Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety.

The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a "should be considered" recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.

Neonatal and pediatric ECMO organization in France: A national survey.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in France has increased since the H1N1 pandemic in 2009. By contrast, neonatal and pediatric ECMO support in France was known to be limited to a few centers offering congenital cardiac surgery. The purpose of this survey conducted in 2017 was to identify the neonatal and pediatric ECMO centers in France as well as networks existing between ECMO and non-ECMO centers. RESULTS: Seventy-two neonatal or pediatric intensive care unit medical directors answered the survey (84% of the centers surveyed). Twenty were identified as ECMO centers, defined as a unit able to start ECMO with its own resources. ECMO centers ranged from 470,000 to 1,180,000 inhabitants (neonates or children under 18). Thirteen of them (65%) reported that they were affiliated with a congenital cardiac surgery department. A total of 187 patients were supported with ECMO in these centers in 2016. Only six of these centers estimated an activity greater than 15 cases per year over the last 5 years. Nearly 30% of ECMO runs were indicated before or after congenital heart surgery. Four of the ECMO centers offered off-site facilities (mobile team). Non-ECMO centers are likely to be neonatal intensive care units. Nine of them (18.7%) declared knowing an ECMO center that provided mobile care with predefined organization, 11 (22.9%) reported knowing an ECMO center providing a mobile activity without predefined organization, nine (18.%), and 18 (37.5%) ICUs declared they knew of the existence of an ECMO program but did not report any possibility of mobile care or any procedure for transfer. CONCLUSIONS: Of the centers reporting the highest case volumes, four offered mobile ECMO abilities. Well-organized networks for the most severe neonates and children were not identified in France.

[Use of levosimendan in children]. / Utilisation du levosimendan chez l'enfant.

Levosimendan is a calcium-sensitizing drug with positive inotropic properties. As an inodilator, this molecule also has a vasodilation effect. While its efficacy has been demonstrated in the adult in the context of cardiac surgery, its pediatric use is still not widespread. Many studies have shown its safety of use in children, including in the newborn. Across the world, a growing number of teams use levosimendan to treat both acute and chronic heart failure. Through a review of the literature, we describe its pharmacodynamic effects, its current applications, and its perspectives of use in children.

Ductal closure and near-infrared spectroscopy for regional oxygenation monitoring in ductus-dependent congenital heart disease.

In ductus-dependent congenital heart disease, preserving the blood flow through the ductus arteriosus (DA) is vital before surgery. We present the cases of three full-term neonates with ductus-dependent congenital heart disease for whom near-infrared spectroscopy (NIRS) monitoring was performed. We recorded cyclical drops in regional oxygen saturation, both cerebral and renal, that corresponded to constrictions of the DA. These findings appeared either simultaneously or previous to SpO2 drops and were corrected by prostaglandin infusion. Through these cases, we assume that cyclical constrictions of ductal cells participate in the DA closure process in its early phase.

[Anesthesia for non-cardiac surgery after Fontan repair]. / Anaesthésie après une opération de Fontan.

The considerable progress, performed for more than 30 years, in paediatric and interventional cardiology, imaging, surgery, anaesthesia and critical care in the congenital heart diseases allowed the survival the adulthood of more than 85 % of the affected children. The univentricular repair in total cavopulmonary connection or Fontan procedure, are realized in three stages, now, before the age of 5 years, with a different physiology after each stage. This point makes anaesthetic care more complicated for a non-cardiac surgery. The precise knowledge of the physiology of the "Fontan" is necessary before proceeding with anaesthesia. It allows to anticipate the pitfalls and to define specific strategies to be applied.

[Pulmonary hypertension in pediatric and neonatal intensive care unit. Part II: diagnosis and treatment]. / Hypertension pulmonaire de l'enfant et du nouveau-né en réanimation. Partie II : diagnostic et traitement.

