Paloma López-Ortego

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Background:Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (CPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LEVO), in newborns is anecdotal; no pharmacokinetic data in this population are available.Methods:This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5–1 μg/kg/min, n = 9) or LEVO (0.1–0.2 μg/kg/min, n = 11) as an i.v. continuous infusion, starting before CPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRS) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. Serial biochemistry and pharmacokinetic studies were performed.Results:During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. Early postsurgery, MR-treated infants showed lower pH, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRS-derived variables from 24 to 96 h. Study drug withdrawal at 96 h was more frequent with LEVO. LEVO intermediate metabolites were detected in plasma at day 14 after surgery.Conclusion:LEVO is well tolerated in critically ill neonates. LEVO may have advantages over MR in terms of the dosing regimen.

Randomized, Placebo-Controlled Trial of Dobutamine for Low Superior Vena Cava Flow in Infants

OBJECTIVE To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow). STUDY DESIGN A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 μg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow ≥ 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes. RESULTS SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow ≥ 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01). CONCLUSION This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB. TRIAL REGISTRATION ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35).

The SafeBoosC phase II clinical trial: an analysis of the interventions related with the oximeter readings

Background The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. Aims To analyse rStO2-alarm-related clinical decisions and their heterogeneity in the NIRS experimental group (NIRS monitoring visible) and their impact on rStO2 and SpO2. Methods Continuous data from NIRS devices and the alarms (area under the curve of the rStO2 out of range had accumulated 0.2%h during 10 min), clinical data at discrete time points and interventions prompted by the alarms were recorded. Results Sixty-seven infants had data that fulfilled the requirements for this analysis. 1107 alarm episodes were analysed. The alarm triggered a treatment guideline intervention in 25% of the cases; the type of intervention chosen varied among clinical sites. More than 55% of alarms were not followed by an intervention (‘No action’); additionally, in 5% of alarms the rStO2 value apparently was considered non-reliable and the sensor was repositioned. The percentage of unresolved alarms at 30 min after ‘No action’ almost doubled the treatment guideline intervention (p<0.001). Changes in peripheral oxygen saturation (SpO2), were observed only after treatment guideline interventions. Conclusions This study shows that 25% of rStO2 alarms were followed by a clinical intervention determined by the treatment guideline. However, the rStO2 and SpO2 returned to normal ranges after the intervention, supporting the notion that decisions taken by the clinicians were appropriate. Trial registration number ClinicalTrial.gov NCT01590316.

Prevention of Low Cardiac Output Syndrome (LCOS) in Neonates Undergoing Open Heart Surgery: a Pilot-Phase Ii Study About the Equivalence of Two Inodilators (INDS)

Background: Neonates are at particular risk of suffering surgery-related LCOS, characterized by impaired myocardial contractility and the peripheral effects of ischemia/reperfusion on endothelium. INDs are strongly recommended although based on suboptimal studies.Aims: Systematic approach to dose-dependent haemodynamic effects of continuous i.v. infusion of Milrinone (MR) and Levosimendan (LEVO), starting before cardiopulmonary bypass.Methods: Intervention (first 48h, blinded): step- increase in INDs dose (D1: intraoperatively; D2: on NICU admission; D3: 2h - 48 h from admission). INDs withdrawal: LEVO at 48 h ; MR beyond 48h as per attending physician criteria. Continuous, time-locked physiological and near-infrared spectroscopy (cerebral-NIRSc/thigh-NIRSp) data recording during the first 24h (T-1), at 48h (T-2) and 96h (T-3) post-surgery. Blood samples for biochemistry and pharmacokinetics (PKs). Serial echocardiography and cranial-Doppler ultrasound studies.Results: 20 infants [postnatal age: MR, 13 (10) days; LEVO, 15 (9) days] were randomized [(MR=9; D1 0.5- D2 0.75- D3 1mg/k/min ); (LEVO=11; D1 0.1- D2 0.15- D3 0.2mg/k/min)]. MR showed lower pH and higher glycemia and more need for other inotropes during the first hours post-surgery. MR and LEVO showed no differences in time-related changes on NIRSc (increased tissue oxygenation) or blood pressure (decreased diastolic pressure) in T-1. However, groups differed in NIRSc-derived variables from T-1 to T-3. INDs withdrawal at T-3 was 37% in MR vs 91% in LEVO. PKs (LEVO and metabolites) were successfully analyzed.Conclusions: LEVO is well tolerated in critically ill neonates. Potential advantages of LEVO related to dose regimen.

Off-label mesenchymal stromal cell treatment in two infants with severe bronchopulmonary dysplasia: clinical course and biomarkers profile

BACKGROUND Bronchopulmonary dysplasia (BPD) is the most prevalent sequelae of premature birth, for which therapeutic options are currently limited. Mesenchymal stromal cells (MSCs) are a potential therapy for prevention or reversal of BPD. SERIES OF CASES We report on two infants with severe BPD in whom off-label treatment with repeated intravenous doses of allogeneic bone marrow-derived MSCs were administered. We analyzed the temporal profile of serum and tracheal cytokines and growth factors as well as safety, tolerability and clinical response. The administration of repeated intravenous doses of MSCs in two human babies with severe and advanced BPD was feasible and safe and was associated with a decrease of pro-inflammatory molecules and lung injury biomarkers. Both patients were at very advanced stages of BPD with very severe lung fibrosis and did not survive the disease. CONCLUSIONS MSCs are a promising therapy for BPD, but they should be administered in early stages of the disease.

