Liposomal bupivacaine reduces opioid requirements following Ravitch repair for pectus excavatum.

Background and Aims: The management of post-operative pain after surgical repair of pectus excavatum with the Ravitch procedure is challenging. Although previous studies have compared various methods of pain control in these patients, few have compared different local anesthetics. This retrospective analysis compares the use of bupivacaine to its longer-acting form, liposomal bupivacaine, in patients who had undergone pectus excavatum repair with the Ravitch method. Material and Methods: Eleven patients who received local infiltration with liposomal bupivacaine were matched to 11 patients who received local infiltration utilizing bupivacaine with epinephrine. The primary outcome was total morphine milligram equivalents per kilogram body weight (MME/kg) over the complete length of hospital stay. Secondary outcomes included total cumulative diazepam, acetaminophen, ondansetron, and NSAID dose per kilogram body weight (mg/kg) over the course of the hospital stay, chest tube drainage (ml/kg body weight), number of post-operative hours until the first bowel movement, Haller Index, patient request for magnesium hydroxide, average pain scores from post-operative day 1 to post-operative day 5, and length of hospital stay. Continuous variables were reported as medians with inter-quartile ranges, and categorical values were reported as percentages and frequencies. Results: The total MME/kg [1.7 (1.2-2.4) vs 2.9 (2.0-3.9), P = 0.007] and hydromorphone (mg/kg) [0.1 (0.0-0.2) vs 0.3 (0.1-0.4), P = 0.006] use in the liposomal bupivacaine group versus bupivacaine with epinephrine was significantly reduced over total length of hospital stay. Similarly, there was a reduction in diazepam use in the liposomal bupivacaine group versus the bupivacaine group [0.4 (0.1-0.8) vs 0.6 (0.4-0.7), P = 0.249], but this did not reach statistical significance. The total dose of ondansetron (mg/kg) was not statistically different when comparing the liposomal bupivacaine group to the bupivacaine group [0.3 (0.0-0.5) vs 0.3 (0.2-0.6), P = 0.332]. Interestingly, the total dose of acetaminophen (mg/kg) was statistically increased in the liposomal bupivacaine group compared to the bupivacaine with epinephrine group [172 (138-183) vs 74 (55-111), P = 0.007]. Additionally, the total chest tube drainage (ml/kg) was significantly reduced in the liposomal bupivacaine group [9.3 (7.5-10.6) vs 12.8 (11.3-18.5), P = 0.027]. Finally, the percentage of patients without requests for magnesium hydroxide to promote laxation was significantly higher in the liposomal bupivacaine group than in the bupivacaine group (63.6% vs 18.2%, P = 0.027). Conclusion: The use of liposomal bupivacaine for local infiltration in patients who undergo the Ravitch procedure for pectus repair offers advantages over plain bupivacaine, including reduced opioid consumption and opioid-related side effects. However, more data are needed to understand the significance of these findings.

Characterization of Circulating Cold Shock Proteins FGF21 and RBM3 in a Multi-Center Study of Pediatric Cardiac Arrest.

Fibroblast Growth Factor 21 (FGF21) is a neuroprotective hormone induced by cold exposure that targets the ß-klotho co-receptor. ß-klotho is abundant in the newborn brain but decreases rapidly with age. RNA-Binding Motif 3 (RBM3) is a potent neuroprotectant upregulated by FGF21 in hypothermic conditions. We characterized serum FGF21 and RBM3 levels in patients enrolled in a prospective multi-center study of pediatric cardiac arrest (CA) via a secondary analysis of samples collected to evaluate brain injury biomarkers. Patients (n = 111) with remnant serum samples available from at least two of three available timepoints (0-24, 24-48 or 48-72 hours post-resuscitation) were included. Serum samples from 20 healthy controls were used for comparison. FGF21 was measured by Luminex and internally validated enzyme-linked immunoassay (ELISA). RBM3 was measured by internally validated ELISA. Of postarrest patients, 98 were managed with normothermia, while 13 were treated with therapeutic hypothermia (TH). FGF21 increased >20-fold in the first 24 hours postarrest versus controls (681 pg/mL [200-1864] vs. 29 pg/mL [15-51], n = 99 vs. 19, respectively, p < 0.0001, median [interquartile range]) with no difference in RBM3. FGF21 did not differ by sex, while RBM3 was increased in females versus males at 48-72 hours postarrest (1866 pg/mL [873-5176] vs. 1045 pg/mL [535-2728], n = 40 vs. 54, respectively, p < 0.05). Patients requiring extracorporeal membrane oxygenation (ECMO) postresuscitation had increased FGF21 versus those who did not at 48-72 hours (6550 pg/mL [1455-66,781] vs. 1213 pg/mL [480-3117], n = 7 vs 74, respectively, p < 0.05). FGF21 and RBM3 did not correlate (Spearman's rho = 0.004, p = 0.97). We conclude that in a multi-center study of pediatric CA patients where normothermic targeted temperature management was largely used, FGF21 was markedly increased postarrest versus control and highest in patients requiring ECMO postresuscitation. RBM3 was sex-dependent. We provide a framework for future studies examining the effect of TH on FGF21 or use of FGF21 therapy after pediatric CA.

