Examining the role of extracorporeal membrane oxygenation in patients following suspected or confirmed suicide attempts: A case series.

The decision to offer extracorporeal membrane oxygenation (ECMO) is based on a risk/benefit assessment and the likelihood of a treatable underlying condition or the feasibility of destination therapy (durable mechanical support or thoracic organ transplantation) should heart-lung function fail to improve. Patients who present following suspected suicide attempts who fail medical therapy may pose a dilemma for clinicians. An assessment to determine if a patient has a high likelihood of psychiatric recovery such that bridging with ECMO or ultimately destination therapy could or should be offered is not always feasible in the setting of critical illness. This case series reviews our institution's experience with ECMO in the management of five patients who presented following suspected or confirmed suicide attempts. All five patients survived to hospital discharge. Two had subsequent psychiatric admissions, one following a repeat suicide attempt. A discussion of these cases demonstrates the effectiveness of ECMO in supporting this group of patients in the short-term. The self-limited natural history of many psychiatric episodes, poisonings and traumatic injuries makes the use of ECMO a potentially reasonable support strategy. However, careful consideration must be given to psychiatric history and follow-up given the substantial commitment of resources, potential for complications and for stranding patients on extracorporeal therapy without definitive destination therapy.

M1 Macrophage-Induced Endothelial-to-Mesenchymal Transition Promotes Infantile Hemangioma Regression.

Infantile hemangiomas are benign tumors of vascular endothelial cells (ECs), characterized by three distinct stages: proliferating phase, involuting phase, and involuted phase. The mechanisms that trigger involution of hemangioma into fibro-fatty tissue remain unknown. We report a novel mechanism by which M1-polarized macrophages induce endothelial-to-mesenchymal transition (EndMT) and promote hemangioma regression. M1- but not M2-polarized macrophages induced EndMT in ECs. Tumor necrosis factor-α and, to a lesser extent, IL-1ß and interferon-γ were the most potent cytokines produced by the M1 macrophages that induce in vitro EndMT. Western blot analysis and gene expression profiling showed that ECs treated with M1 macrophages, tumor necrosis factor-α, or IL-1ß decreased the expression of endothelial markers, whereas mesenchymal markers increased concomitantly. Immunohistochemical staining of patient samples revealed that a significant perivascular infiltration of M1, but not M2, macrophages coincides with endothelial expression of the critical EndMT transcription factors Snail/Slug in involuting hemangiomas. Most strikingly, M1 macrophage-treated ECs isolated from patient hemangiomas (HemECs) but not untreated HemECs readily differentiated into adipocytes on adipogenic induction. Thus, in vitro EndMT and adipogenesis of HemECs have, in part, recapitulated the natural history of hemangioma regression. In conclusion, our findings indicate that EndMT induced by M1 macrophages promotes infantile hemangioma regression and may lead to novel therapeutic treatments for this vascular tumor.

Nonoperative treatment of acute appendicitis in children: A feasibility study.

PURPOSE: Nonoperative treatment of acute appendicitis appears to be feasible in adults. It is unclear whether the same is true for children. METHODS: Children 5-18 years with <48 h symptoms of acute appendicitis were offered nonoperative treatment: 2 doses of piperacillin IV, then ampicillin/clavulanate ×1 week. Treatment failure (worsening on therapy) and recurrence (after completion of therapy) were noted. Patients who declined enrollment were asked to participate as controls. Cost-utility analysis was performed using Pediatric Quality of Life Scale (PedsQL®) to calculate quality-adjusted life month (QALM) for study and control patients. RESULTS: Twenty-four patients agreed to undergo nonoperative management, and 50 acted as controls. At a mean follow-up of 14 months, three of the 24 failed on therapy, and 2/21 returned with recurrent appendicitis at 43 and 52 days, respectively. Two patients elected to undergo an interval appendectomy despite absence of symptoms. Appendectomy-free rate at one year was therefore 71% (C.I. 50-87%). No patient developed perforation or other complications. Cost-utility analysis shows a 0.007-0.03 QALM increase and a $1359 savings from $4130 to $2771 per nonoperatively treated patient. CONCLUSION: Despite occasional late recurrences, antibiotic-only treatment of early appendicitis in children is feasible, safe, cost-effective and is experienced more favorably by patients and parents.

