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Levosimendan in Congenital Cardiac Surgery: A Randomized, Double-Blind Clinical Trial

OBJECTIVE In this study, the authors used a continuous infusion of either levosimendan or milrinone as inotropic support after corrective congenital cardiac surgery. The hemodynamic and biochemical parameters were compared. DESIGN A prospective, randomized, double-blind clinical study. SETTING A university hospital. PARTICIPANTS Forty-one patients between 0 and 5 years old requiring inotropic support for corrective congenital heart surgery under cardiopulmonary bypass (CPB) were enrolled in this trial. Thirty-six patients completed the study. INTERVENTIONS Patients were randomized in a double-blind fashion to a continuous infusion of either levosimendan at 0.05 μg/kg/min or milrinone at 0.4 μg/kg/min started at the onset of CPB. Epinephrine was started at 0.02 μg/kg/min after aortic cross-clamp release in both groups. MEASUREMENTS AND MAIN RESULTS There was no significant difference between serum lactate levels of groups. The rate-pressure index (the product of heart rate and systolic blood pressure), which is an indicator of myocardial oxygen demand, was significantly lower at 24 hours and 48 hours postoperatively in the levosimendan group (p < 0.001) in comparison to the milrinone group. Although not significantly different, the troponin values in the levosimendan group were less at 1 hour (median [P(25)-P(75)]: 20.7 [15.3- 48.3] v 34.6 [23.8- 64.5] ng/mL and 4 hours postoperatively: 30.4 [17.3-59.9] v 33.3 [25.5-76.7] ng/mL). CONCLUSION Levosimendan is at least as efficacious as milrinone after corrective congenital cardiac surgery in neonates and infants.

Living Donor Liver Transplantation in Children: Surgical and Immunological Results in 250 Recipients at Université Catholique de Louvain.

Objectives: To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance. Background: LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field. Methods: Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate. Results: Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients. Conclusions: LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.

Cardiac and neurological assessment of normothermia/warm blood cardioplegia vs hypothermia/cold crystalloid cardioplegia in pediatric cardiac surgery : insight from a prospective randomized trial.

OBJECTIVE Although normothermia and warm blood cardioplegia are widely used in adults, cold crystalloids and hypothermia remain routinely used in pediatric cardiac surgery. The superiority of either technique in both brain and myocardial protection remains controversial. We designed a prospective randomized study to compare both approaches in terms of early myocardial protection and late neurodevelopmental status. METHODS From 2004 to 2005, 47 patients were randomly assigned to either mild hypothermia associated to cold crystalloid cardioplegia (CCC, 22 patients) or normothermia with intermittent warm blood cardioplegia (IWBC, 25 patients). Intramyocyte adenosine triphosphate (ATP) was measured before, during and after cardioplegic arrest and results between groups were compared. In addition to their cardiac status, early and late neurologic assessment was performed by psychometric evaluation tests. RESULTS Intracellular ATP levels were not significantly different between the two groups. However, intragroup comparison revealed different profiles according to myocardial protection: in the normothermia/warm blood cardioplegia group, ATP concentration increased during cardioplegic arrest and returned to initial values afterward (11 nmol mg(-1) vs 21 nmol mg(-1) vs 10 nmol mg(-1), p < 0.001), such changes did not occur in the cold protocol (17 nmol mg(-1) vs 19 nmol mg(-1) vs 14 nmol mg(-1), p = NS). Early neurological outcome was similar in both groups. At late follow-up (mean = 4 years), no significant difference was observed between the two groups. CONCLUSIONS This study demonstrates that normothermia/IWBC protocols are not deleterious when compared with more conventional approaches. A more physiologic ATP steady state, reflecting the absence of cellular ischemic insult was observed in the IWBC group. Importantly, no significant difference was found between IWBC and CCC groups in terms of early and late neurodevelopmental status.

Feasibility Study on Neurally Adjusted Ventilatory Assist in Noninvasive Ventilation After Cardiac Surgery in Infants

