Microcirculatory Monitoring in Children with Congenital Heart Disease Before and After Cardiac Surgery.

In this prospective observational study, we investigated whether congenital heart disease (CHD) affects the microcirculation and whether the microcirculation is altered following cardiac surgery with cardiopulmonary bypass (CPB). Thirty-eight children with CHD undergoing cardiac surgery with CPB and 35 children undergoing elective, non-cardiac surgery were included. Repeated non-invasive sublingual microcirculatory measurements were performed with handheld vital microscopy. Before surgery, children with CHD showed similar perfused vessel densities and red blood cell velocities (RBCv) but less perfused vessels (p < 0.001), lower perfusion quality (p < 0.001), and higher small vessel densities (p = 0.039) than children without CHD. After cardiac surgery, perfused vessel densities and perfusion quality of small vessels declined (p = 0.025 and p = 0.032), while RBCv increased (p = 0.032). We demonstrated that CHD was associated with decreased microcirculatory perfusion and increased capillary recruitment. The microcirculation was further impaired after cardiac surgery. Decreased microcirculatory perfusion could be a warning sign for altered tissue oxygenation and requires further exploration.

Single pot in situ aqueous derivatization and subsequent determination of streptomycin and dihydrostreptomycin residues in honey by means of mass spectrometry.

Streptomycin (STR) and dihydrostreptomycin (DSTR) are the typically encountered aminoglycoside (AMG) residues in honey. For AMG analysis, studies in literature involve impractical and expensive applications such as ion-pairing chromatography, immunoassays, pre and post column derivatizations, or SPE approaches. Pretreatments of these methods are toilsome and costly. Herein, one-pot, aqueous in-situ derivatization method was presented as a superior protocol. Time and cost-efficient UHPLC-MS/MS method has been developed, and practical sample preparation was introduced. Satisfactory results were reported in method verification studies. The mean recovery values were 102.6% for STR and 101.3% for DSTR. Average values between 1.5% and 9.9% RSDs were found at intra and inter-day precisions. CCα (5.7 and 5.8 µg/kg) and CCß (6.2 and 6.4 µg/kg) values were calculated for STR and DSTR respectively. AMG residues were found in 29 out of 110 analyzed samples using validated method. Described novelty enabled comprehensive analysis in an inexpensive and straightforward manner.

Use of rotational thromboelastometry to predict hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation: A retrospective cohort study.

BACKGROUND: The incidence of hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) is high. The optimal anticoagulation strategy in children undergoing ECMO is unknown. OBJECTIVES: To study the association between hemostatic complications, coagulation tests, and clinical parameters in pediatric patients undergoing ECMO and their effect on survival. METHODS: We performed a retrospective cohort study of pediatric patients undergoing centrifugal pump ECMO. Collected data included patient characteristics, risk factors, and coagulation test results. Statistical analysis was done using logistic regression analysis for repeated measurements. Dependent variables were thrombosis and bleeding, independent variables were rotational thromboelastometry (ROTEM), activated partial thromboplastin time (aPTT) and antifactor-Xa assay (aXa) results, ECMO duration, age <29 days, sepsis and surgery. RESULTS: Seventy-three patients with 623 ECMO days were included. Cumulative incidences of thrombosis and bleeding were 43.5% (95% confidence interval [CI], 26.0%-59.8%) and 25.4% (95% CI, 13.4%-39.3%), respectively. A lower maximum clot firmness of intrinsic ROTEM (INTEM; odds ratio [OR], 0.946; 95% CI, 0.920-0.969), extrinsic ROTEM (OR, 0.945; 95% CI, 0.912-0.973), and INTEM with heparinase (OR, 0.936; 95% CI, 0.896-0.968); higher activated partial thromboplastin time aPTT; OR, 1.020; 95% CI, 1.006-1.024) and age <29 days (OR, 2.900; 95% CI, 1.282-6.694); surgery (OR, 4.426; 95% CI, 1.543-12.694); and longer ECMO duration (OR, 1.149; 95% CI, 1.022-1.292) significantly increased thrombotic risk. Surgery (OR, 2.698; 95% CI, 1.543-12.694) and age <29 days (OR 2.242, 95% CI 1.282-6.694) were significantly associated with major bleeding. Patients with hemostatic complications had significantly decreased survival to hospital discharge (P = .009). CONCLUSION: The results of this study help elucidate the role of ROTEM, aPTT, anti-factor Xa, and clinical risk factors in predicting hemostatic complications in pediatric patients undergoing ECMO.