Iatrogenic Preterm Premature Rupture of Membranes after Fetoscopic Laser Ablative Surgery.

INTRODUCTION: To describe the incidence and risk factors for iatrogenic premature preterm rupture of membranes (iPPROM) after fetoscopic laser surgery for the twin-to-twin-transfusion syndrome. MATERIALS AND METHODS: This is a retrospective review of all patients who have undergone fetoscopic laser surgery at a single fetal treatment center since 2000. We defined iPPROM as spontaneous rupture of membranes before the onset of labor prior to 34 weeks of gestation. The iPPROM cohort was compared to the cohort without iPPROM for several preoperative, operative, and delivery characteristics. RESULTS: Ninety-two consecutive patients were reviewed. The overall rate of iPPROM was 18.5% (n = 17). The rates of iPPROM within 1 and 4 weeks were 5.4 and 10.9%, respectively. The median interval from surgery to delivery was significantly shorter in the iPPROM group (21 vs. 62 days, p = 0.01). The mean gestational age at delivery (27.0 vs. 31.1 weeks, p = 0.02) was lower in the iPPROM group. No other characteristics studied differed significantly between the groups. DISCUSSION: The incidence of iPPROM was substantially lower than in recent multicenter reports; however, no risk factors of iPPROM could be identified. Whether this is related to variations in surgical or anesthetic management will require further investigation.

Extracorporeal life support in critically ill adults.

Extracorporeal life support (ECLS) has become increasingly popular as a salvage strategy for critically ill adults. Major advances in technology and the severe acute respiratory distress syndrome that characterized the 2009 influenza A(H1N1) pandemic have stimulated renewed interest in the use of venovenous extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide removal to support the respiratory system. Theoretical advantages of ECLS for respiratory failure include the ability to rest the lungs by avoiding injurious mechanical ventilator settings and the potential to facilitate early mobilization, which may be advantageous for bridging to recovery or to lung transplantation. The use of venoarterial ECMO has been expanded and applied to critically ill adults with hemodynamic compromise from a variety of etiologies, beyond postcardiotomy failure. Although technology and general care of the ECLS patient have evolved, ECLS is not without potentially serious complications and remains unproven as a treatment modality. The therapy is now being tested in clinical trials, although numerous questions remain about the application of ECLS and its impact on outcomes in critically ill adults.

Maternal and fetal safety of fluid-restrictive general anesthesia for endoscopic fetal surgery in monochorionic twin gestations.

STUDY OBJECTIVE: To review our experience with general anesthesia in endoscopic fetal surgery for twin-to-twin transfusion syndrome (TTTS), and to compare fetomaternal outcome before and after protocol implementation. DESIGN: Retrospective impact study. SETTING: University-affiliated medical center. MEASUREMENTS: Data from 85 consecutive patients who underwent endoscopic laser ablation of placenta vessels for severe TTTS were studied. Outcomes were compared in patients before (2000-2007) and after (2008-2012) a change to strict intraoperative intravenous (IV) fluid and liberal vasopressor management. Perioperative parameters (IV fluid administration, vasopressor use, maternal hemoglobin [Hb] concentration); maternal complication rate (respiratory, hemorrhagic); pregnancy outcome; and fetal and neonatal survival were recorded. MAIN RESULTS: Patients in the early group (2000-2007; n = 55) received 1634 ± 949 mL of crystalloid fluid intraoperatively, compared with 485 ± 238 mL (P < 0.001; Student's t test) given to the late group (2008-2012; n = 30). Maternal pulmonary edema and any respiratory distress were seen in 5.5% and 12.7% of patients in the early group, respectively, and in none of the late group patients (P < 0.05; Chi-square analysis). CONCLUSIONS: A significant risk of maternal respiratory complications exists after general anesthesia for endoscopic fetal surgery. Judicious fluid management significantly decreases this risk.