QRS Duration After Pulmonary Valve Replacement in Adults with Repaired Tetralogy of Fallot: Association with Ventricular Arrhythmia and Correlation with Right Ventricular Size.

The aim of this study is to analyze the relationship between QRS duration after pulmonary valve replacement (PVR) and ventricular arrhythmias (VA) in patients with repaired tetralogy of Fallot (ToF). ToF patients may face complications such as heart failure and VA after primary repair, often mitigated by PVR. Prior studies have shown a decrease in QRS duration and right ventricular (RV) size following PVR. It remains unclear whether a lack of QRS duration reduction identifies patients at risk of VA. We retrospectively identified adult patients with repaired ToF who underwent surgical or transcatheter PVR. EKG data (pre-PVR, 30 days to 1-year post-PVR, and closest to CMR) was collected. The primary endpoint was sustained ventricular tachycardia (VT), ICD shock for sustained VT, or inducible VT on EP study. 85 patients were included (median follow-up 3.6 years; median age 34 years; 51% females). The primary outcome was noted in 8 patients. Mean QRS duration decreased by 5 ms following PVR (p = 0.0001). Increased age at PVR, QRS ≥ 180 ms post-PVR, no reduction in QRS after PVR, and a history of VT were associated with higher risk of the primary endpoint. The change in QRS was linearly correlated with the change in RVEDVi (R = 0.66). Adults with repaired ToF experience a reduction in QRS duration post-PVR that correlates with the change of the RV size. Patients with QRS ≥ 180 ms post-PVR, no reduction in QRS, increased age at repair, and a history of VT are at risk for recurrent VT and warrant closer monitoring/ICD consideration.

FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia-ischemia.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking. METHODS: We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O2/92% N2) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor ß-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury. RESULTS: HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal ß-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d. CONCLUSIONS: FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI. IMPACT: Hypoxic-ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain. HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury. HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner. Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP). Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.

Factors associated with the need for inotropic support following pulmonary artery banding surgery for CHD.

OBJECTIVE: We aimed to identify factors independently associated with the need for inotropic support for low cardiac output or haemodynamic instability after pulmonary artery banding surgery for CHD. METHODS: We performed a retrospective chart review of all neonates and infants who underwent pulmonary banding between January 2016 and June 2019 at our institution. Bivariate and multivariable analyses were performed to identify factors independently associated with the use of post-operative inotropic support, defined as the initiation of inotropic infusion(s) for depressed myocardial function, hypotension, or compromised perfusion within 24 hours of pulmonary artery banding. RESULTS: We reviewed 61 patients. Median age at surgery was 10 days (25%,75%:7,30). Cardiac anatomy was biventricular in 38 patients (62%), hypoplastic right ventricle in 14 patients (23%), and hypoplastic left ventricle in 9 patients (15%). Inotropic support was implemented in 30 patients (49%). Baseline characteristics of patients who received inotropic support, including ventricular anatomy and pre-operative ventricular function, were not statistically different from the rest of the cohort. Patients who received inotropic support, however, were exposed to larger cumulative doses of ketamine intraoperatively - median 4.0 mg/kg (25%,75%:2.8,5.9) versus 1.8 mg/kg (25%,75%:0.9,4.5), p < 0.001. In a multivariable model, cumulative ketamine dose greater than 2.5mg/kg was associated with post-operative inotropic support (odds ratio 5.5; 95% confidence interval: 1.7,17.8), independent of total surgery time. CONCLUSIONS: Inotropic support was administered in approximately half of patients who underwent pulmonary artery banding and more commonly occurred in patients who received higher cumulative doses of ketamine intraoperatively, independent of the duration of surgery.

Serial Magnetic Resonance Imaging for Aortic Dilation in Tetralogy of Fallot With Pulmonary Stenosis.