BACKGROUND: Our objective was to evaluate the feasibility, the quality of synchronization, and the influence on respiratory parameters of the noninvasive neurally adjusted ventilatory assist (NIV-NAVA) mode in infants after cardiac bypass surgery. We conducted a prospective, randomized cross-over study in infants undergoing noninvasive ventilation (NIV) after cardiac surgery. METHODS: Subjects were 10 infants < 5 kg. After extubation, subjects underwent 2 consecutive ventilatory modes after randomization into groups. In the CPAP first group, the subjects were ventilated first in nasal CPAP-1 and then in NIV-NAVA-2 for 30 min in each mode. In the NIV-NAVA first group, periods were reversed. All children were ventilated using the same interface. RESULTS: The analysis of curves showed a synchronization rate of 99.3% for all respiratory cycles. The rate of pneumatic inspiratory trigger was 3.4%. Asynchronies were infrequent. Some typical respiratory patterns (continuous effort and discontinuous inspiration) were found at rates of 10.9% and 31.1%, respectively. The respiratory trends showed a lower maximum diaphragmatic electrical activity (EAdi(max)) in NIV-NAVA periods compared with CPAP periods (P < .001 in the beginning of periods). The breathing frequency decreased significantly during the nasal CPAP-2 and NIV-NAVA-1 periods (P < .05). The inspiratory pressure increased significantly during the NIV-NAVA-1 and NIV-NAVA-2 periods (P < .05), but there was no significant difference for each parameter when comparing Δ values between the beginning and the end of each period. The EAdi signal was easy to obtain in all subjects, and no major side effects were associated with the use of NIV-NAVA. CONCLUSIONS: NIV-NAVA allows good synchronization in bi-level NIV in infant cardiac subjects weighing < 5 kg. The analysis of respiratory parameters shows that NIV NAVA decreases the work of breathing more effectively than nasal CPAP. The study shows some typical respiratory patterns in infants. (ClinicalTrials.gov registration NCT01570933.)

Acute amiodarone toxicity due to an administration error: could excipient be responsible?

Amiodarone is widely used for ventricular and supraventricular tachyarrythmia and is a relatively safe choice of drug, particularly in its enteral form in paediatric patients, because of its low negative inotropic action. Severe side-effects have been described, mostly dose and treatment duration dependent. The use of the intravenous form has aroused concern because of the presence of excipients, polysorbate 80 and benzyl alcohol, considered as possible alternative causes for severe hypotensive events. We report the case of a newborn presenting with supraventricular tachycardia. After receiving a high loading dose of amiodarone intravenously instead of orally, the infant rapidly developed cardiogenic shock and multiple organ dysfunction. This case report illustrates an underestimated side-effect of a supposiedly safe drug, probably related to the negative haemodynamic effects of the excipients. A previously healthy newborn presented on day 4 with re-entrant supraventricular tachycardia, confirmed by electrocardiograph in a regional hospital. The arrhythmia spontaneously ceased before any manoeuvre was attempted. In order to prevent recurrence of arrhythmia, the physician prescribed a loading dose (1200 mg/m2 = 47 mg kg−1) of amiodarone, without determining the route of administration. The ‘oral’ loading dose was administrated intravenously, over a 30-min period (preparation infused in glucose). The baby remained stable during the infusion. Thirty minutes after the end of the infusion, the child suddenly deteriorated, with profound hypotension, requiring cardiopulmonary resuscitation for 20 min. Inotropic support with epinephrine and dobutamine at high doses was started. On arrival of the PICU medical transport team, the baby was unreactive and presenting signs of systemic and peripheral hypoperfusion with severe lactic acidosis. Inotropic support treatment was adapted with introduction of milrinone and weaning of catecholamines, considering the haemodynamic stabilization. During the first 24 h, he developed multiple organ failure with acute hepatic and renal failure, myocardial ischaemia and severe encephalopathy. Organ function slowly recovered. No recurrence of supraventricular tachycardia occurred, but mild sinus bradycardia down to 90 min−1 spontaneously resolved. We eliminated every other major aetiologies (allergies, infection) causing profound shock, and therefore concluded that the 10 times recommended i.v. dose of Cordarone® was the most probable cause of this adverse event. Serum amiodarone and desethylamiodarone (DEA) levels were monitored (Figure 1). The highest serum concentrations never exceeded the usual steady-state concentrations (between 1 and 3 µg ml−1). Excipient dosage was unfortunately not available. Figure 1 Time-dependent evolution (hours after administration) of desethylamiodarone and amiodarone levels. amiodarone (); desethylamiodarone () The child was discharged 1 week after admission with normal cardiac and neurological functions. Amiodarone is a Vaughan-Williams class III antiarrythmic drug, with negative chronotropic and dromotropic effects. The vasodilatory action is responsible for decreased cardiac workload and myocardial oxygen consumption. Amiodarone accumulates in various sites, especially in adipose tissue. Amiodarone is metabolized to DEA by two cytochromes P450, CYP3A4 and CYP2C8. The CYP3A4 isoenzyme is present in the liver and the intestines, with large interindividual variability in its activity and consequently variable systemic availability of oral amiodarone (between 33 and 65%) [1]. Amiodarone and its metabolite are eliminated by hepatic metabolism and biliary excretion; neither amiodarone nor DEA is dialysable. DEA has similar haemodynamic properties, but accumulates to a greater extent than its precursor. Recommended loading dose ranges from 800 to 1200 mg m−2 orally and 5 mg kg−1 intravenously. Maintenance dose ranges from 200 to 500 mg m−2 orally and 5 to 20 µg kg−1 min−1 intravenously. After a single i.v. loading dose, the expected serum peak concentration in healthyvolunteers ranges from 5 to 41 mg l−1. Serum concentration decreases to 10% of its peak value 30–45 min after the end of the loading dose [1]. The commercial presentation of amiodarone contains two solvents, benzyl alcohol and polysorbate 80. Those molecules exert haemodynamic effects [2–4]. Benzyl alcohol is an aromatic alcohol used as a bacteriostatic and solvent. Based on animal studies, it is estimated that in normal adults a rapid infusion with up to 4.5 mg kg−1 remains safe [5]. In the 1980s, numerous cases of neonatal death after the use of benzyl alcohol-containing intravenous solutions were published [6]. Benzyl alcohol has been responsible for metabolic acidosis, respiratory insufficiency, seizures, intracranial haemorrhage and hypotension leading to cardiovascular collapse [7]. Benzyl alcohol is metabolized to benzoic acid, glycinoconjugated into the liver and excreted as hippuric acid by the kidneys. This pathway could be underdeveloped in the newborn, resulting in metabolite accumulation and toxic side-effects [7]. Toxic effects have also been described with polysorbate 80 (Tween 80®). In 1982, Gough et al. studied the cardiovascular effects of the commercial form of amiodarone (amiodarone plus polysorbate) and amiodarone alone in anaesthetized dogs. Only the commercial form caused a 60% drop in mean blood pressure and left ventricular work. They concluded that those adverse events were related to the potent vasodilator and negative inotropic effects of polysorbate 80 [3]. Two studies (Gallik, and Somberg) have compared the classic Cordarone® formulation with the Amio-Aqueous® formula, free of the two previously incriminated solvents. Amio-Aqueous® formula infusion resulted in an increase of peripheral vascular resistance, compensating for an initial decrease in myocardial contractility. Conversely, the classic Cordarone® formulation containing polysorbate 80 resulted in vasodilation and hypotension [8, 9]. Amiodarone itself produces bradycardia and progressive negative inotropic effects [10], minimized by a slower rate of infusion, especially in hypovolaemic patients [2, 11]. One single study on amiodarone use for the treatment of supraventricular and ventricular tachycardias has been conducted in paediatric patients. It showed that amiodarone given intravenously was as safe and effective as the oral form. Half of the infants were haemodynamically unstable, under inotropic support. This instability may have altered the final results and underestimated the side-effects of amiodarone and its solvents [12]. The hypothesis that the two excipients, benzyl alcohol and polysorbate 80, precipitated the occurrence of the cardiogenic shock seems plausible, and appears particularly realistic because the plasma concentration of amiodarone and DEA never reached toxic level. Unfortunately, we were unable to measure the serum level of the two excipients to confirm the hypothesis. This report underlines the potential for severe, even lethal, haemodynamic side-effects of a drug recognized as safe and widely used for paediatric arrhythmia. The actual i.v. formulation used in Belgium should be reconsidered and be replaced by an excipient-free formulation like Amio-Aqueous®, preventing serious side-effects. We emphasize also the need to double check at both physician and nursing levels when unusual medications are prescribed.