Long-term morbidity after fetal endoscopic surgery for severe twin-to-twin transfusion syndrome.

BACKGROUND/PURPOSE: Severe twin-to-twin transfusion syndrome (TTTS) leads to 80% to 100% dual mortality. Endoscopic laser coagulation of connecting vessels improves outcome to 80% survival of at least 1 twin. There is limited long-term follow-up of surviving TTTS patients. The aim of this study was to analyze gestational age-stratified, long-term morbidity in these patients. METHODS: A retrospective case-control study of TTTS surviving patients (38 patients, 72% follow-up rate) from one center. Perinatal and pediatric records were reviewed, and outcomes were compared with published reports and gestational age-matched controls. RESULTS: Forty percent (15/38) had at least 1 major sequela, all but 6 of which were fully resolved at a median follow-up of 4.4 years. There were no permanent cardiac, genitourinary, renal, or respiratory sequelae. All major complications were in patients born <29 weeks. There were no significant differences in complications between this cohort of patients and gestational age (GA)-matched control patients. CONCLUSIONS: The long-term morbidity of monochorionic twins after fetal laser surgery for severe TTTS is 13%. At a median follow-up of more than 4 years, these children fare no worse than gestational age-matched, non-operated twins and singletons. The degree of prematurity at birth is the best predictor of temporary or permanent sequela in this group of patients.

Laser ablation of placental vessels in twin-to-twin transfusion syndrome: a paradigm for endoscopic fetal surgery.

Endoscopic fetal surgery is most commonly used for the treatment of twin-to-twin transfusion syndrome (TTTS), but the surgical techniques can be applied to other forms of fetal surgery. We present our experience with endoscopic fetal surgery over the past 10 years. From 2000 to 2010, 70 endoscopic laser ablations of placental vessels for TTTS were performed. Median number of placental vessels ablated was four. The incidence of preterm rupture of membranes (PROM) was 6%. Overall survival was 70%, with at least one twin surviving in 82%. Tocolysis was used in 73% of patients for a median of 12 hours. The combination of an open surgical approach, Seldinger technique, and uterine plugging led to outcomes similar to other reports, with a significantly lower PROM rate. Although TTTS is the most common application of endoscopic fetal surgery, this approach is applicable for other indications. Insertion and removal of tracheal occlusion balloons for severe congenital diaphragmatic hernia are currently being performed at our institution.

Influence of experience, case load, and stage distribution on outcome of endoscopic laser surgery for TTTS--a review.

OBJECTIVE: Survival (> or =1 twin) after laser surgery for patients with twin-to-twin transfusion syndrome (TTTS) ranges from 65 to 93%. However, most studies are noncontrolled and retrospective, and have included a limited number of patients. The aim of this study was to perform a systematic review of outcomes after laser surgery in patients with TTTS. METHODS: We conducted database and manual searches of reference lists and pertinent journals published between 1995 and 2009 that report outcomes of laser surgery in patients with TTTS. Two authors performed the search independently of each other. There exist only two randomized controlled trials, each with fewer than 80 patients having undergone laser surgery. Uncontrolled and retrospective series were therefore considered as well. Studies had to report sufficient information on inclusive dates, stage distribution, overall neonatal survival, and neonatal survival of at least one twin. Of the 486 studies identified, we considered 19 studies. RESULTS: For each series, 95% confidence intervals (CI) were calculated. Survival was plotted against the date of publication, number of patients/series, gestational age at delivery, and proportion of advanced cases. Univariate analysis was performed to detect significant differences. Our meta-analysis, which included 1484 patients, shows 81.2% survival of at least one twin (CI: 79.1-83.2%). The average survival of at least one twin for the entire population remained within the CI of all but one series. Neither case load, nor stage distribution, nor chronological date of the study affected the survival. CONCLUSION: A systematic review of endoscopic laser surgery performed in patients with TTTS failed to show a significant impact of high caseloads, disease severity distribution, or improvements in technique.

