Enno D. Wildschut

Haemofiltration in newborns treated with extracorporeal membrane oxygenation: a case-comparison study

IntroductionExtracorporeal membrane oxygenation is a supportive cardiopulmonary bypass technique for patients with acute reversible cardiovascular or respiratory failure. Favourable effects of haemofiltration during cardiopulmonary bypass instigated the use of this technique in infants on extracorporeal membrane oxygenation. The current study aimed at comparing clinical outcomes of newborns on extracorporeal membrane oxygenation with and without continuous haemofiltration.MethodsDemographic data of newborns treated with haemofiltration during extracorporeal membrane oxygenation were compared with those of patients treated without haemofiltration in a retrospective 1:3 case-comparison study. Primary outcome parameters were time on extracorporeal membrane oxygenation, time until extubation after decannulation, mortality and potential cost reduction. Secondary outcome parameters were total and mean fluid balance, urine output in mL/kg/day, dose of vasopressors, blood products and fluid bolus infusions, serum creatinin, urea and albumin levels.ResultsFifteen patients with haemofiltration (HF group) were compared with 46 patients without haemofiltration (control group). Time on extracorporeal membrane oxygenation was significantly shorter in the HF group: 98 hours (interquartile range (IQR) = 48 to 187 hours) versus 126 hours (IQR = 24 to 403 hours) in the control group (P = 0.02). Time from decannulation until extubation was shorter as well: 2.5 days (IQR = 0 to 6.4 days) versus 4.8 days (IQR = 0 to 121.5 days; P = 0.04). The calculated cost reduction was €5000 per extracorporeal membrane oxygenation run. There were no significant differences in mortality. Patients in the HF group needed fewer blood transfusions: 0.9 mL/kg/day (IQR = 0.2 to 2.7 mL/kg/day) versus 1.8 mL/kg/day (IQR = 0.8 to 2.9 mL/kg/day) in the control group (P< 0.001). Consequently the number of blood units used was significantly lower in the HF group (P< 0.001). There was no significant difference in inotropic support or other fluid resuscitation.ConclusionsAdding continuous haemofiltration to the extracorporeal membrane oxygenation circuit in newborns improves outcome by significantly reducing time on extracorporeal membrane oxygenation and on mechanical ventilation, because of better fluid management and a possible reduction of capillary leakage syndrome. Fewer blood transfusions are needed. All in all, overall costs per extracorporeal membrane oxygenation run will be lower.

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

ABSTRACT Extracorporeal membrane oxygenation (ECMO) is used to temporarily sustain cardiac and respiratory function in critically ill infants but can cause pharmacokinetic changes necessitating dose modifications. Cefotaxime (CTX) is used to prevent and treat infections during ECMO, but the current dose regimen is based on pharmacokinetic data obtained for non-ECMO patients. The objective of this study was to validate the standard dose regimen of 50 mg/kg of body weight twice a day (postnatal age [PNA], <1 week), 50 mg/kg three times a day (PNA, 1 to 4 weeks), or 37.5 mg/kg four times a day (PNA, >4 weeks). We included 37 neonates on ECMO, with a median (range) PNA of 3.3 (0.67 to 199) days and a median (range) body weight of 3.5 (2.0 to 6.2) kg at the onset of ECMO. Median (range) ECMO duration was 108 (16 to 374) h. Plasma samples were taken during routine care, and pharmacokinetic analysis of CTX and its active metabolite, desacetylcefotaxime (DACT), was done using nonlinear mixed-effects modeling (NONMEM). A one-compartment pharmacokinetic model for CTX and DACT adequately described the data. During ECMO, CTX clearance (CLCTX) was 0.36 liter/h (range, 0.19 to 0.75 liter/h), the volume of distribution of CTX (VCTX) was 1.82 liters (0.73 to 3.02 liters), CLDACT was 1.46 liters/h (0.48 to 5.93 liters/h), and VDACT was 11.0 liters (2.32 to 28.0 liters). Elimination half-lives for CTX and DACT were 3.5 h (1.6 to 6.8 h) and 5.4 h (0.8 to 14 h). Peak CTX concentration was 98.0 mg/liter (33.2 to 286 mg/liter). DACT concentration varied between 0 and 38.2 mg/liter, with a median of 10 mg/liter in the first 12 h postdose. Overall, CTX concentrations were above the MIC of 8 mg/liter over the entire dose interval. Only 1 of the 37 patients had a sub-MIC concentration for over 50% of the dose interval. In conclusion, the standard cefotaxime dose regimen provides sufficiently long periods of supra-MIC concentrations to provide adequate treatment of infants on ECMO.