Plasma and tissue determination of 4-methylpyrazole for pharmacokinetic analysis in acute adult and pediatric methanol/ethylene glycol poisoning.

Methanol and ethylene glycol poisoning may result in severe intoxication. The inhibition of alcohol dehydrogenase by ethanol or 4-methylpyrazole (4-MP, fomepizole) is fundamental to their treatment. 4-MP presents several advantages over ethanol therapy and has been recently approved as a specific antidote for both intoxications. The authors have developed a simple gas chromatographic method to determine blood and tissue 4-MP concentrations. This method has been validated for its reproducibility (between-day CV < 6.3%), sensitivity (LOD 0.2 μg/mL), and linearity. It has been used in 4 adult patients intoxicated by methanol and 1 child accidentally intoxicated by ethylene glycol. 4-MP was used for each patient, and its blood levels were monitored every 4 hours over 2–3 days for pharmacokinetics purposes. In the population studied, after repeated administration of 10 mg/kg fomepizole, plasma 4-MP concentrations ranged from 1.4 to 21.6 μg/mL, always above the active level of 0.8 μg/mL. The mean peak concentration observed in the 4 adult patients was 18.5 ± 2.6 μg/mL and in the child was 18.9 ± 2.2 μg/mL. Even though 4-MP is characterized by a dose-dependent kinetic profile, under our conditions of dosage and blood sampling, its elimination better fitted a first-order kinetic model. At steady state and without any concomitant therapies, the mean apparent elimination half-life was 14.5 ± 3 hours. Elimination seemed faster in the child. A trend toward a progessive enhancement of the 4-MP elimination rate is suggested in the pediatric case, with the duration of the treatment resulting in a t½ below 5 hours after 48 hours. One patient died, and samples of blood and hepatic tissue were removed simultaneously during autopsy for 4-MP analysis. Interestingly, when the plasma concentration was subtherapeutic (<1 μg/mL) the tissue concentration observed was still significant with 12 μg/g, supporting an intermittent scheme of administration.