Reflectance spectrometry for real-time hemoglobin determination of placental vessels during endoscopic laser surgery for twin-to-twin transfusion syndrome.

OBJECTIVE: The objective of the study was to develop a noninvasive technique to determine hemoglobin (Hb) content through spectral analysis of diffusely reflected broadband visible illumination from individual blood vessels during endoscopic fetal surgery for twin-to-twin transfusion syndrome (TTTS). METHODS: The reflection of an incoming xenon endoscopic light source was captured through a 630-mum-diameter optic fiber coupled to a fixed grating spectrometer (2-nm resolution). A 450- to 700-nm wavelength range was used for analysis. Three data-capturing methods were studied: (1) fixed-image spectrum capture with fiber aimed at (but not touching) center of a vessel, (2) no-touch scanning perpendicular to the vessel and dynamic spectral capture, and (3) dynamic spectral capture and analysis of the reflectance spectra during brief vessel touch. RESULTS: Eight controls (elective laparoscopic and thoracoscopic operations in children aged 1-17 years) were enrolled. Four vessels were analyzed in each case. The brief-touch technique with intensity peak analysis yielded the most reproducible results between multiple vessels in the same patient. Spectrometry was also applied to 2 TTTS patients. The (anemic) donor and (polycythemic) recipient twin fetuses could be differentiated with good correlation between vessels (arteries and vein) of the same fetus. CONCLUSIONS: It is possible to differentiate donor from recipient placental vessels by spectral analysis of the reflected light through the endoscope using a noninvasive and real-time method. This may improve the accuracy of endoscopic laser ablation of placental vessels in TTTS and may allow instant endoscopic Hb determination for laparoscopic procedures as well.

Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat livers.

Biliary obstruction results in a well-characterized cholestatic inflammatory and fibrogenic process; however, the mechanisms and potential for liver repair remain unclear. We previously demonstrated that Kupffer cell depletion reduces polymorphonuclear cell (neutrophil) (PMN) and matrix metalloproteinase (MMP)8 levels in repairing liver. We therefore hypothesized that PMN-dependent MMP activity is essential for successful repair. Male Sprague-Dawley rats received reversible biliary obstruction for 7 days, and the rat PMN-specific antibody RP3 was administered 2 days before biliary decompression (repair) and continued daily until necropsy, when liver underwent morphometric analysis, immunohistochemistry, quantitative RT-PCR, and in situ zymography. We found that RP3 treatment did not reduce Kupffer cell or monocyte number but significantly reduced PMN number at the time of decompression and 2 days after repair. RP3 treatment also blocked resorption of type I collagen. In addition, biliary obstruction resulted in increased expression of MMP3, MMP8, and tissue inhibitor of metalloproteinase 1. Two days after biliary decompression, both MMP3 and tissue inhibitor of metalloproteinase 1 expression declined toward sham levels, whereas MMP8 expression remained elevated and was identified in bile duct epithelial cells by immunohistochemistry. PMN depletion did not alter the hepatic expression of these genes. Conversely, collagen-based in situ zymography demonstrated markedly diminished collagenase activity following PMN depletion. We conclude that PMNs are essential for collagenase activity and collagen resorption during liver repair, and speculate that PMN-derived MMP8 or PMN-mediated activation of intrinsic hepatic MMPs are responsible for successful liver repair.

The pediatric surgeons' contribution to in utero treatment of twin-to-twin transfusion syndrome.