Aortic dilation occurs in patients with repaired tetralogy of Fallot (TOF), but the rate of growth is incompletely characterized. The aim of this study was to assess the rates of growth of the aortic root and ascending aorta in a cohort of pediatric and adult patients with sequential magnetic resonance angiography Magnetic Resonance Imaging (MRI) data. Using serial MRI data from pediatric and adult patients with repaired TOF, we performed a retrospective analysis of the rates of growth and associations with growth of the aortic root and ascending aorta. Patients with pulmonary atresia or absent pulmonary valve were excluded. Between years 2005 to 2021, a total of 99 patients were enrolled. A follow-up MRI was performed an average of 5.9 ± 3.7 years from the initial study. For the cohort aged ≥16 years, the mean rate of change in diameter was 0.2 ± 0.5 mm/year at the ascending aorta and 0.2 ± 0.6 mm/year at the sinus of Valsalva. For the entire cohort, the mean change in cross-sectional area indexed to height at the ascending aorta was 7 ± 12 mm2/m/year and at the sinus of Valsalva was 10 ± 16 mm2/m/year. Younger age was associated with higher rates of growth of the sinus of Valsalva while the use of ß blockers or angiotensin-converting enzyme inhibitors was associated with a slower rate of growth. There were no cases of aortic dissection in this cohort. We conclude that serial MRI demonstrates a slow rate of growth of the aorta in the TOF.

Impact of Home Monitoring Program and Early Gastrostomy Tube on Interstage Outcomes following Stage 1 Norwood Palliation.

Nutritional management and home monitoring programs (HMPs) may be beneficial for improving interstage morbidity and mortality following stage I Norwood palliation (S1P) for hypoplastic left heart syndrome (HLHS). We recognized an increasing trend towards early feeding gastrostomy tube (GT) placement prior to discharge in our institution, and we aimed to investigate the effect of HMPs and GTs on interstage mortality and growth parameters. Single-institutional review at a tertiary referral center between 2008 and 2018. Individual patient charts were reviewed in the electronic medical record. Those listed for transplant or hybrid procedures were excluded. Baseline demographics, operative details, and interstage outcomes were analyzed in GT and non-GT patients (nGT). Our HMP was instituted in 2009, and patients were analyzed by era: I (early, 2008-2012), II (intermediate, 2013-2016), and III (recent, 2017-2018). 79 patients were included in the study: 29 nGTs and 50 GTs. GTs had higher number of preoperative risk factors more S1P complications, longer ventilation times, longer lengths of stay, and shorter times to readmission. There were no differences in interstage mortality or overall mortality between groups. There was one readmission for a GT-related issue with no periprocedural complications in the group. Weight gain doubled after GT placement in the interstage period while waiting periods for placement decreased across Eras. HMPs and early GTs, especially for patients with high-risk features, provide a dependable mode of nutritional support to optimize somatic growth following S1P.

Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease.

Background Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality (P=0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality (P=0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.

Perioperative and long-term outcomes of Ross versus mechanical aortic valve replacement.

BACKGROUND: The ideal aortic valve replacement strategy in young- and middle-aged adults remains up for debate. Clinical practice guidelines recommend mechanical prostheses for most patients less than 50 years of age undergoing aortic valve replacement. However, risks of major hemorrhage and thromboembolism associated with long-term anticoagulation may make the pulmonary autograft technique, or Ross procedure, a preferred approach in select patients. METHODS: Data were retrospectively collected for patients 18-50 years of age who underwent either the Ross procedure or mechanical aortic valve replacement (mAVR) between January 2000 and December 2016 at a single institution. Propensity score matching was performed and yielded 32 well-matched pairs from a total of 216 eligible patients. RESULTS: Demographic and preoperative characteristics were similar between the two groups. Median follow-up was 7.3 and 6.9 years for Ross and mAVR, respectively. There were no early mortalities in either group and no statistically significant differences were observed with respect to perioperative outcomes or complications. Major hemorrhage and stroke events were significantly more frequent in the mAVR population (p < .01). Overall survival (p = .93), freedom from reintervention and valve dysfunction free survival (p = .91) were equivalent. CONCLUSIONS: In this mid-term propensity score-matched analysis, the Ross procedure offers similar perioperative outcomes, freedom from reintervention or valve dysfunction as well as overall survival compared to traditional mAVR but without the morbidity associated with long-term anticoagulation. At specialized centers with sufficient expertize, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement.

Bartonella endocarditis and diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition.