Fomepizole alone for severe infant ethylene glycol poisoning.

Objective: To report a case of a massive ingestion of ethylene glycol in an infant successfully treated by fomepizole without hemodialysis. Design: Descriptive case report. Setting: Pediatric intensive care unit. Patient: A 5-mo-old boy who ingested 200 mL of an antifreeze solution. Interventions: Antidotal therapy with a total of seven doses of fomepizole administered intravenously with an interval of 12 hrs (15 mg/kg as loading dose, then 10 mg/kg). Hemodialysis was not performed. Measurements and Main Results: Iterative determination of ethylene glycol concentration was obtained in blood and urine. Kinetics were calculated for ethylene glycol and fomepizole elimination. The infant made a complete recovery with no change in renal function. Conclusions: Although not yet approved for this indication in the child, fomepizole seemed safe and effective in a case of severe ethylene glycol poisoning, without the need for hemodialysis.

ACUTE KIDNEY INJURY IN PAEDIATRIC BONE MARROW PATIENTS

Abstract Bone marrow transplantation (BMT) is a life-saving intervention that has changed the prognosis of a wide range of haemato-oncologic, immunological and metabolic diseases over the last decades. The incidence of both autologous and allogenic BMT exponentially increased in both the adult and paediatric populations since the 1980s. One of the most frequent complications of BMT is renal failure, with 5% to 15% of all BMT developing acute kidney injury (AKI) and 5% to 20% of the survivors developing chronic renal failure (CRF) (1). From those patients, about 50% will require renal replacement therapy (RRT) (2). Risk factors for BMT-associated AKI are numerous and the pathogenesis is usually complex. Primary diagnosis, drug toxicity, total body irradiation, preexisting kidney dysfunction, veno-occlusive disease,sepsis, relative dehydration, non HLA-identical-related or matched-unrelated donors are risk factors for AKI after BMT. As AKI has been recognized to be predictive of long-term kidney dysfunction (3) , prompt recognition and control of the risk factors are crucial to avoid increased morbidity and mortality due to CRF. With the improvement of BMT techniques, a better recognition of risk factors and aggressive management, there appears to be a steady decline with time in the occurrence of both AKI and CRF (3).

Acute life-threatening presentation of unknown lymphatic malformation

Lymphatic malformations (LMs) are rare congenital vascular malformations. Lymphatic malformations include a wide variety of diseases, such as lymphangiomatosis, macro or microcystic lymphatic malformation, and lymphangiectasia. Lymphatic malformations are often first seen at birth, although intrauterine diagnosis is not uncommon. Depending on their size and location, they can be asymptomatic or threaten life by compression of vital structures. We report 2 children admitted to the emergency department with an acute life-threatening presentation of undiagnosed LM. They both required immediate cardiopulmonary resuscitation. Because acute presentations of LM are rare, proper diagnosis can be difficult. Emergency physicians must be aware that sudden enlargement of an unknown thoracic LM can result in airway compression, cardiac tamponade, or rapidly progressive pleural or pericardial effusion. Prompt diagnosis is essential to avoid further morbidity or mortality. The treatment of extensive forms is challenging, requiring a multidisciplinary approach. The prognosis can be poor. Lymphaticmalformations (LMs) consist of rare andcomplex congenital disorders of the development of the lymphatic system. Several forms of LMs are described depending on the timing of the arrest in lymphangiogenesis, including micro and macrocystic lymphatic malformation, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasias [1,2]. Although most of LMs are diagnosed in utero or during the first 2 years of age, it can be diagnosed as late as in adulthood. Diagnosis requires recognition of the clinical features, including bone and spleen involvement, analysis of fluid effusion, and imaging studies. The evolution is usually slow, but rapid deterioration can occur after local infection or bleeding into the malformation or accumulation of chyle in a serosal cavity. A previously healthy 22-month-old boy presented in the emergency department with rapidly progressive respiratory distress associated with a 24-hour history of rhinitis, without fever.Onadmission,hepresentedrespiratory insufficiencywith obnubilation, exhaustion, and hypoxemia despite full flow face mask oxygen. On auscultation, air entry was very poor. There 0735-6757/

Aortic valve repair in the paediatric population: insights from a 38-year single-centre experience.

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