A Prospective Study of Sensory Changes in Pediatric Patients After Minimally Invasive Repair of Pectus Excavatum With Cryoablation.

BACKGROUND: Cryoablation during minimally invasive repair for pectus excavatum (MIRPE) reduces opioid use and hospital length of stay. Skin hypoesthesia of the chest wall also occurs. This study sought to determine the frequency, onset, duration, and location of sensory changes and neuropathic pain after cryoablation. METHODS: A prospective study was conducted on patients aged ≤21 years undergoing MIRPE with cryoablation of T3 to T7 dermatomes bilaterally for 120 s at a single institution between March 2021 to December 2022. Patients underwent sensory testing of the chest wall and neuropathic pain surveys (S-LANSS) preoperatively and then postoperatively for 6 months. Incidence and duration of hypoesthesia and neuropathic pain were evaluated. RESULTS: Of 61 patients enrolled in the study, 45 completed evaluations at six months postoperatively. All patients had skin hypoesthesia on postoperative day (POD)1. The mean percentage of the treated anterior chest wall surface area (TACWSA) with hypoesthesia to cold stimulus was 52% (±29.3) on POD 0 and 55% (±19.7) on POD 1. Sensation returned over time, with hypoesthesia affecting 11.1% (±15.5) TACWSA at 6 months. At study completion 58% of patients (26/45) had complete return of sensation; hypoesthesia was found at: 1 dermatome 13% (2/45), 2 dermatomes 22% (11/45), and 3 dermatomes 4% (2/45). Neuropathic pain (S-LANSS ≥12) was documented in 16% (9/55) of patients at hospital discharge but decreased to 6.7% of patients at 6 months. CONCLUSION: Onset of skin hypoesthesia after cryoablation occurred on POD0 and affected 52% of the TACWSA. All patients experienced return of sensation to varying degrees, with 58% experiencing normal sensation in all dermatomes by 6 months. The etiology of persistent hypoesthesia to select dermatomes is unknown but may be related to operative technique or cryoablation. Chronic neuropathic pain is uncommon. LEVEL OF EVIDENCE: II. TYPE OF STUDY: Prognosis Study.

Preoperative Metal Allergy Testing for Pectus Excavatum Repair Does Not Effectively Identify Patients Who Develop Metal bar Allergy.

BACKGROUND: Metal allergy following placement of a metal pectus bar for minimally invasive repair of pectus excavatum (MIRPE) is a rare complication with potentially significant morbidity. There is no consensus regarding preoperative metal allergy testing (MAT). This study aims to assess incidence of metal allergy and titanium bar use in tested and untested patients and trends in MAT with different approaches to MAT. METHODS: A retrospective chart review was performed on patients who underwent MIRPE from July 2009 to June 2022 at a single institution. During this time, MAT was performed routinely (RT; routine testing) and selectively (ST; selective testing). RESULTS: The cohort included 741 patients for analysis. Metal bar allergy was documented in 1.3 % of all patients; the incidence was 1.3 % in patients with MAT and 1.4 % without MAT. The incidence of bar allergy was 1.1 % in the RT group and 1.6 % in the ST group. In the RT group, bar allergy occurred in 1.4 % (3/216) of patients with a negative MAT. In the ST group, bar allergy occurred in 1.2 % (2/164) of patients with a negative MAT and in 1.9 % (3/162) of untested patients with a stainless-steel bar. Titanium bar use was not significantly different between the RT and ST groups (18.3 % vs 16.3 %, p > 0.05). CONCLUSION: The incidence of metal bar allergy after MIRPE was less than 2 %, and titanium bar use was not significantly different in routine and selective testing groups. MAT was not associated with a reduction in bar allergy, and its use remains unsupported. LEVEL OF EVIDENCE: III.

Cryoablation in 350 Nuss Procedures: Evolution of Hospital Length of Stay and Opioid Use.

INTRODUCTION: Current studies show cryoablation decreases opioid requirements and lengths of stay (LOS) in patients undergoing the Nuss procedure for pectus excavatum. This study evaluated the relationship between cryoablation and clinical outcomes for the Nuss procedure. METHODS: A retrospective single-center chart review was performed on patients undergoing the Nuss procedure with intercostal cryoablation from December 2017-August 2021. Demographics, hospital course, and postoperative complications were abstracted. To evaluate the evolution of outcomes over time, the earliest quarter (Q1) of cryoablation patients was compared to the last quarter (Q4). RESULTS: Over 45 months, 350 Nuss procedures with cryoablation were performed. The mean age at operation was 15.7 ± 2.3 years with an average Haller Index of 5.4 ± 4.2. The mean operative time was 136 ± 40.5 minutes. On average, patients used 2.8 ± 2.5 OME/kg of opioid in hospital with a LOS of 2.7 ± 1.1 days. The Q4 patients were discharged 1.3 days earlier (p<0.05) than Q1 patients, with 80% of Q4 discharged by postoperative day #2 vs. 23% in Q1 (p<0.05). Q4 patients received 74% (p<0.05) less opioid in hospital and 21% (p<0.05) less on discharge. Within 90 days postoperatively, complication rates (chest tube placement, wound infection, readmission, neuropathic pain) were similar. Only two patients (0.6%) required reoperation for bar migration/slippage. CONCLUSION: With increased experience, cryoablation for the Nuss procedure decreased opioid use by 74% and was associated with 80% of patients achieving early discharge. Major complication rates were not increased. Cryoablation can be successfully implemented as an effective method of postoperative analgesia. LEVEL OF EVIDENCE: Level III.

Intercostal Nerve Cryoablation in Minimally Invasive Repair of Pectus Excavatum: Effect on Pulmonary Function.