Plasma Concentrations of Oseltamivir and Oseltamivir Carboxylate in Critically Ill Children on Extracorporeal Membrane Oxygenation Support

Introduction To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children. Methodology Steady state 0–12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC0–12 h were calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support. Principal Findings Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility. Conclusion Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted.

Brain injury associated with neonatal extracorporeal membrane oxygenation in the Netherlands: a nationwide evaluation spanning two decades.

Objective: To determine the prevalence of and to classify ultrasound-proven brain injury during neonatal extracorporeal membrane oxygenation in The Netherlands. Design: Retrospective nationwide study (Rotterdam and Nijmegen), spanning two decades. Setting: Level III university hospitals. Subjects: All neonates who underwent neonatal extracorporeal membrane oxygenation from 1989 to 2010. Interventions: None. Measurements and Main Results: Cranial ultrasound images were reviewed independently by two investigators without knowledge of primary diagnosis, outcome, type of extracorporeal membrane oxygenation, or statistics. The scans were reviewed for lesion type and timing, with the use of a refined classification method for focal brain injury. Extracorporeal membrane oxygenation type was venoarterial in 88%. Brain abnormalities were detected in 17.3%: primary hemorrhage was most frequent (8.8%). Stroke was identified in 5% of the total group, with a notable significant preference for the left hemisphere (in 70%). Lobar hematoma (prevalence 2.2 %) was also significantly left predominant. Conclusion: The incidence of brain injury found with cranial ultrasound in The Netherlands of the patients treated with extracorporeal membrane oxygenation during the neonatal period was 17.3%. Primary hemorrhage was the largest group of lesions, not clearly side-specific except for lobar bleeding, most probably related to changes in venous flow. Arterial ischemic stroke occurred predominant in the left hemisphere.

Microanalysis of β-Lactam Antibiotics and Vancomycin in Plasma for Pharmacokinetic Studies in Neonates

ABSTRACT Rational dosing of antibiotics in neonates should be based on pharmacokinetic (PK) parameters assessed in specific populations. PK studies of neonates are hampered by the limited total plasma volume, which restricts the sample volume and sampling frequency. Available drug assay methods require large sample volumes and are labor-intensive or time-consuming. The objective of this study was to develop a rapid ultra-performance liquid chromatographic method with tandem mass spectrometry detection for simultaneous quantification of amoxicillin, meropenem, cefazolin, cefotaxime, deacetylcefotaxime, ceftriaxone, and vancomycin in 50 μl of plasma. Cleanup consisted of protein precipitation with cold acetonitrile (1:4) and solvent evaporation before reversed-phase chromatographic separation and detection using electrospray ionization tandem mass spectrometry. Standard curves were prepared over a large dynamic range with adequate limits of quantitation. Intra- and interrun accuracy and precision were within 100% ± 15% and 15%, respectively, with acceptable matrix effects. Coefficients of variation for matrix effects and recovery were <10% over six batches of plasma. Stability in plasma and aqueous stocks was generally sufficient, but stability of meropenem and ceftriaxone in extracts could limit autosampler capacity. The instrument run time was approximately 3.50 min per sample. Method applicability was demonstrated with plasma samples from an extracorporeal membrane oxygenation-treated neonate. Different β-lactam antibiotics can be added to this method with additional ion transitions. Using ultra-performance liquid chromatography mass spectrometry, this method allows simple and reliable quantification of multiple antibiotics in 50 μl of plasma for PK studies of neonates.

The impact of extracorporeal life support and hypothermia on drug disposition in critically ill infants and children.

Extracorporeal membrane oxygenation (ECMO) support is an established lifesaving therapy for potentially reversible respiratory or cardiac failure. In 10% of all pediatric patients receiving ECMO, ECMO therapy is initiated during or after cardiopulmonary resuscitation. Therapeutic hypothermia is frequently used in children after cardiac arrest, despite the lack of randomized controlled trials that show its efficacy. Hypothermia is frequently used in children and neonates during cardiopulmonary bypass (CPB). By combining data from pharmacokinetic studies in children on ECMO and CPB and during hypothermia, this review elucidates the possible effects of hypothermia during ECMO on drug disposition.