Coagulation complications after conversion from roller to centrifugal pump in neonatal and pediatric extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Coagulation complications are frequent, unwanted occurrences in extracorporeal membrane oxygenation (ECMO) treatment, possibly influenced by the pump in the ECMO-circuit. We hypothesized that fewer complications would occur with a smaller, heparin-coated ECMO system with a centrifugal pump (CP) than with one with a roller pump (RP) and that after conversion, complication rates would decrease over time. METHODS: This single-center, retrospective chart study included all first neonatal and pediatric ECMO runs between 2009 and 2015. Differences between groups were assessed with Mann-Whitney U tests and Kruskal-Wallis tests. Determinants of complication rates were evaluated through Poisson regression models. The CP group was divided into three consecutive groups to assess whether complication rates decreased over time. RESULTS: The RP group comprised 90 ECMO runs and the CP group 82. Hemorrhagic complication rates were significantly higher with the CP than with the RP, without serious therapeutic consequences, while thrombotic complications rates were unaffected. Intracranial hemorrhage rates and coagulation-related mortality rates were similar. Gained experience with the CP did not improve complication rates or survival over time. CONCLUSIONS: Although the CP seems safe, it does not seem beneficial over the RP. Further research is warranted on how pump type affects coagulation, taking into account the severity and implications of coagulation complications. LEVEL OF EVIDENCE: Level III.

Automated Algorithm Analysis of Sublingual Microcirculation in an International Multicentral Database Identifies Alterations Associated With Disease and Mechanism of Resuscitation.

OBJECTIVES: Reliable automated handheld vital microscopy image sequence analysis and the identification of disease states and effects of therapy are prerequisites for the routine use of quantitative sublingual microcirculation measurements at the point-of-care. The present study aimed to clinically validate the recently introduced MicroTools software in a large multicentral database of perioperative and critically ill patients and to use this automatic algorithm to data-mine and identify the sublingual microcirculatory variable changes in response to disease and therapy. DESIGN: Retrospective algorithm-based image analysis and data-mining within a large international database of sublingual capillary microscopy. Algorithm-based analysis was compared with manual analysis for validation. Thereafter, MicroTools was used to identify the functional microcirculatory alterations associated with disease conditions and identify therapeutic options for recruiting functional microcirculatory variables. SETTING: Ten perioperative/ICU/volunteer studies in six international teaching hospitals. PATIENTS: The database encompass 267 adult and pediatric patients undergoing surgery, treatment for sepsis, and heart failure in the ICU and healthy volunteers. INTERVENTIONS: Perioperative and ICU standard of care. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred twenty-five handheld vital microscopy image sequences containing 149,257 microscopy images were analyzed. 3.89 × 10 RBC positions were tracked by the algorithm in real time, and offline manual analysis was performed. Good correlation and trending ability were found between manual and automatic total and functional capillary density (r = 0.6-0.8; p < 0.0001). RBC tracking within the database demonstrated changes in functional capillary density and/or RBC velocity in septic shock, heart failure, hypovolemia, obstructive shock, and hemodilution and thus detected the presence of a disease condition. Therapies recruiting the microcirculatory diffusion and convection capacity associated with systemic vasodilation and an increase in cardiac output were separately identified. CONCLUSIONS: Algorithm-based analysis of the sublingual microcirculation closely matched manual analysis across a broad spectrum of populations. It successfully identified a methodology to quantify microcirculatory alterations associated with disease and the success of capillary recruitment, improving point-of-care application of microcirculatory-targeted resuscitation procedures.

Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ∼27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables. METHODS: We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule (n = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 (n = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots. RESULTS: With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities. CONCLUSIONS: In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model's ability to predict mortality in a population of patients with prenatally diagnosed CDH.

Corrigendum: Assessing the Microcirculation With Handheld Vital Microscopy in Critically lll Neonates and Children: Evolution of the Technique and Its Potential for Critical Care.

[This corrects the article DOI: 10.3389/fped.2019.00273.].

Assessing the Microcirculation With Handheld Vital Microscopy in Critically Ill Neonates and Children: Evolution of the Technique and Its Potential for Critical Care.

Assuring adequate tissue oxygenation in the critically ill, but still developing child is challenging. Conventional hemodynamic monitoring techniques fall short in assessing tissue oxygenation as these are directed at the macrocirculation and indirect surrogates of tissue oxygenation. The introduction of handheld vital microscopy (HVM) has allowed for the direct visualization of the microcirculation and with this has offered insight into tissue oxygenation on a microcirculatory level. Since its introduction, technical improvements have been made to HVM, to both hardware and software, and guidelines have been developed through expert consensus on image assessment and analysis. Using HVM, the microcirculation of the skin, the buccal mucosa, and the sublingual mucosa of healthy and (critically) ill neonates and children have been visualized and investigated. Yet, integration of HVM in hemodynamic monitoring has been limited due to technical shortcomings. Only superficial microcirculatory beds can be visualized, inter-observer and intra-observer variabilities are not accounted for and image analysis happens offline and is semi-automated and time-consuming. More importantly, patients need to be cooperative or fully sedated to prevent pressure and movement artifacts, which is often not the case in children. Despite these shortcomings, observational research with HVM in neonates and children has revealed the following: (1) age-related developmental changes in the microcirculation, (2) loss of hemodynamic coherence, i.e., microcirculatory disturbances in the presence of a normal macrocirculation and, (3) microcirculatory disturbances which were independently associated with increased mortality risk. Although these observations underline the importance of microcirculatory monitoring, several steps have to be taken before integration in the decision process during critical care can happen. These steps include technological innovations to ease the use of HVM in the pediatric age group, measuring additional functional parameters of microvascular blood flow and integrated automated analysis software. As a next step, reference values for microcirculatory parameters need to be established, while also accounting for developmental changes. Finally, studies on microcirculatory guided therapies are necessary to assess whether the integration of microcirculatory monitoring will actually improve patient outcome. Nevertheless, HVM remains a promising, non-invasive tool to help physicians assure tissue oxygenation in the critically ill child.