In pediatric and neonate intensive care units, the most common causes of pulmonary hypertension (PHT) are congenital cardiac malformations, whether operated or not, respiratory diseases leading to acute or chronic hypoxemia, and left heart failure. In children and neonates, ultrasound is now the reference exam to detect and/or diagnose a PHT. Most often, the changes in morphology of the right ventricle and/or septal kinetics provide the diagnosis; the presence of valvular regurgitation (tricuspid, pulmonary) as well as cardiac or extrapulmonary shunts enables quantifying pulmonary arterial pressures with the Doppler flow. Monitoring the factors favoring PHT (hypoxemia, acidosis, hypercapnia, stress, etc.), oxygenation, ventilation, and systemic hemodynamics is crucial before planning specific treatment. Nitric oxide is the first treatment attempted in the ICU; other treatments (prostacyclin, sildenafil, bosentan) can be used in severe PHT, but cautiously because their usefulness in children has only been suggested in small case series.

[Pulmonary hypertension in pediatric and neonatal intensive care unit. Part I: Physiopathology]. / Hypertension pulmonaire de l'enfant et du nouveau-né en réanimation. Partie I : physiopathologie.

Pulmonary hypertension may be encountered in the pediatric and neonatal intensive care unit. Managing these patients in the intensive care unit can prove extremely challenging, particularly when they become hemodynamically unstable. Pulmonary hypertension in pediatric patients is frequently associated with critical illnesses such as congenital heart disease, acute respiratory disease, and left heart failure. In neonates, pulmonary hypertension is idiopathic or related to respiratory distress or congenital heart failure. This review discusses the pathogenesis and physiology of pulmonary hypertension, the cardiopulmonary interactions in this pathology, and the adaptation to extra-uterine life.

Results of the arterial switch operation in neonates with transposed great arteries.

BACKGROUND: The arterial switch operation is judged the best palliative operation for neonates with transposed great arteries. We aimed to assess the value of analysing a large series of unselected cases by this technically demanding operation and formulate a realistic prognosis. METHODS: We reviewed all 432 neonates (mean age at operation 7 days, mean weight 3.25 kg) who underwent an arterial switch operation between 1987 and 1999. Follow-up (mean time: 4.9 years) was complete in 412 patients. FINDINGS: Survival probability and freedom from reoperation was 94% and 78% at 10 years, respectively. 26 patients died, 16 because of myocardial ischaemia. Risk factors for death included early experience, low weight, associated cardiovascular malformations (especially hypoplasia of the right ventricle or aortic arch), and difficult patterns of coronary arteries. The risk of the coronary artery pattern was greatly reduced in those who had recent operations. At last follow-up, 90% of patients had normal life without treatment, and 94% a normal heart function on echocardiography. INTERPRETATION: The arterial switch operation in neonates achieves excellent results mid-term. Obstruction of the translocated coronary arteries is responsible for most deaths and a substantial number of reoperations. Although confirmation is needed, these results allow anticipation of a favourable long-term prognosis.

Neonatal arterial switch operation: coronary artery patterns and coronary events.

OBJECTIVE: To determine the incidence of coronary events following neonatal arterial switch and to identify potential risk factors for death and coronary events. METHODS: The total experience (236 consecutive arterial switch operations) of one surgeon was studied. Associated procedures included ventricular septal defect closure in 37 patients (16%) and aortic arch repair in 14 patients (6%)). The influence of various patient, procedural, support technique and experience variables was analyzed. RESULTS: There were 19 deaths (8-70% confidence limits = 6-10%). Survival at 1 month, 1 year and 5 years was 93, 92 and 92%, respectively. Risk factors for death included small birth weight (P = 0.0015), hypoplasia of right ventricle (P < 0.0001), aortic arch obstruction (P < 0.0001) and coronary patterns with coronary arteries coursing between the great arteries (P = 0.0066). Coronary events occurred in 26 patients (11-70% confidence limits = 9-13%) and involved coronary deaths (11 patients), non fatal myocardial infarctions (8 patients) and coronary stenoses or occlusions (7 patients). Freedom from coronary events at 1 month, 1 year and 5 years was 94, 91 and 88%, respectively. Risk factors for coronary events included coronary patterns with retropulmonary course of the left main or left circumflex coronary artery (P = 0.0122), coronary patterns with coronary arteries coursing between the great arteries (P < 0.0001), all variations of intramural coronary arteries (P = 0.0010) and commissural origin of coronary ostia (P = 0.0171). CONCLUSIONS: (1) In most neonates, arterial switch operation carries a low operative risk and provides excellent mid-term results; (2) The operative risk remains increased in some subsets; and (3) Some coronary patterns increase the risk of coronary events. Further surgical experience may improve the results.