Effect of hypothermia and extracorporeal life support on drug disposition in neonates

Extracorporeal membrane oxygenation (ECMO) is a valuable treatment modality in neonates with reversible cardiopulmonary failure in therapy-resistant pulmonary hypertension after perinatal asphyxia, septic shock or ECMO cardiopulmonary resuscitation. Neonates with severe perinatal asphyxia are currently treated with therapeutic hypothermia to improve neurological outcome. Consequently, therapeutic hypothermia may be indicated in the neonatal ECMO population. Both ECMO and hypothermia have been associated with changes in drug disposition. However, little is known about the combined effects of these treatment modalities. This review will explore the available literature, identify possible changes in pharmacokinetics and make suggestions for future research directions.

Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies

Substance use among pregnant women is a major public health issue. Both prescription opioid use and illicit opioid abuse have increased dramatically in recent years. Prolonged in utero drug exposure may result in neonatal abstinence syndrome (NAS), an acute multisystemic clinical entity that occurs in the first days of life. This syndrome is caused by abrupt discontinuation of fetal exposure to licit or illicit drugs chronically consumed by the mother during pregnancy and transmitted to the fetus through the placenta. It usually requires prolonged hospitalization and may have long‐term effects. The interplay of many factors contributes to its clinical heterogeneity, and its pathophysiology has not been fully unveiled. The first step in NAS management consists of nonpharmacologic interventions and includes promoting breastfeeding when not contraindicated. If withdrawal signs become severe, pharmacotherapy is needed. The Finnegan scoring system supports care providers across the pharmacotherapy process from initiation through the monitoring phase, until weaning and discontinuation. However, a standardized approach to pharmacotherapy is still lacking. Morphine is usually the first‐line agent to treat NAS. Methadone is a valid option, but its safety profile is not completely known. Phenobarbital, despite its lack of effect on gastrointestinal symptoms and unfavorable pharmacologic features, has been identified as a second‐line agent to be used in infants unresponsive to opiates. Although buprenorphine and clonidine seem promising, their use requires further validation. Long‐term developmental effects of NAS therapy call for more‐comprehensive, longitudinal assessments. In this article, key points for use of recommended therapies are outlined, and directions for future research are suggested.

Risk and relevance of open lung biopsy in pediatric ECMO patients: the Dutch experience

BACKGROUND Open lung biopsy can help differentiate between reversible and irreversible lung disease and may guide therapy. To assess the risk-benefit ratio of this procedure in pediatric extracorporeal membrane oxygenation (ECMO) patients, we reviewed data of all patients who underwent an open lung biopsy during ECMO in one of the two pediatric ECMO centers in a nationwide study in the Netherlands. RESULTS In nineteen neonatal and six pediatric patients (0-15.5years), twenty-five open lung biopsies were performed during the study period. In 13 patients (52%), a classifying diagnosis of underlying lung disease could be made. In another nine patients (36%), specific pathological abnormalities were described. In three patients (12%), only nonspecific abnormalities were described. The histological results led to withdrawal of ECMO treatment in 6 neonates with alveolar capillary dysplasia/misalignment of pulmonary veins (24%) and in another 6 patients, corticosteroids were started (24%). All patients survived the biopsy procedure. Hemorrhagic complications were rare. CONCLUSION An open lung biopsy during an ECMO run in neonates and children is a safe procedure with a minimum risk for blood loss and biopsy-related death. It can be very useful in diagnosing the underlying pathology and can guide cessation of ECMO treatment and thereby avoid continuation of futile treatment, especially in neonatal patients. LEVEL OF EVIDENCE III. TYPE OF STUDY Diagnostic study.

Insufficient serum caspofungin levels in a paediatric patient on ECMO

Caspofungin, aechinocandin, is a relatively new lipophilic antifungal drug. Little is known concerning the pharmacokinetics of caspofungin in children. Extracorporeal membrane oxygenation (ECMO) allows prolonged cardiopulmonary support in patients with life-threatening respiratory or cardiac failure. Pharmacokinetics may be altered by ECMO. We describe the case of a paediatric patient on ECMO with severe pneumonia and sepsis, who had subtherapeutic exposure of caspofungin despite normal to high dosages of caspofungin. Therapeutic drug monitoring is warranted.