Risky Behavior: Hospital Transfers Associated with Early Mortality and Rates of Goals of Care Discussions.

INTRODUCTION: Inter-hospital transfer (IHT) patients have higher in-hospital mortality, higher healthcare costs, and worse outcomes compared to non-transferred patients. Goals of care (GoC) discussions prior to transfer are necessary in patients at high risk for decline to ensure that the intended outcome of transfer is goal concordant. However, the frequency of these discussions is not well understood. This study was intended to assess the prevalence of GoC discussions in IHT patients with early mortality, defined as death within 72 hours of transfer, and prevalence of primary diagnoses associated with in-hospital mortality. METHODS: This was a retrospective study of IHT patients aged 18 and older who died within 72 hours of transfer to Wake Forest Baptist Medical Center between October 1, 2016-October 2018. Documentation of GoC discussions within the electronic health record (EHR) prior to transfer was the primary outcome. We also assessed charts for primary diagnosis associated with in-hospital mortality, code status changes prior to death, in-hospital healthcare interventions, and frequency of palliative care consults. RESULTS: We included in this study a total of 298 patients, of whom only 10.1% had documented GoC discussion prior to transfer. Sepsis (29.9%), respiratory failure (28.2%), and cardiac arrest (27.5%) were the top three diagnoses associated with in-hospital mortality, and 73.2% of the patients transitioned to comfort measures prior to death. After transfer, 18.1% of patients had invasive procedures performed with 9.7% undergoing major surgery. Palliative care consultation occurred in only 4.4%. CONCLUSION: The majority (89.9%) of IHT patients with early mortality did not have GoC discussion documented within EHR prior to transfer, although most transitioned to comfort measures prior to their deaths, highlighting that additional work is needed in this area.

Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats.

l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the l-DOPA-treated hemi-parkinsonian rat. Protein analysis of striatal monoamine transporters in unilateral sham or 6-hydroxydopamine-lesioned rats treated with l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and l-DOPA-induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with GBR-12909 (5, 10 mg/kg) and nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated dyskinesia expression. Transporter inhibition did not significantly alter l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.

Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in l-DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.