Donor-recipient size matching in pediatric heart transplantation: a word of caution about small grafts.

BACKGROUND: The increased shortage of donor organs led centers to extend the conventional donor criteria, particularly regarding donor-recipient size mismatching. Little information is available in the pediatric age group. METHODS: Between December 1987 and May 1994, 73 pediatric orthotopic heart transplantations were performed. Indications for heart transplantation included congenital heart defect (29 patients), cardiomyopathy (40 patients), valvular disease (1 patient), and retransplantation (3 patients). Patients ranged in age from 9 days to 18 years (mean: 5.7 +/- 5 years). The following factors were evaluated: cardiomyopathy, congenital heart disease, age, pretransplantation pulmonary hypertension, previous sternotomy, status at transplantation, donor to recipient weight ratio, graft ischemic time, degree of donor inotropic support, ABO compatibility, gender mismatch. RESULTS: The overall mortality rate before discharge (7 days to 4.5 months) was 27.4%. Donor heart failure occurred in 31.5%. Donor heart failure and early mortality were strongly correlated (p = 0.0002). Risk factors for donor heart failure were pretransplantation pulmonary hypertension (p = 0.024), donor/recipient ratio (p = 0.033), and major donor inotropic support (p = 0.034). Donor heart failure rate was 50% in donor/recipient ratio less than 1, 33% in donor/recipient ratio between 1 and 1.6, and 7% in donor/recipient ratio more than 1.6. Donor/recipient ratio less than 1 was the only significant risk of postoperative death by univariate (p = 0.0045) and multivariate (p < 0.01) analysis. CONCLUSIONS: Donor heart failure remains the main cause of early mortality in pediatric heart transplantation. The use of oversized donor may be beneficial, particularly in patients with pretransplantation pulmonary hypertension. The use of undersized donor grafts should be strongly discouraged.

Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components.

BACKGROUND: This prospective study was intended to determine in a homogeneous population of children whether hemofiltration, performed during cardiopulmonary bypass rewarming, is able to improve hemodynamics and biologic hemostasis variables, to reduce postoperative blood loss, time to extubation, and plasma cytokines, and complement fragments. METHODS: Thirty-two children undergoing surgical correction of tetralogy of Fallot were randomly assigned to a hemofiltration or control group. Hemofiltration was performed with a polysulphone hemofilter during rewarming of cardiopulmonary bypass. Plasma clotting factors, D-dimers, antithrombin-III, complement fragments C3a and C5a, interleukin-1 beta, interleukin-6, interleukin-8, and tumor necrosis factor-alpha were measured before and after hemofiltration. Systemic mean arterial pressure, left atrial pressure, time to extubation, and postoperative blood loss were monitored. RESULTS: In the hemofiltration group, significant reductions in 24-h blood loss (250 (176-356) vs. 319 (182-500) ml/m2, median (minimum-maximum), time to extubation (15 (9-22) vs. 19 (11-24) h), plasma concentrations of C3a, C5a, interleukin-6, and tumor necrosis factor-alpha were observed compared to control. Arterial oxygen tension on admission to the intensive care unit was significantly greater in the hemofiltration group (136 +/- 20 vs. 103 +/- 25 mmHg, mean +/- SD). Significant increases in mean arterial pressure, clotting factors, and antithrombin-III were noted for the hemofiltration group. No intergroup difference was observed in left atrial pressure, platelets count, D-dimers, interleukin-8, and duration of stay in the intensive care unit. CONCLUSIONS: Hemofiltration during cardiopulmonary bypass in children improves hemodynamics and early postoperative oxygenation and reduces postoperative blood loss and duration of mechanical ventilation. Hemofiltration is able to remove some major mediators of the inflammatory response.

Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects.

Seventeen infants were treated with inhaled nitric oxide for critical pulmonary artery hypertension after operations for congenital heart defects. In all 17 patients conventional medical therapy consisting of hyperventilation, deep sedation/analgesia, and correction of metabolic acidosis had failed. All children were monitored with a transthoracic pulmonary artery catheter inserted at operation. Pulmonary artery hypertension was defined as an acute rise in pulmonary pressure associated with a decrease in oxygen arterial or venous saturation. After failure of conventional medical therapy, 20 ppm of inhaled nitric oxide was administered to the patient. In all patients the pulmonary pressures decreased (mean pulmonary arterial pressure decreased by -34% +/- 21%) without significant change in systemic arterial pressure, whereas the oxygen arterial saturation and oxygen venous saturation increased by 9.7% +/- 12% and 37% +/- 28%, respectively. Fifteen children were discharged from the intensive care unit at 10 +/- 6 days (range 3 to 26 days) and two died. This study demonstrates that inhaled nitric oxide exerts a selective pulmonary vasodilation without decreasing systemic arterial pressure in children with congenital heart disease. The increased values of mixed venous oxygen saturation and urinary output suggest that this selective lowering of pulmonary vascular resistance improved the overall hemodynamics. The potential toxic effects of nitric oxide and nitrogen dioxide necessitate careful consideration of the risks and benefits of inhaled nitric oxide therapy.

Assessment of coagulation factor activation during cardiopulmonary bypass with a new monoclonal antibody.

Antithrombin-III (AT) is a key inhibitor of blood coagulation that neutralizes activated serine esterases by forming covalent modified complexes (ATm). A new monoclonal antibody directed against short-lived AT-activated serine protease complexes provides a means of measuring subclinical coagulation activity during cardiopulmonary bypass (CPB). Twelve patients undergoing CPB for coronary artery bypass grafting were studied and AT, ATm, D-dimers (DD), and several other coagulation and fibrinolytic markers were measured during the surgical procedure. There were decreases in AT, factors V, II, X, IX, protein S (total and free), C4b-binding protein, thrombomodulin, and platelets counts, whereas heparin, ACT, thrombospondin, plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) increased. ATm and the percentage of ATm available (ATm/AT) showed a peak during CPB. These results demonstrate that during CPB, the use of heparin produces an equilibrium involving increased coagulation activation and consumption in association with increased fibrinolysis. The equilibrated consumption of both coagulation and fibrinolytic factors leads to low levels of all factors after cardiac surgery. The ATm assay allows assessment of the differential effects of CPB and surgical trauma on coagulation activation. It is speculated that ATm levels may be useful in monitoring the consumption of coagulation factors.

[Erythropoietin for autologous transfusion. Use in a case of severe anemia with allo-immunization]. / Erythropoiétine pour transfusion autologue. Utilisation dans un cas d'anémie grave avec allo-immunisation.

In view of the transfusional risks of viral transmission (notably HIV), autologous transfusion is increasingly used; it is often the only possible type of transfusion. A 42-year-old woman with lupus erythematosus, chronic renal failure and triple cardiac valve disease demanding surgery was admitted for multifactorial severe anaemia. Treatment with erythropoietin (8000 units/day) iron replenishment, corticosteroids and polyvalent immunoglobulins was initiated. The patient was operated upon in April 1990. A preoperative cell-saver autotransfusion was performed during surgery. The postoperative period was uneventful. Homologous transfusion was not necessary. In this case where homologous transfusion was ruled out, erythropoiesis stimulated by erythropoietin enabled autotransfusion and cardiac surgery to be performed.

Arterial switch operation: a new technique of coronary transfer.