The Sublingual Microcirculation Throughout Neonatal and Pediatric Extracorporeal Membrane Oxygenation Treatment: Is It Altered by Systemic Extracorporeal Support?

Background: Extracorporeal membrane oxygenation (ECMO) treatment alleviates systemic cardiorespiratory failure. However, it is unclear whether ECMO also improves microcirculatory function, as the microcirculation can be disturbed despite normal systemic hemodynamics. We therefore aimed to study the sublingual microcirculation (SMC) throughout neonatal and pediatric ECMO treatment. We hypothesized that the SMC improves after starting ECMO, that the SMC differs between venovenous (VV) and venoarterial (VA) ECMO, and that insufficient recovery of microcirculatory disturbances during ECMO predicts mortality. Methods: This single-center prospective longitudinal observational study included 34 consecutive children (April 2016-September 2018). The SMC was assessed daily with a handheld vital microscope (integrated with incident dark field illumination) before, during, and after ECMO. Validated parameters of vessel density, perfusion, and flow quality were assessed for all vessels (diameter <100 µm) and small vessels (<20 µm). Linear mixed models and logistic regression models were built to assess changes over time and identify significant covariates. Using ROC curves, the predictive values of microcirculatory parameters were assessed for mortality on ECMO and overall mortality. Results: The study population comprised 34 patients (median age 0.27 years, 16 neonates, 16 females). Twelve patients were treated with VV and 22 with VA ECMO. Twelve patients died during ECMO (stopped due to futility) and 3 died after ECMO but before discharge. Microcirculatory parameters did not change significantly before, during or after ECMO. Except between microcirculatory flow index (MFI) and mean arterial pressure (MAP), no significant associations were found between microcirculatory parameters and global systemic hemodynamics. The probability of an undisturbed MFI (>2.6) increased with higher MAP (OR: 1.050, 95%CI: 1.008-1.094). Microcirculatory parameters did not significantly differ between VV and VA ECMO or between survivors and non-survivors. None of the microcirculatory parameters could predict mortality on ECMO or overall mortality. Conclusion: In this heterogeneous study population, we were not able to demonstrate an effect of ECMO on the sublingual microcirculation. Microcirculatory parameters did not change throughout ECMO treatment and did not differ between VV and VA ECMO or between survivors and non-survivors. Future research should focus on determining which neonatal and pediatric ECMO patients would benefit from microcirculatory monitoring and how.

Cognitive evaluation of bupropion sustained release in heavy tobacco smokers using event-related potentials.

OBJECTIVE. The aim of this study was to investigate the effects of bupropion sustained release (SR) on cognitive function, evaluated by event-related potentials (ERPs), in heavy tobacco smokers. MATERIAL AND METHODS. A total of 10 healthy volunteers (6 men and 4 women) were enrolled into the study. P3a and P3b components were evaluated by the novelty P3 paradigm. The ERP recordings were taken after the overnight abstaining and the first dose on the 1st day, on the 7th day, and 45th day of the therapy. RESULTS. The analysis of electrophysiological data in response to the standard stimuli in the parietal area after 7-day bupropion SR treatment revealed a significant increase in the P2 latency (P<0.05). With respect to the drug use × topography effect, an increasing trend of borderline significance in the P3b and P2 amplitudes against target events in the parietal area was observed (P=0.08 for both). A significant increase in the P3a amplitude in the parietocentral area was also observed on the seventh day of treatment (P<0.05). CONCLUSIONS. The reduction of P3a in the frontal area may be due to the decreased distractibility of task-irrelevant novel events, which may mean an augmentation of focused attention to task-relevant target events. The increases in the P3b and P2 amplitudes for target events in the parietal area are very suggestive of this hypothesis, since these components reflect the response to task-relevant target events. Meanwhile, the increased P2 latency for standard events may reflect reduced attention resources for the processing of standard events due to increased attention resources allocated for task-relevant target events. Decreased distractibility and increased attention are believed to be caused by bupropion.