BACKGROUND: Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of organs other than skin and lymph nodes, such as the kidney. CASE PRESENTATION: This was a 13-year-old girl presenting with fever, chest and abdominal pain, acute kidney injury, nephrotic-range proteinuria and low complement levels. Her kidney biopsy showed diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition shown by immunofluorescence, which was initially considered consistent with systemic lupus erythematous-associated glomerulonephritis (lupus nephritis). After extensive workup, Bartonella endocarditis was diagnosed. Antibiotic treatment and valvular replacement surgery were undertaken with subsequent return of kidney function to normal range. CONCLUSION: This case demonstrates the importance of considering the full clinical picture when interpreting clinical, laboratory and biopsy findings, because the treatment strategy for infective endocarditis versus lupus nephritis is drastically different.

Hypoxia-ischemia-mediated effects on neurodevelopmentally regulated cold-shock proteins in neonatal mice under strict temperature control.

BACKGROUND: Neonates have high levels of cold-shock proteins (CSPs) in the normothermic brain for a limited period following birth. Hypoxic-ischemic (HI) insults in term infants produce neonatal encephalopathy (NE), and it remains unclear whether HI-induced pathology alters baseline CSP expression in the normothermic brain. METHODS: Here we established a version of the Rice-Vannucci model in PND 10 mice that incorporates rigorous temperature control. RESULTS: Common carotid artery (CCA)-ligation plus 25 min hypoxia (8% O2) in pups with targeted normothermia resulted in classic histopathological changes including increased hippocampal degeneration, astrogliosis, microgliosis, white matter changes, and cell signaling perturbations. Serial assessment of cortical, thalamic, and hippocampal RNA-binding motif 3 (RBM3), cold-inducible RNA binding protein (CIRBP), and reticulon-3 (RTN3) revealed a rapid age-dependent decrease in levels in sham and injured pups. CSPs were minimally affected by HI and the age point of lowest expression (PND 18) coincided with the timing at which heat-generating mechanisms mature in mice. CONCLUSIONS: The findings suggest the need to determine whether optimized therapeutic hypothermia (depth and duration) can prevent the age-related decline in neuroprotective CSPs like RBM3 in the brain, and improve outcomes during critical phases of secondary injury and recovery after NE. IMPACT: The rapid decrease in endogenous neuroprotective cold-shock proteins (CSPs) in the normothermic cortex, thalamus, and hippocampus from postnatal day (PND) 11-18, coincides with the timing of thermogenesis maturation in neonatal mice. Hypoxia-ischemia (HI) has a minor impact on the normal age-dependent decline in brain CSP levels in neonates maintained normothermic post-injury. HI robustly disrupts the expected correlation in RNA-binding motif 3 (RBM3) and reticulon-3 (RTN3). The potent neuroprotectant RBM3 is not increased 1-4 days after HI in a mouse model of neonatal encephalopathy (NE) in the term newborn and in which rigorous temperature control prevents the manifestation of endogenous post-insult hypothermia.

Time-Related Risk of Pulmonary Conduit Re-replacement: A Congenital Heart Surgeons' Society Study.

BACKGROUND: Patients receiving a right ventricle to pulmonary artery conduit (PC) in infancy will require successive procedures or replacements, each with variable longevity. We sought to identify factors associated with time-related risk of a subsequent surgical replacement (PC3) or transcatheter pulmonary valve insertion (TPVI) after a second surgically placed PC (PC2). METHODS: From 2002 to 2016, 630 patients from 29 Congenital Heart Surgeons' Society member institutions survived to discharge after initial valved PC insertion (PC1) at age ≤ 2 years. Of those, 355 underwent surgical replacement (PC2) of that initial conduit. Competing risk methodology and multiphase parametric hazard analyses were used to identify factors associated with time-related risk of PC3 or TPVI. RESULTS: Of 355 PC2 patients (median follow-up, 5.3 years), 65 underwent PC3 and 41 TPVI. Factors at PC2 associated with increased time-related risk of PC3 were smaller PC2 Z score (hazard ratio [HR] 1.6, P < .001), concomitant aortic valve intervention (HR 7.6, P = .009), aortic allograft (HR 2.2, P = .008), younger age (HR 1.4, P < .001), and larger Z score of PC1 (HR 1.2, P = .04). Factors at PC2 associated with increased time-related risk of TPVI were aortic allograft (HR: 3.3, P = .006), porcine unstented conduit (HR 4.7, P < .001), and older age (HR 2.3, P = .01). CONCLUSIONS: Aortic allograft as PC2 was associated with increased time-related risk of both PC3 and TPVI. Surgeons may reduce risk of these subsequent procedures by not selecting an aortic homograft at PC2, and by oversizing the conduit when anatomically feasible.