Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects.

OBJECTIVES: Congenital heart disease with increased pulmonary blood flow results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Using our ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide signaling, and enhanced reactive oxygen species generation. However, potential alterations in these parameters in patients with congenital heart disease have not been investigated. The objective of this study was to test the hypothesis that children with increased pulmonary blood flow will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide levels, and increased reactive oxygen species generation. DESIGN: A prospective single-center cohort study. SETTING: A tertiary care cardiac ICU/PICU. PATIENTS: Arterial blood samples from 18 patients with congenital heart disease associated with increased pulmonary blood flow (ventricular septal defect), 20 with congenital heart disease without increased pulmonary blood flow (tetralogy of Fallot), and 10 without heart disease (controls) were obtained. INTERVENTIONS: Plasma levels of total carnitine, free carnitine, acylcarnitine, and lactate-to-pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with ventricular septal defect and controls. Statistical analysis was performed using an unpaired t test and analysis of variance. MEASUREMENTS AND MAIN RESULTS: Baseline acylcarnitine levels (25.7 ± 13 vs 12.7 ± 8.3; p < 0.05), the acylcarnitine-to-free carnitine ratio (0.8 ± 0.1 vs 0.3 ± 0.05; p < 0.05), and the lactate-to-pyruvate ratio were higher in ventricular septal defect (27.5 ± 3.8 vs 11.1 ± 4.1, p < 0.05) than tetralogy of Fallot; there were no differences between tetralogy of Fallot and control. Superoxide and H2O2 levels were also higher in ventricular septal defect compared with controls, and NOx levels were lower in ventricular septal defect patients compared with tetralogy of Fallot and controls (p < 0.05). CONCLUSIONS: These data suggest that increased pulmonary blood flow from ventricular septal defect results in altered carnitine and mitochondrial homeostasis, decreased nitric oxide signaling, and increased reactive oxygen species production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased reactive oxygen species production, and decreased bioavailable nitric oxide. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased pulmonary blood flow and warrants further investigation.

ICU-Acquired Weakness Is Associated With Differences in Clinical Outcomes in Critically Ill Children.

OBJECTIVE: ICU-acquired weakness, comprised critical illness myopathy and critical illness neuropathy, occurs in a significant proportion of critically ill adults and is associated with high morbidity and mortality. Little is known about ICU-acquired weakness among critically ill children. We investigated the incidence of ICU-acquired weakness among PICUs participating in the Virtual PICU Systems database. We also sought to identify associated risk factors for ICU-acquired weakness and evaluate the hypothesis that ICU-acquired weakness is associated with poor clinical outcomes. DESIGN: Retrospective cohort study. SETTING: PICU. MEASUREMENTS AND MAIN RESULTS: Virtual PICU System was queried for critical illness myopathy and critical illness neuropathy between January 2009 and November 2013. Demographic, admission, and clinical outcome variables including mechanical ventilation days, PICU length of stay, and discharge disposition were analyzed. The Pediatric Index of Mortality-2 was used to evaluate and control for illness severity and risk of mortality. Among 203,875 admissions, there were 55 cases of critical illness myopathy reported and no cases of critical illness neuropathy, resulting in an incidence of 0.02%. Mechanical ventilation days were higher among patients with ICU-acquired weakness versus those who did not develop ICU-acquired weakness (31.6 ± 28.9 vs 9.3 ± 20.6; p < 0.001). In our multivariable analysis, when controlling for Pediatric Index of Mortality-2, ICU-acquired weakness was more frequently reported in those with admission diagnoses of respiratory illness and infection and the need for mechanical ventilation, renal replacement therapy, extracorporeal life support, and tracheostomy. ICU-acquired weakness was associated with a longer PICU length of stay, episodes requiring mechanical ventilation, and discharge to an intermediate, chronic care, and rehabilitation care unit. ICU-acquired weakness was not independently associated with mortality. CONCLUSIONS: ICU-acquired weakness is uncommonly diagnosed among PICU patients reported in Virtual PICU System. ICU-acquired weakness is associated with critical care therapies, invasive procedures, and resource utilization. Limitations of our retrospective study include underrecognition of ICU-acquired weakness and lack of standardized diagnostic criteria within Virtual PICU System. Prospective studies are needed to better understand the true incidence, risk factors, and clinical course for patients who develop ICU-acquired weakness.

Utility of flexible fiberoptic bronchoscopy for critically ill pediatric patients: A systematic review.

