Charles G. Minard

Prenatal Diagnosis, Birth Location, Surgical Center, and Neonatal Mortality in Infants With Hypoplastic Left Heart Syndrome

Background— Most studies have not demonstrated improved survival after prenatal diagnosis of critical congenital heart disease, including hypoplastic left heart syndrome (HLHS). However, the effect of delivery near a cardiac surgical center (CSC), the recommended action after prenatal diagnosis, on HLHS mortality has been poorly investigated. Methods and Results— Using Texas Birth Defects Registry data, 1999 through 2007, which monitored >3.4 million births, we investigated the association between distance (calculated driving time) from birth center to CSC and neonatal mortality in 463 infants with HLHS. Infants with extracardiac birth defects or genetic disorders were excluded. The associations between prenatal diagnosis, CSC HLHS volume, and mortality were also examined. Neonatal mortality in infants born <10 minutes from a CSC was 21.0%, 10 to 90 minutes 25.2%, and >90 minutes 39.6% (P for trend <0.001). Prenatal diagnosis alone was not associated with improved survival (P=0.14). In multivariable analysis, birth >90 minutes from a CSC remained associated with increased mortality (odds ratio, 2.03; 95% confidence interval, 1.19–3.45), compared with <10 minutes. In subanalysis, birth >90 minutes from a CSC was associated with higher pretransport mortality (odds ratio, 6.69; 95% confidence interval, 2.52–17.74) and birth 10 to 90 minutes with higher presurgical mortality (odds ratio, 4.45; 95% confidence interval, 1.17–17.00). Higher surgical mortality was associated with lower CSC HLHS volume (odds ratio per 10 patients, 0.88; 95% confidence interval, 0.84–0.91). Conclusions— Infants with HLHS born far from a CSC have increased neonatal mortality, and most of this mortality is presurgical. Efforts to improve prenatal diagnosis of HLHS and subsequent delivery near a large volume CSC may significantly improve neonatal HLHS survival.

Bilateral Transversus Abdominis Plane Block Does Not Decrease Postoperative Pain After Laparoscopic Cholecystectomy When Compared With Local Anesthetic Infiltration of Trocar Insertion Sites

Background and Objectives Transversus abdominis plane (TAP) block has been shown to reduce pain and analgesic requirements after abdominal surgery. Our hypothesis was that bilateral TAP blocks decrease pain after laparoscopic cholecystectomy when compared with local anesthetic infiltration of trocar insertion sites. Methods Eighty patients undergoing laparoscopic cholecystectomy were randomized to receive either bilateral TAP blocks or local anesthetic infiltration of trocar insertion sites with ropivacaine 0.5%. Postoperative pain scores and analgesic use for the first 24 hrs were recorded. Results Eighty patients were enrolled in the study. After exclusions, data were analyzed on 39 patients in group T (bilateral TAP block) and 35 patients in group I (infiltration). There was no statistically significant difference in pain scores on the numeric analog scale (0–10) between the groups at 4 hrs after surgery (P = 0.18) or during the 24 hrs after surgery (P = 0.23). The time interval from anesthesia start to surgery start was greater in group T than group I (48 vs 35 mins, P < 0.001). There was no significant difference found in analgesic use during the first 24 hrs after surgery. Conclusions Bilateral ultrasound-guided TAP block is equivalent to local anesthetic infiltration of trocar insertion sites for overall postoperative pain in a heterogeneous group of patients undergoing laparoscopic cholecystectomy.

Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: A prospective, multicenter, comparative study

OBJECTIVE To compare the 1-year results after aortic valve-sparing (AVS) or valve-replacing (AVR) aortic root replacement from a prospective, international registry of 316 patients with Marfan syndrome (MFS). METHODS Patients underwent AVS (n = 239, 76%) or AVR (n = 77, 24%) aortic root replacement at 19 participating centers from 2005 to 2010. One-year follow-up data were complete for 312 patients (99%), with imaging findings available for 293 (94%). The time-to-events were compared between groups using Kaplan-Meier curves and Cox proportional hazards models. RESULTS Two patients (0.6%)--1 in each group--died within 30 days. No significant differences were found in early major adverse valve-related events (MAVRE; P = .6). Two AVS patients required early reoperation for coronary artery complications. The 1-year survival rates were similar in the AVR (97%) and AVS (98%) groups; the procedure type was not significantly associated with any valve-related events. At 1 year and beyond, aortic regurgitation of at least moderate severity (≥2+) was present in 16 patients in the AVS group (7%) but in no patients in the AVR group (P = .02). One AVS patient required late AVR. CONCLUSIONS AVS aortic root replacement was not associated with greater 30-day mortality or morbidity rates than AVR root replacement. At 1 year, no differences were found in survival, valve-related morbidity, or MAVRE between the AVS and AVR groups. Of concern, 7% of AVS patients developed grade ≥2+ aortic regurgitation, emphasizing the importance of 5 to 10 years of follow-up to learn the long-term durability of AVS versus AVR root replacement in patients with MFS.

Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors

PURPOSE Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. PATIENTS AND METHODS IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. RESULTS In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). CONCLUSION PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.

Real-Time Imaging of NADPH Oxidase Activity in Living Cells Using a Novel Fluorescent Protein Reporter

Production of reactive oxygen species (ROS) has been implicated in the pathology of many conditions, including cardiovascular, inflammatory and degenerative diseases, aging, muscular dystrophy, and muscle fatigue. NADPH oxidases (Nox) have recently gained attention as an important source of ROS involved in redox signaling. However, our knowledge of the source of ROS has been limited by the relatively impoverished array of tools available to study them and the limitations of all imaging probes to provide meaningful spatial resolution. By linking redox-sensitive GFP (roGFP) to the Nox organizer protein, p47phox, we have developed a redox sensitive protein to specifically assess Nox activity (p47-roGFP). Stimulation of murine macrophages with endotoxin resulted in rapid, reversible oxidation of p47-roGFP. In murine skeletal muscle, both passive stretch and repetitive electrical stimulation resulted in oxidation of p47-roGFP. The oxidation of p47-roGFP in both macrophages and skeletal muscle was blocked by a Nox specific peptide inhibitor. Furthermore, expression of p47-roGFP in p47phox deficient cells restored Nox activity. As Nox has been linked to pathological redox signaling, our newly developed Nox biosensor will allow for the direct assessment of Nox activity and the development of therapeutic Nox inhibitors.

Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study.

Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying pediatric anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs). We assessed the activity of the ALK inhibitor crizotinib in patients who had no known curative treatment options at diagnosis or with relapsed/recurrent disease. Methods In this study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily. Study objectives were measurement of efficacy and safety. Correlative studies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL. Results The overall response rates for patients with ALCL treated at doses of 165 (ALCL165) and 280 (ALCL280) mg/m2 were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m2/dose) was 86%. A complete response was observed in 83% (five of six) of ALCL165, 80% (16 of 20) of ALCL280, and 36% (five of 14) of patients with IMT. Partial response rates were 0% (none of six), 10% (two of 20), and 50% (seven of 14), respectively. The median duration of therapy was 2.79, 0.4, and 1.63 years, respectively, with 12 patients ceasing protocol therapy to proceed to transplantation. The most common drug-related adverse event was decrease in neutrophil count in 33% and 70% of the ALCL165 and ALCL280 groups, respectively, and in 43% of patients with IMT. Levels of NPM-ALK decreased during therapy in most patients with ALCL. Conclusion The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable IMT highlight the importance of the ALK pathway in these diseases.

Postoperative analgesic and behavioral effects of intranasal fentanyl, intravenous morphine, and intramuscular morphine in pediatric patients undergoing bilateral myringotomy and placement of ventilating tubes.

BACKGROUND:Bilateral myringotomy and placement of ventilating tubes (BMT) is one of the most common pediatric surgical procedures in the United States. Many children who undergo BMT develop behavioral changes in the postanesthesia care unit (PACU) and require rescue pain medication. The incidence of these changes is lower in children receiving intraoperative opioids by the nasal, IM, or IV route compared with placebo. However, there are no data to indicate which route of administration is better. Our study was designed to compare the immediate postoperative analgesic and behavioral effects of 3 frequently used intraoperative techniques of postoperative pain control for patients undergoing BMT under general anesthesia. METHODS:One hundred seventy-one ASA physical status I and II children scheduled for BMT were randomized into 1 of 3 groups: group 1—nasal fentanyl 2 &mgr;g/kg with IV and IM saline placebo; group 2—IV morphine 0.1 mg/kg with nasal and IM placebo; or group 3—IM morphine 0.1 mg/kg with nasal and IV placebo. All subjects received a standardized general anesthetic with sevoflurane, N2O, and O2 and similar postoperative care. The primary end point of the study was the pain scores measured by the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale in the PACU. RESULTS:There were no significant differences in peak FLACC pain among the 3 groups (mean [95% CI] 2.0 [1.2–2.8] for intranasal fentanyl, 2.7 [1.7–3.6] for IV morphine, and 2.9 [2.1–3.7] for IM morphine, respectively). There were no differences in the scores on the Pediatric Anesthesia Emergence Delirium (PAED) scale, incidence of postoperative emergence delirium (PAED score ≥12), emesis, perioperative hypoxemia, or need for airway intervention, and postoperative rescue analgesia. There were also no differences in the duration of PACU stay or parental satisfaction among the groups. CONCLUSION:In this double-blind, double-dummy study, there was no difference in the efficacy of intranasal fentanyl, IM and IV morphine in controlling postoperative pain and emergence delirium in children undergoing BMT placement. The IM route is the simplest and avoids the potential for delays to establish vascular access for IV therapy and the risks of laryngospasm if intranasal drugs pass through the posterior nasopharynx and irritate the vocal cords.

