medical devices. The magnitude of exposure was compared to the National Health and Nutrition Examination Survey (NHANES) observations in 3–5-year-old children.

Results: Five or more VOC metabolites were detected in every sample [measured value > limit of detection (LOD)]. The median number of metabolites in each sample > LOD was 14 (range: 5-15). In a model controlling for other factors, the use of extracorporeal membrane oxygenation (ECMO) was associated with significantly (p≤0.05) higher metabolite levels of acrolein, acrylonitrile, ethylene oxide, propylene oxide, styrene, and ethylbenzene. Non-intubated patients had higher levels of 2-aminothiazoline-4-carboxylic acid, a metabolite of cyanide suggesting exposure from the ambient air (p=0.023). Compared to NHANES, daily levels frequently were > 75th percentile for the following analytes: N-acetyl-S-(benzyl)-L-cysteine (63 of 100 samples), N-acetyl-S-(2-cyanoethyl)-L-cysteine (47 of 100 samples), and N-acetyl-S-(2-hydroxyethyl)-L-cysteine (87 of 100 samples).

Conclusions: VOC exposure in newborns undergoing cardiac surgery is pervasive. Sources of exposure likely include medical devices (ECMO) and inhalation from the air in the intensive care unit. The safe levels of VOC exposure in neonates are unknown. The magnitude of exposure to some VOCs is greater than the reference population. The contribution of VOC exposure during cardiac surgery in newborns to adverse outcomes warrants further evaluation. 

OBJECTIVE:
Patients with connective tissue disease with aortic root aneurysm are at risk of dissection and progression of the dilatation. Standard treatment is either a total root replacement or a valve-sparing root replacement. Both procedures have drawbacks such as the need for anticoagulation and complications of the aortic valve. Personalized External Aortic Root Support has been introduced to reduce these risks with similar beneficial outcome. Our purpose is to evaluate the safety and efficacy in the first patients undergoing Personalized External Aortic Root Support in the Netherlands.
METHODS:
From January 2018 to September 2022, a total of 76 patients underwent either an isolated Personalized External Aortic Root Support procedure or Personalized External Aortic Root Support with concomitant valve- and/or rhythm surgery or a combined Ross and Personalized External Aortic Root Support procedure in two centres. Isolated Personalized External Aortic Root Support was generally performed off-pump under controlled hypotension. Patient characteristics, preoperative and postoperative echocardiography and computed tomography or magnetic resonance imaging were assessed.
RESULTS:
Median age was 34 (SD±15) years and 51 (67%) patients were male. Among all patients 36 (48%) had Marfan syndrome, 10 (13%) Loeys-Dietz syndrome and 18 (24%) had a bicuspid aortic valve. Fifty three (70%) patients underwent isolated Personalized External Aortic Root Support, 17 (22%) a Ross-Personalized External Aortic Root Support and 6 (8%) patients underwent Personalized External Aortic Root Support with concomitant surgery. Mean sinus of Valsalva diameter prior to surgery was 45.1 mm (SD±5.1). All but one patient had a successful placement of root support. Three patients (in the isolated Personalized External Aortic Root Support group) were converted to cardiopulmonary bypass. Two Ross-Personalized External Aortic Root Support patients needed reoperation due to Personalized External Aortic Root Support-related issues in the follow-up period. No death, aortic dissection, endocarditis or thrombo-embolic complications occurred in 32 postoperative patient years of follow-up. At follow-up all aortic diameters were stable or even reduced (median 39.5 (IQR 36-42)).
CONCLUSIONS:
Personalized External Aortic Root Support has promising in-hospital and early follow-up results in selected patients. Longer follow up is needed to assess the incidence of late aortic complic 

Objective: Peripheral regional anesthesia is proposed to enhance recovery. We sought to evaluate: the efficacy of bilateral continuous erector spinae blocks (B-ESpB) for postoperative analgesia in children undergoing cardiac surgery in an Enhanced Recovery After Surgery (ERAS) program; the opioid-sparing effect of the B-ESpB; and the impact on recovery.