A successful outcome after arterial switch operation (ASO) for transposition of the great arteries (TGA) depends in large part on the adequacy of transfer of the coronary arteries to the neoaorta. The present paper describes a new technique of coronary transfer which was used in 43 patients: 28 neonates with TGA and intact septum (with coarctation in one), 10 neonates with TGA and ventricular septal defect (with coarctation in one), 2 children undergoing ASO after failed Senning operation and 3 patients with complex TGA. A standardized uniform technique of coronary transfer was used; this technique involved reimplantation of the two coronary ostia side by side after excision of a single button of neoaortic wall. Most coronary patterns were encountered: the usual pattern in 30, circumflex from right coronary artery in 7, inverted coronary arteries in 3, inverted circumflex and right coronary arteries in 3. There was no early coronary-related mortality or morbidity. One late death (3 months) was probably coronary-related. The overall coronary risk was 2.3% (70% confidence limits = 0.3%-7.5%). The proposed technique of coronary transfer can be used in most patients with TGA (all patients without coronary arteries running between the great arteries) and entails a low coronary risk.

Pediatric cardiac transplantation for congenital heart defects: surgical considerations and results.

Among 54 children who underwent 55 heart transplantations, 24 (44%) (mean age, 4.9 +/- 4.8 years; range, 9 days to 18 years) had congenital defects with the following diagnoses: single-ventricle variants (6), hypoplastic left heart syndrome variants (5), transposition complex (6), and miscellaneous defects (7). Twenty patients (83%) had undergone 43 prior operations. Additional surgical procedures included repositioning of transposed great arteries (11), reconstruction of the aortic pathway (4), reconstruction of the pulmonary pathway (8), correction of situs inversus (1), and correction of anomalous pulmonary (1) or systemic (1) venous drainage. Reconstructive procedures were performed using donor or recipient tissue or both. There were six early deaths (hyperacute rejection, 1 patient; pulmonary hypertension, 1; graft failure, 2 patients; infection, 2) and six late deaths (sudden death, 2; chronic rejection, 2; nonspecific graft dysfunction, 1; lymphoproliferative disease, 1). The survival rate was 43% +/- 12% at 3 years. No deaths were related to surgical technique. Survival was not significantly different in pediatric recipients with cardiomyopathy (67% +/- 9%; p = 0.22). Accelerated coronary artery disease was noted in 4 operative survivors (22%; 70% confidence limits, 12% to 36%). All late survivors were free from cardiac symptoms after a mean follow-up of 34 +/- 24 months (range, 6 to 71 months). Based on this study, we reached three conclusions. (1) Careful planning of both harvesting and transplantation procedures allows heart transplantation in recipients with congenital heart diseases. (2) The surgical technique may be demanding, but the early risk is not increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffuse subaortic stenosis: modified Konno procedures with aortic valve preservation.

The Konno procedure provides adequate relief of diffuse subaortic stenosis but requires aortic valve replacement. This may be questionable in patients without aortic valve lesions. Eleven patients had diffuse subaortic stenosis and normal aortic orifice: tunnel subaortic stenosis (6 patients) or diffuse hypertrophic obstructive cardiomyopathy (5 patients). The mean age was 16 +/- 14 years (range: 3 months to 45 years). The mean subaortic gradient was 95 +/- 24 mmHg (range: 60 to 150 mmHg). Two patients had previously undergone resection of discrete subaortic stenosis. Modified Konno procedures were used: aortoseptal approach with aortic annulus division in 5 patients, conal enlargement without aortic annulus division in 6 patients. There was one early death (9%, 70% CL = 1%-27%) and no late deaths. Reoperation was required in two patients: one early for iatrogenic aortic regurgitation and one late for residual ventricular septal defect and mitral regurgitation. The mean follow-up was 3.8 +/- 4.2 years (range: 2 months to 10 years). The survivors were in functional class I (8/10), had a normal left ventricular function (9/10), were in sinus rhythm (10/10) and had left ventricular outflow tract gradients ranging up to 25 mmHg (mean = 6 +/- 10 mmHg). Residual surgery-related defects included ventricular septal defect (one) and aortic regurgitation (one). In patients with diffuse subaortic stenosis and normal aortic orifice, modified Konno procedures with aortic valve preservation are preferable, effective and can be safely performed in infants and children.