AIM: To investigate the diagnostic yield, therapeutic efficacy, and rate of adverse events related to flexible fiberoptic bronchoscopy (FFB) in critically ill children. METHODS: We searched PubMed, SCOPUS, OVID, and EMBASE databases through July 2014 for English language publications studying FFB performed in the intensive care unit in children < 18 years old. We identified 666 studies, of which 89 full-text studies were screened for further review. Two reviewers independently determined that 27 of these studies met inclusion criteria and extracted data. We examined the diagnostic yield of FFB among upper and lower airway evaluations, as well as the utility of bronchoalveolar lavage (BAL). RESULTS: We found that FFB led to a change in medical management in 28.9% (range 21.9%-69.2%) of critically ill children. The diagnostic yield of FFB was 82% (range 45.2%-100%). Infectious organisms were identified in 25.7% (17.6%-75%) of BALs performed, resulting in a change of antimicrobial management in 19.1% (range: 12.2%-75%). FFB successfully re-expanded atelectasis or removed mucus plugs in 60.3% (range: 23.8%-100%) of patients with atelectasis. Adverse events were reported in 12.9% (range: 0.5%-71.4%) of patients. The most common adverse effects of FFB were transient hypotension, hypoxia and/or bradycardia that resolved with minimal intervention, such as oxygen supplementation or removal of the bronchoscope. Serious adverse events were uncommon; 2.1% of adverse events required intervention such as bag-mask ventilation or intubation and atropine for hypoxia and bradycardia, normal saline boluses for hypotension, or lavage and suctioning for hemorrhage. CONCLUSION: FFB is safe and effective for diagnostic and therapeutic use in critically ill pediatric patients.

Endostatin, an inhibitor of angiogenesis, decreases after bidirectional superior cavopulmonary anastamosis.

Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.

Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B.

Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis.

Comparative study of the efficacy of the common topical hemostatic agents with fibrin sealant in a rabbit aortic anastomosis model.

OBJECTIVE: The purpose of this study was to compare the hemostatic efficacy of the common surgical hemostatic agents with fibrin sealant (FS) and to assess their functional strength to secure hemostasis in lieu of placing additional sutures. METHODS: End-to-end anastomosis of transected abdominal aorta was performed in moderately anticoagulated rabbits using 4 or 6 interrupted sutures. The suture line was covered either with gauze alone ("untreated") or with gauze plus Gelfoam, Avitene, Surgicel, FloSeal, or FS, following which blood flow was restored. Blood loss was absorbed by gauze and measured. The surviving rabbits were recovered and the repaired vessel was examined histologically 4 weeks after operation. The investigators were blinded to the treatment groups. Aortic anastomoses using 8 or 12 sutures (untreated) were also performed. RESULTS: Untreated 4-suture anastomosis of aorta resulted in a profuse hemorrhage with an average 108.0 +/- 19.2 (mean +/- SD) ml blood loss and 100% mortality (n = 4). FS application sealed the anastomoses, prevented blood loss (P < 0.01 vs untreated) and exsanguination of the rabbits (n = 4). Other hemostatic agents reduced the bleeding to varying degrees compared to the untreated animals (Gelfoam 66.4 +/- 17.6, Avitene 80.6 +/- 34, Surgicel 66.7 +/- 16.7, FloSeal 44.2 +/- 8.5 ml blood loss, n = 4/group), but the changes were not statistically significant. One to three rabbits in each group survived the operation. Six-suture aortic anastomoses, untreated, resulted in 67.7 +/- 21.8 ml blood loss and 100% survival (n = 6). Application of FS produced immediate and sustained hemostasis in all the animals (P < 0.01 vs untreated). Other hemostatic agents also reduced the bleeding (Gelfoam 42.5 +/- 10, Avitene 50.9 +/- 12.4, Surgicel 32.1 +/- 14, FloSeal 33.9 +/- 5.4 ml blood loss, n = 6/group), but the changes were not statistically significant. The 8- and 12-suture aorta repairs resulted in a moderate blood loss (43.9 +/- 19 and 21.3 +/- 14.9 ml, respectively), followed by a stable hemostasis that precluded the need to use any hemostatic agent. The aortic cross-clamping time of the 12-suture and time to hemostasis for both the 8- and the 12-suture techniques were significantly longer than those of the 4-suture plus FS application (P < 0.01, P < 0.01 and P < 0.05, respectively). CONCLUSION: In a moderate coagulopathy, FS was proven to be the most efficacious hemostatic agent, producing immediate and sustained hemostasis at the arterial anastomotic site. This high efficacy is in part attributed to the strong tissue adhesive property of this agent. FS application may potentially ease the anastomosis and shorten the duration of timely critical vascular procedures.