Potential and Actual Neonatal Organ and Tissue Donation After Circulatory Determination of Death.

IMPORTANCE: The need for transplants continues to exceed organ and tissue donor availability. Although recent surgical advances have resulted in successful transplants using very small pediatric donors, including neonates, the actual practice of neonatal organ donation after circulatory determination of death (DCDD) remains uncommon. OBJECTIVE: To describe the percentage of neonates potentially eligible for DCDD, including those who underwent successful donation, and reasons for ineligibility in those who did not in a single neonatal intensive care unit (NICU). DESIGN, SETTING, AND PARTICIPANTS: We obtained data from the Children's Hospital Neonatal Database and Intermountain Donor Services (IDS) organ procurement records. The 136 deaths that occurred in the NICU of the Primary Children's Hospital, Salt Lake City, Utah, from January 1, 2010, through May 7, 2013, were reviewed retrospectively from January 12 through July 1, 2014, to determine potential eligibility for DCDD as determined by IDS minimum eligibility criteria (requirement of life-sustaining interventions and weight >2 kg). For patients who did not undergo DCDD, we reviewed records to determine the reasons for ineligibility. MAIN OUTCOMES AND MEASURES: Potential eligibility for DCDD among neonates who died in the study NICU. RESULTS: Of 136 deaths in the NICU, 60 (44.1%) met criteria for DCDD; however, fewer than 10% were referred appropriately to the regional organ procurement organization for evaluation. Forty-five neonates (33.1%) ultimately died within 90 minutes of withdrawal of life-sustaining interventions and thus would have been eligible for organ donation based on warm ischemic time. The most common causes of death among the 60 potentially eligible neonatal donors were neonatal encephalopathy (n = 17) and multiple congenital anomalies (n = 14). Nonreferral or late referral by the medical team was the most frequent reason for donor ineligibility, including 49 neonates (36.0%). Overall, only 4 neonates (2.9%) underwent successful DCDD. CONCLUSIONS AND RELEVANCE: Although almost half of all neonatal deaths identified met minimum IDS criteria, most of these patients were not referred or were referred too late for evaluation. Although small size remains the primary reason for exclusion from DCDD, improved education with regard to criteria and the importance of timely referral by neonatologists and other members of the NICU team would likely result in a significant increase of future donations.

Neonatal medications.

Neonatal abstinence syndrome (NAS) is reaching epidemic proportions related to perinatal use of opioids. There are many approaches to assess and manage NAS, including one we have outlined. A standardized approach is likely to reduce length of stay and variability in practice. Circumcision is a frequent, painful procedure performed in the neonatal period. The rationale for providing analgesia is presented as well as a review of methods. Pharmacogenomics and pharmacogenetics have expanded our understanding of diseases and their drug therapy. Some applications of pharmacogenomics to the neonatal period are presented, along with pediatric challenges of developmental expression of drug-metabolizing enzymes.

Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants.

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. ß-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize ß-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration-time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.

Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications.

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.

Arabidopsis AtSPL14, a plant-specific SBP-domain transcription factor, participates in plant development and sensitivity to fumonisin B1.

The recessive Arabidopsis thalianafumonisin B1-resistant (fbr6) mutant was identified by its ability to survive in the presence of a programmed cell death (PCD)-inducing fungal toxin FB1. The fbr6 mutant also displays altered plant architecture in the absence of FB1, most notably elongated petioles and enhanced leaf margin serration. These phenotypes are a result of a T-DNA insertion in the SQUAMOSA promoter binding protein (SBP) domain gene, AtSPL14. AtSPL14 encodes a plant-specific protein with features characteristic of a transcriptional regulator, including a nuclear localization signal sequence, a plant-specific DNA binding domain (the SBP box), and a protein interaction motif (ankyrin repeats). A transiently expressed fusion of the AtSPL14 protein to green fluorescent protein is directed to the plant nucleus. DNA sequences immediately upstream of the translation start site direct expression of the beta-glucuronidase reporter gene primarily in the vascular tissues, consistent with the phenotypes of the fbr6 mutant. AtSPL14 activates transcription in yeast, with a transactivation domain residing within the N-terminal region of the protein. Recombinant AtSPL14 protein binds A. thaliana genomic DNA in vitro in the absence of other proteins. These results indicate that FBR6/SPL14 functions as a transcriptional regulator that plays a role not only in sensitivity to FB1, but also in the development of normal plant architecture.