Perioperative respiratory complications following awake and deep extubation in children undergoing adenotonsillectomy.

Perioperative respiratory complications after adenotonsillectomy (T&A) are common and have been described to occur more frequently in children below 3 years of age, those with cranio‐facial abnormalities, Down syndrome, obstructive sleep apnea, morbid obesity, and failure to thrive.

Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study

Objective To investigate the association of neonatal hypoglycaemia and hyperglycaemia with outcomes in infants with hypoxic ischaemic encephalopathy (HIE). Design Post hoc analysis of the CoolCap Study. Setting 25 perinatal centres in the UK, the USA and New Zealand during 1999–2002. Patients 234 infants at ≥36 weeks’ gestation with moderate-to-severe HIE enrolled in the CoolCap Study. 214 (91%) infants had documented plasma glucose and follow-up outcome data. Intervention Infants were randomised to head cooling for 72 h starting within 6 h of birth, or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation. Main outcome measure The unfavourable primary outcome of the study was death and/or severe neurodevelopmental disability at 18 months. Hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L) and hyperglycaemia (>150 mg/dL, >8.3 mmol/L) during the first 12 h after randomisation were investigated for univariable and multivariable associations with unfavourable primary outcome. Results 121 (57%) infants had abnormal plasma glucose values within 12 h of randomisation. Unfavourable outcome was observed in 126 (60%) infants and was more common among subjects with hypoglycaemia (81%, p=0.004), hyperglycaemia (67%, p=0.01) and any glucose derangement within the first 12 h (67%, p=0.002) compared with normoglycaemic infants (48%) in univariable analysis. These associations remained significant after adjusting for birth weight, Apgar score, pH, Sarnat stage and hypothermia therapy. Conclusions Both hypoglycaemia and hyperglycaemia in infants with moderate-to-severe HIE were independently associated with unfavourable outcome. Future studies are needed to investigate the prognostic significance of these associations and their role as biomarkers of brain injury. Trial registration number (ClinicalTrials.gov NCT00383305).

Matrix metalloproteinase levels in chronic thoracic aortic dissection

BACKGROUND Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) can lead to aortic wall failure. We hypothesized that patients with aneurysms resulting from chronic descending thoracic aortic dissection have elevated tissue and plasma levels of specific MMPs and decreased tissue levels of TIMPs. MATERIALS AND METHODS Aortic tissue was obtained from 25 patients who required surgical repair of descending thoracic aortic aneurysm due to chronic aortic dissection and from 17 organ-donor controls without aortic disease. Tissue levels of MMP-1, -2, -3, -9, -12, and -13 and TIMP-1 and -2 were measured by colorimetric activity assay or enzyme-linked immunosorbent assay and confirmed by Western blot and immunohistochemistry. Blood obtained from the 25 patients and 15 controls without aortic diseases was used to compare plasma levels of MMP-3, -9, and -12. RESULTS Total MMP-1, total MMP-9, and active MMP-9 levels were higher and total MMP-2 levels were lower in dissection tissue than in control tissue. Additionally, the MMP-9 to TIMP-1 and active to total MMP-2 ratios were higher and the MMP-2 to TIMP-2 ratio was lower in dissection tissue. Furthermore, patients had higher plasma active to total MMP-9 ratios than the controls. Age and hypertension were associated with increased MMP levels. CONCLUSIONS Increased levels of several MMPs and increased MMP to TIMP ratios in aortic tissue from patients suggest an environment that favors proteolysis, which may promote progressive extracellular matrix destruction and medial degeneration after aortic dissection. An elevated active to total MMP-9 ratio in plasma may be a biomarker for end-stage aneurysm development in patients with chronic thoracic aortic disease.