OBJECTIVE: To evaluate the outcome of twin-to-twin transfusion syndrome (TTTS) treated using a combination of endoscopic fetal surgery-specific techniques and surgical restraint. SUMMARY BACKGROUND DATA: TTTS is a condition of identical twins that, if progressive and left untreated, leads to 100% mortality. The best treatment option is obliteration of the intertwin placental anastomoses, but fetal surgery carries significant maternal and fetal risks. Even if successful, percutaneous endoscopic laser ablation of placental vessels (LASER) causes premature rupture of membranes (PROM) in 10% to 20% of pregnancies. Patient selection is particularly critical because the progression of the disease is unpredictable. This has prompted many to intervene early, yielding survival rates of >=1 twin of 75% to 80%. METHODS: We developed a minimally invasive approach to fetal surgery, a unique membrane sealing technique and a conservative algorithm that reserves intervention for severe TTTS. Pregnancies with TTTS (stages I-IV) managed in the last 8 years were reviewed. LASER was offered in stage III/IV only. RESULTS: Ninety-eight cases of TTTS were managed in a pediatric surgery/maternal-fetal medicine collaborative Fetal Treatment Program-39 were observed (40%) and 59 underwent LASER (60%). Survival of >= twin was seen in 82.7%, and overall survival was 69.4%. These survival rates are similar to, or better than, other comparable series with similar stage distribution (low:high stage ratio 1:1) in which all patients underwent LASER. PROM rate was 4%. CONCLUSIONS: Reserving LASER treatment for severe TTTS results in outcomes similar to, or better than, LASER for all stages. Applying fetal surgery-specific endoscopic techniques, including port-site sealing, reduces postoperative complications.

Dexamethasone alters the hepatic inflammatory cellular profile without changes in matrix degradation during liver repair following biliary decompression.

BACKGROUND: Biliary atresia is characterized by extrahepatic bile duct obliteration along with persistent intrahepatic portal inflammation. Steroids are standard in the treatment of cholangitis following the Kasai portoenterostomy, and were advocated for continued suppression of the ongoing immunologic attack against intrahepatic ducts. Recent reports, however, have failed to demonstrate an improved patient outcome or difference in the need for liver transplant in postoperative patients treated with a variety of steroid regimes compared with historic controls. In the wake of progressive liver disease despite biliary decompression, steroids are hypothesized to suppress inflammation and promote bile flow without any supporting data regarding their effect on the emerging cellular and molecular mechanisms of liver repair. We have previously shown in a reversible model of cholestatic injury that repair is mediated by macrophages, neutrophils, and specific matrix metalloproteinase activity (MMP8); we questioned whether steroids would alter these intrinsic mechanisms. METHODS: Rats underwent biliary ductal suspension for 7 d, followed by decompression. Rats were treated with IV dexamethasone or saline at the time of decompression. Liver tissue obtained at the time of decompression or after 2 d of repair was processed for morphometric analysis, immunohistochemistry, and quantitative RT-PCR. RESULTS: There was a dramatic effect of dexamethasone on the inflammatory component with the initiation of repair. Immunohistochemistry revealed a reduction of both ED1+ hepatic macrophages and ED2+Kupffer cells in repair compared with saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by day 2. TNF-alpha expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (day 2) whereas IL-6, IL-10, and CINC-1 remained unchanged compared with saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by day 2, whereas MMP9, 13, and 14 were unchanged compared with sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups CONCLUSION: Dexamethasone has clear effects on both the hepatic macrophage populations and infiltrating neutrophils following biliary decompression. Altered MMP and TIMP gene expression might suggest that steroids have the potential to modify matrix metabolism during repair. Nevertheless, successful resorption of collagen fibrosis proceeded presumably through other MMP activating mechanisms. We conclude that steroids do not impede the rapid intrinsic repair mechanisms of matrix degradation required for successful repair.

Endotoxin alters early fetal lung morphogenesis.

