The lifesaving processes of organ donation and transplantation in neonatology and pediatrics carry important ethical considerations. The medical community must balance the principles of autonomy, non-maleficence, beneficence, and justice to ensure the best interest of the potential donor and to provide equitable benefit to society. Accordingly, the US Organ Procurement and Transplantation Network (OPTN) has established procedures for the ethical allocation of organs depending on several donor-specific and recipient-specific factors. To maximize the availability of transplantable organs and opportunities for dying patients and families to donate, the US government has mandated that hospitals refer potential donors in a timely manner. Expedient investigation and diagnosis of brain death where applicable are also crucial, especially in neonates. Empowering trained individuals from organ procurement organizations to discuss organ donation with families has also increased rates of consent. Other efforts to increase organ supply include recovery from donors who die by circulatory criteria (DCDD) in addition to donation after brain death (DBD), and from neonates born with immediately lethal conditions such as anencephaly. Ethical considerations in DCDD compared to DBD include a potential conflict of interest between the dying patient and others who may benefit from the organs, and the precision of the declaration of death of the donor. Most clinicians and ethicists believe in the appropriateness of the Dead Donor Rule, which states that vital organs should only be recovered from people who have died. The medical community can maximize the interests of organ donors and recipients by observing the Dead Donor Rule and acknowledging the ethical considerations in organ donation.
Background As important mediators of solute transport at the blood–brain and blood–cerebrospinal fluid barriers, ATP-binding cassette (ABC) transporters (including ABCB1, ABCC1, and ABCC2), impact the bioavailability of drugs and endogenous substrates in the brain. While several ABCB1, ABCC1, and ABCC2 single nucleotide polymorphisms (SNPs) have been identified, their impact on outcome after traumatic brain injury (TBI) is unknown. Hypothesis ABCB1, ABCC1, and ABCC2 SNPs are associated with Glasgow Outcome Scale (GOS) score after TBI. Methods DNA samples from 305 adult patients with severe TBI (Glasgow Coma Scale, GCS score ≤ 8) were genotyped for tagging SNPs of ABCB1 (rs1045642; rs1128503), ABCC1 (rs212093; rs35621; rs4148382), and ABCC2 (rs2273697). For each SNP, patients were dichotomized based on presence of variant allele for multivariate analysis to determine associations with GOS assigned at 6 months adjusting for GCS, Injury Severity score, age, and patient sex. Results For ABCB1 rs1045642, patients homozygous for the T allele were less likely to be assigned poor outcome versus those possessing the C allele [CT/CC; odds of unfavorable GOS = 0.71(0.55−0.92)]. For ABCC1 rs4148382, patients homozygous for the G allele were less likely to be assigned poor outcome versus those possessing the A allele [AG/AA; odds of unfavorable GOS = 0.73(0.55−0.98)]. Conclusions In this single-center study, patients homozygous for the T allele of ABCB1 rs1045642 or the G allele of ABCC1 rs4148382 were found to have better outcome after severe TBI. Further study is necessary to replicate these very preliminary findings and to determine whether these associations are due to central nervous system bioavailability of ABC transporter drug substrates commonly used in the management of TBI, brain efflux of endogenous solutes, or both.
Poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the cellular response to stress and DNA damage. However, excessive activity of PARP-1 exacerbates brain injury via NAD þ depletion and energy failure. The purpose of this study was to determine if tagging single nucleotide polymorphisms (tSNPs) covering multiple regions of the PARP-1 gene are related to outcome after traumatic brain injury (TBI) in humans. DNA from 191 adult patients with severe TBI was assayed for four tSNPs corresponding to haplotype blocks spanning the PARP-1 gene. Categorization as favorable or poor outcome was based on Glasgow Outcome Scale (GOS) score assigned at 6 months. PARP-1 enzyme activity was indirectly evaluated by quantifying poly-ADP-ribose (PAR)-modified proteins in cerebrospinal fluid (CSF) using an enzyme-linked immunosorbent assay. In multiple logistic regression analysis controlling for age, initial Glasgow Coma Scale score, and gender, the AA genotype of SNP rs3219119 was an independent predictor of favorable neurologic outcome. This SNP tags a haplotype block spanning the automodification and catalytic domains of the PARP-1 gene. SNP rs2271347 correlated with CSF PAR-modified protein level. This SNP, which did not correlate with outcome, tags a haplotype block spanning the promoter region of the PARP-1 gene. We conclude that after severe TBI in humans, a PARP-1 polymorphism within the automodification-catalytic domain is associated with neurological outcome, while a polymorphism within the promoter region was associated with CSF PAR-modified protein level. These findings must be replicated in a prospective study before the relevance of PARP-1 polymorphisms after TBI can be established.
Objectives Small series have suggested that outcomes after abusive head trauma (AHT) are less favorable than after other injury mechanisms. We sought to determine the impact of AHT on mortality and identify factors that differentiate children with AHT from those with TBI from other mechanisms. Design First 200 subjects from the Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial – a comparative effectiveness study using an observational, cohort study design. Setting Pediatric intensive care units in tertiary children’s hospitals in USA and abroad. Participants Consecutive children (age <18 y) with severe TBI (GCS ≤ 8; intracranial pressure (ICP) monitoring). Interventions None Measurements and Main Results Demographics, injury-related scores, prehospital and resuscitation events were analyzed. Children were dichotomized based on likelihood of AHT. A total of 190 children were included (n = 35 with AHT). AHT subjects were younger (1.87 y ± 0.32 vs. 9.23 y ± 0.39, p < 0.001) and a greater proportion were female (54.3% vs. 34.8%, p = 0.032). AHT were more likely to (i) be transported from home (60.0% vs. 33.5%, p < 0.001), (ii) have apnea (34.3% vs. 12.3%, p = 0.002) and (iii) seizures (28.6% vs. 7.7%, p < 0.001) during pre-hospital care. AHT had a higher incidence of seizures during resuscitation (31.4 vs. 9.7%, p = 0.002). After adjusting for covariates, there was no difference in mortality (AHT, 25.7% vs. non-AHT, 18.7%, HR 1.758, p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (AHT, 66.7% vs. non-AHT, 69.0%). Conclusion In this large, multicenter series, children with AHT had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other TBI populations in children, female predominance was seen in AHT in our cohort. Similar mortality rates and refractory ICP deaths suggest that children with severe AHT may benefit from therapies including invasive monitoring and adherence to evidenced-based guidelines.
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