Introduction: Cryoablation of intercostal nerves is performed for pain control after minimally invasive repair of pectus excavatum (MIRPE). Cryoablation affects both sensory and motor neurons, resulting in temporary anesthesia to the chest wall and loss of intercostal motor function. The study objective is to determine the effect of cryoablation on incentive spirometry (IS) volumes, as a measure of pulmonary function, after MIRPE. Materials and Methods: A single-institution retrospective review of pediatric patients undergoing MIRPE was performed. All patients received a multimodal regimen (MMR) of analgesics postoperatively. Three groups were compared-cryoablation (CRYO), elastomeric pain pump (EPP), and MMR alone. The primary outcomes were postoperative IS volumes and IS volumes as a ratio of preoperative forced vital capacity (FVC). Secondary outcomes included pain scores, opioid use, length of stay (LOS), and infectious complications. Results: MIRPE was performed in 115 patients: 50 CRYO, 50 EPP, and 15 MMR alone. Groups were similar for demographics and pectus excavatum severity. Postoperative spirometry measurements were similar across groups: IS (CRYO 750 mL [500,961] versus EPP 750 mL [590,1019] versus MMR 696 mL [500,1037], P = .77); IS/FVC (CRYO 0.19 [0.14,0.26] versus EPP 0.20 [0.16,0.26] versus MMR 0.16 [0.15,0.24], P = .69). Although pain scores were also similar across groups, CRYO patients used less opioid (P < .05) and had shorter LOS (P < .05). Postoperative pneumonia was rare and similar across groups (P = 1.00). Conclusion: Intercostal nerve cryoablation during MIRPE does not adversely affect postoperative IS volumes or increase pneumonia rate, despite the temporary loss of motor innervation to intercostal muscles. Cryoablation provides effective pain control with less opioid use.

The Use of Cryoanalgesia in Minimally Invasive Repair of Pectus Excavatum: Lessons Learned.

Introduction: Cryoanalgesia has been applied to minimally invasive repair of pectus excavatum (MIRPE). After implementation of cryoanalgesia at our institution, we had several cases of delayed postoperative pneumothorax. The purpose of this study was to critically evaluate the complications and efficacy of cryoanalgesia in MIRPE. Materials and Methods: We performed a single institution retrospective review of pediatric patients undergoing MIRPE from June 2017 to July 2018. Multimodal (MM) analgesia was used in all patients. In addition, most patients received either cryoanalgesia or elastomeric pain pumps (EPPs) as adjuncts to postoperative analgesia. Primary outcome was clinically significant late pneumothorax. Secondary outcomes included length of stay, pain scores, opiate use, and bar displacement requiring reoperation. Results: A total of 101 patients undergoing MIRPE were included: 45 had cryoanalgesia + MM, 45 EPP + MM, and 11 MM alone. Postoperative tube thoracostomy was placed in 5 patients with cryoanalgesia (4 pneumothorax; 1 effusion), 1 patient with EPP (1 pneumothorax), and none in MM alone (P = .25). Pain scores at discharge were similar in all groups. Cryoanalgesia patients received less overall inpatient opioids than other groups (P < .05). No patient required reoperation for bar displacement. Conclusion: Cryoanalgesia is an effective therapy for pain control in MIRPE. Because thermal injury can occur on the lung and chest wall with cryoanalgesia, we implemented techniques to limit and prevent this injury. Cryoanalgesia offers a safe alternative for postoperative analgesia with significant reduction in inpatient opioid requirement. Larger prospective studies are required to assess the long-term impact and complications of cryoanalgesia.

Thoraco-abdominal enteric duplication cyst in association with neurenteric cyst, axial skeletal anomalies, and malrotation.

We report a case of a 2-year old boy with cervicothoracic deformity with vertebral rib anomalies, neurenteric cyst, separate thoracoabominal enteric duplication cyst, concurrent intestinal malrotation, and dextroposition of the heart. This combination of abnormalities is very rare. When these lesions are suspected, the patient must be investigated carefully. This case is presented to show the importance of cross-sectional imaging (MR and CT) for surgical planning.

Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma.

Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.

Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade.

Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both overexpression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.

Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.

Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF.

Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling.

Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.

Extracorporeal membrane oxygenation in pediatric cardiac transplantation.

BACKGROUND: We reviewed a single institution experience with extracorporeal membrane oxygenation (ECMO) in the perioperative management of cardiac transplantation. METHODS: Of all pediatric cardiac transplant candidates (1984-2003), patients requiring ECMO pretransplantation/posttransplantation were identified, with particular attention to use of ECMO as a bridge to transplantation. Parameters reviewed included proportionate survival, incidence of pre-ECMO cardiac arrest, ECMO duration, and United Network for Organ Sharing list time. RESULTS: Three hundred patients were listed for transplantation. Twenty-nine required ECMO: 18 pretransplant, 3 pretransplant and posttransplant, 6 posttransplant, and 2 for delayed acute rejection. There were 21 bridge-to-transplant candidates, of which 10 eventually transplanted with 60% survival; 11 not transplanted had no survivors (P = .004). Thirteen of 21 had cardiac arrest pre-ECMO with 1 (8%) survivor; 8 of 21 had no arrest with 5 (63%) survivors (P = .014). Mean ECMO duration and United Network for Organ Sharing list times between transplanted and not transplanted were not significant. Nine received ECMO posttransplantation for cardiopulmonary support; 5 (56%) of 9 survived. Two patients supported with ECMO for rejection-related cardiovascular collapse survived. CONCLUSION: ECMO can bridge children to cardiac transplantation. Survival is significantly impaired in bridge-to-transplant candidates stratified by pre-ECMO cardiac arrest. ECMO can also help transition from cardiopulmonary bypass after transplantation and provide effective support during acute rejection.