Methods: Patients ages 2 to <18 yrs undergoing cardiac surgery in the ERAS program were prospectively enrolled to receive B-ESpB at the end of the procedure, with continuous infusions for 48 hrs. Participants wore a smartwatch in the ICU until discharge. B-ESpB patients were retrospectively matched 1:2 with control patients in the ERAS program according to procedure and diagnosis. Other characteristics for matching included: Age, BMI, CPB, gender, prior sternotomies, and associated conditions. Outcomes of the matched clusters were compared using exact conditional logistic regression and generalized linear modeling. To meet model assumptions, variables were log- or square-root-transformed when necessary.

Results: Group sizes were 40 B-ESpB and 78 ERAS controls. There were no major complications from the B-ESpBs, and additional operating room time was 31 min. There was no difference in early extubation between groups (table). B-ESpB received fewer opioids in oral morphine equivalent (OME) than ERAS controls at 24 hours (0.60±0.06 vs 0.78±0.04, OME; mg/kg, p= 0.02) and at 48 hours (1.13±0.08 vs 1.35±0.06, OME; mg/kg, p= 0.04), respectively. Fewer non-opioid analgesics were administered in B-ESpB than ERAS controls: 2.5±1.1 vs. 2.9±1.0 mg/kg IV ketorolac, p= 0.049. Both groups had similar low median pain scores per shift. There was no difference in early mobilization, length of stay, and complications. At 6-day follow-up (IQR 5-9), similar percentages of patients reported use of pain medication, and no opioids in the B-ESpB group. In the B-ESpB patients with smartwatch, there was no correlation of OME or pain score with measures of heart rate variability or steps taken prior to discharge. There was a mild correlation (R=0.28) between OME and ratio of REM vs. total sleep (p=0.10).

Conclusion: B-ESpB are safe in children undergoing cardiac surgery. When B-ESpB is performed as part of a multimodal pain strategy in an ERAS program, pediatric patients experience good pain control and require fewer opioids in the first 48 hours however, there was no impact on length of stay. 

Objective: To evaluate neonatal outcomes depending on different treatment strategies for hemodynamically significant patent ductus arteriosus (hsPDA) in preterm very-low-birth-weight (VLBW) infants, in regard to treatment time point.
Methods: This retrospective cohort study was conducted including 430 preterm infants with PDA (186 hsPDA, 43.3%) born between September 2014 and January 2021. Outcomes were compared between treatment strategies (277 conservative vs 153 active). To identity the optimal timing of surgical closure, surgical patients were classified in three subgroups: early primary closure (≤14 post-natal age), late primary closure (>14 post-natal age), and secondary closure after failed pharmacological closure. Adjusted linear logistic regression was conducted to analyze risk factors for in-hospital death, bronchopulmonary dysplasia, post-ligation cardiac syndrome, and acute kidney injury. Significant risk factors were adjusted to identify the optimal period for surgical closure by non-linear regression model.
Results: Active treatment group showed significantly lower in-hospital death compared to the conservative treatment group in overall (adjusted odd ratio (aOR), 0.29; p=0.002) and when subanalyzed in infants with hsPDA (aOR, 0.22; p=0.003). With non-linear regression, the primary surgical closure group presented lower probability for the composite outcome of in-hospital death or bronchopulmonary dysplasia when postmenstrual age was greater than 28 weeks, compared to the secondary closure group. In terms of postoperative complications, the probability for composite outcome of post-ligation cardiac syndrome or acute kidney injury was also lower in the primary closure group when postmenstrual age was less than 32 weeks, compared to the secondary closure group. At postmenstrual age 28 to 32 weeks, early primary closure group experienced the most benefit in terms of in-hospital death or bronchopulmonary dysplasia (early 51.5% vs late 82.1% vs secondary 82.3%, p<0.001) and post-ligation syndrome or acute kidney injury (early 17.8% vs late 22.6% vs secondary 38.4%, p<0.001).
Conclusion: Considering in-hospital death, active treatment is recommended in VLBW infants with hsPDA. In particular, primary surgical closure rather than secondary closure provides maximal benefit and minimal risk of surgery at postmenstrual age 28 to 32 weeks, implying that this could serve as the optimal timing for primary surgical closure of hsPDA in VLBW infants.