Sevoflurane for Short Painful Procedures in the Neonatal Intensive Care Unit

Objective The aim of this study is to evaluate the use and safety of a sedation protocol with sevoflurane for short painful procedures in newborns. Study Design This was a prospective and observational study conducted in a tertiary neonatal intensive care unit. Sevoflurane was recommended in patients undergoing an invasive procedure of short length, especially in those with spontaneous breathing or without venous access. Its safety and efficacy was assessed by continuous monitoring of respiratory and hemodynamic variables and clinical data recording. Results Sevoflurane was used for 39 procedures, the main indications were: intravitreal bevacizumab injection (12), central venous catheterization (11), and biopsy (6). The median administration length was 14 minutes (range: 5‐65 minutes). The median minimum dose was 1.5% (range: 1‐3%). The median maximum dose was 2.5% (range: 1‐6%). An effective control of nociceptive manifestations was achieved in 35 cases (90%). No major adverse effects were noticed. Main adverse effects were hypotension (8), desaturation (4), and apnea (3). All of them were solved by decreasing (14) or discontinuing (1) the administration of sevoflurane. Conclusion Sevoflurane is relatively easy to use and provides an optimal control of pain‐related symptoms. Its prescription should be individualized and more long‐term follow‐up data are needed.

159 Pharmacokinetics (PKS) of Levosimendan (LEVO) and Intermediate Metabolites (OR-1855 and OR-1896) in Newborns Undergoing Cardiovascular Surgery with Cardiopulmonary Bypass (CPB)

Background and aims LEVO is a novel inodilator developed to treat heart failure. Biotransformation of LEVO in the intestinal tract gives rise to intermediate metabolites with prolonged beneficial haemodynamic effects. There are no data on LEVO PKs in neonates. We aim to investigate LEVO and intermediate metabolites PKs in newborns undergoing CPB. Methods Eleven infants received step-wise dose increase of LEVO (0.10, 0.15, 0.20 mg/k/min) delivered as i.v. continuous infusion, starting before CPB up to 48h post-surgery. Eleven blood samples per subject were collected up to day 14 post-infusion started. Samples were quantified by HPLC-MS/MS. Non-compartmental methods were used for PK parameters. Median (IQR) values are reported. Results Area under the curve (AUC, ng*h/mL) OR-1855 plasma concentration [1717.10 (930.38–3756.41)] was 2.3- and 8.2-fold higher than LEVO [742.10 (527.23–1046)] and OR-1896 [209.78 (99.54–275.36)], respectively. LEVO clearance (CL, L/h/k) was 0.67 (0.44–1.0). OR-1855 maximum concentration (Cmax, ng/ml) was 5.2-fold higher than OR-1896 [18.5 (10.44–33.25) vs. 3.58 (2.94–4.38)]. OR-1896 and OR-1855 Cmax were respectively achieved 2h before and 120h after LEVO infusion stopped. LEVO CL increased and AUC decreased with postnatal age, explaining 66.23% (p=0.023) and 34.51% (p=0.047) of their respective variance. LEVO AUC and pre-surgery antibiotics explained 38.89% (p=0.016) and 26.68% (p=0.035) of OR-1855 AUC variance, respectively. Use of additional diuretics to furosemide explained 27.21% (p=0.025) of OR-1896 AUC. No other covariates influenced LEVO or metabolites PKs. Conclusions This study describes the pharmacokinetic profile of LEVO and intermediate metabolites in newborns as well as covariates explaining a significant part of their variance.

784 Seeking for Definitions of Poor Perfusion States (PPS) In Low Birth Weight Infants (LBWI) (Part I)

Background and Aims Echocardiography-derived low superior vena cava flow (SVCF) associates intraventricular haemorrhage, neurodisability and death. The weaknesses of the method relate to its variability. We aim to explore the relationship between two SVCF cut-off values to define PPS in LBWI and the patients’ short-term neonatal co-morbidities. Methods One hundred LBWI [27.4 (2) wks; 1014 (316) g] who reached illness score below threshold, underwent early (< 12h) and serial echocardiography for the first 96hs after birth. The primary outcome was low SVCF prevalence according to two thresholds: < 41 ml/k/min and [< 41 ml/k/min + SVCF repeatability index (RI)](RI is twice the standard deviation of the differences divided by the mean of all the measures). Secondary outcomes were short-term neonatal clinical outcomes in relation to SVCF status. Results SVCF< 41 ml/k/min prevalence was 30% and was associated with immaturity (p=0.02), corioamnionitis (0.007), advanced resuscitation at birth (0.004), lower Apgar scores (p<0.01) and postnatal ischemic events (bowel perforation or arterial vasospasm) (p=0.002). At SVCF < 51 ml/k/min (41 ml/k/min + repeatability index) cut-off value, the PPS prevalence was 50%; in addition to the above-mentioned co-morbidities trends showed an association between PPS and combined adverse outcome (death or intracranial haemorrhage). Conclusions Low SVCF is highly prevalent in the sick LBWI during the early postnatal period. The association of low SVCF with ischemic events and adverse outcome supports this biomarker as an indicator of PPS. Disclaimer No conflict of interest. Study supported by the Spanish Health Ministry, SAS/2481/2009, the SAMID network (RD08/0072/0018).