BACKGROUND: The effects of immaturity and hypoplasia of the premature lung can be affected by proinflammatory stimuli in late gestation or the postnatal period from acute lung injury secondary to intensive ventilatory management or the metabolic consequences of surgery. These stimuli alter alveolarization and contribute to bronchopulmonary dysplasia. While prior research has focused primarily on late gestational effects of inflammation on alveolar development, we sought to study whether early gestational exposure to endotoxin affects branching morphogenesis, during the critical pseudoglandular stage of lung development. METHOD: Gestational day 15 (E15) fetal rat lung explants (term = 22 d) were treated with either 200 ng/mL or 2 microg/mL lipopolysaccharides (LPS) with controls and examined daily by phase microscopy. After 5 d, explants were fixed in 4% formaldehyde, paraffin embedded, and sectioned at 5 mum in the coronal plane. Immunohistochemical analysis was performed with platelet endothelial cell adhesion molecule (PECAM) to define endothelial cells, vascular endothelial growth factor (VEGF) to examine endothelial mitogenesis, and COX-2 antibodies as a marker for prostaglandin synthesis. Real-time PCR examined inducible nitric oxide synthase (iNOS), FGF9, FGF10, and FGFr2 gene expression. Air space fraction and airway epithelium were analyzed with Image J software. RESULTS: Phase contrast microscopy and hematoxylin-eosin histology revealed progressive, dose-related changes in air sac contraction and interstitial thickening. Compared with control E15 explants, day 5 explants incubated with high dose LPS demonstrated thickened and shrunken airway sacs with stunted branching and increased matrix deposition in interstitial areas. By immunohistochemical staining, COX-2 was quantitatively increased after high dose LPS exposure, while PECAM was reduced. VEGF expression was unaltered. LPS increased iNOS, but decreased FGF9, FGF10, and FGFr2 gene expression. CONCLUSIONS: These data support evidence for an inflammatory effect of LPS on the early phase of lung development in the fetal rat, affecting branching morphogenesis during the pseudoglandular phase. Fetal endothelial cells are clearly affected, while COX-2 elevation suggests activation of an as yet undefined fetal pulmonary inflammatory cascade. We speculate that proinflammatory stimuli may ultimately lead to abnormal pulmonary development via fibroblastic growth factor (FGF)-directed mechanisms that affect epithelial-mesenchymal interaction and differentiation at a much earlier gestational age than was previously recognized.

Survival after laser surgery for twin-to-twin transfusion syndrome: when are they out of the woods?

PURPOSE: Severe, progressive twin-to-twin transfusion syndrome (TTTS) is associated with near-100% mortality if left untreated. Endoscopic laser ablation of placental vessels (ELA) is associated with 75% to 80% survival of at least one twin. The actuarial risk of fetal demise after ELA has not yet been described. STUDY DESIGN: A retrospective cohort study from 2 centers on a consecutive series of 163 sets of monochorionic twins with severe TTTS (18 Quintero stage I, 55 stage II, 71 stage III, 19 stage IV) who underwent ELA. Actuarial survival was calculated and stratified for donor vs recipient and according to stage. RESULTS: Median gestational age at diagnosis was 20.1 weeks; median operative time was 60 minutes. Overall survival was 63%, and survival of at least one twin was seen in 76% of pregnancies. Of fetal demises, 10% occurred within 48 hours after ELA, and 90% of all fetal demises occurred within 1 month. There was a 10% survival advantage of recipients over donors. Survival was similar for stages I, II, and IV (75%-80%), compared with 55% for stage III. CONCLUSIONS: Actuarial survival curves for TTTS confirms a greater burden on donor than on recipient but not at a previously reported 2:1 ratio. The current staging system does not accurately reflect post-ELA mortality risk. The unexpected higher mortality in stage III may reflect a more acute progression of the disorder in this group, an adverse effect of LA on an as yet unknown subgroup with stage III or, alternatively, preoperative demise of fulminant stage IV patients, leaving a stage IV subgroup with a more benign course and better outcome.