Is Liver Transplant Justified at Any MELD Score?

BACKGROUND: Assessing the survival benefit of transplantation in patients with end-stage liver disease is critical in guiding the decision-making process for liver allocation. Previous studies established increased mortality risk for those transplanted below Model for End-Stage Liver Disease (MELD) 18 compared with candidates who remained on the waitlist; however, improved outcomes of liver transplantation and a changing landscape in the donor supply warrant re-evaluation of this idea. METHODS: Using the United Network for Organ Sharing database, we analyzed 160 290 candidates who were waitlisted for liver transplantation within MELD cohorts. We compared patients who were transplanted in a MELD cohort with those listed but not transplanted in that listed MELD cohort with an intent-to-treat analysis. RESULTS: Those transplanted at a MELD between 6 and 11 showed a 31% reduction in adjusted mortality (HR = 0.69 [95% confidence interval [CI], 0.66-0.75]; P < 0.001) compared with the intent-to-treat cohort in a Cox multivariate regression. This mortality benefit increased to a 37% adjusted reduction for those transplanted at MELD between 12 and 14 (HR = 0.63 [95% CI, 0.60-0.66]; P < 0.001) and a 46% adjusted reduction for those transplanted at a MELD between 15 and 17 (HR = 0.54 [95% CI, 0.52-0.57]; P < 0.001), effects that remained in sensitivity analyses excluding patients with hepatocellular carcinoma, encephalopathy, ascites, and variceal bleeds. A multivariate analysis of patients transplanted at MELD < 18 found younger age and cold ischemia time were protective, whereas older age, lower functional status, and socioeconomic factors increased mortality risk. CONCLUSIONS: These findings challenge the current practice of deferring liver transplants below a particular MELD score by demonstrating survival benefits for most transplant patients at the lowest MELD scores and providing insight into who benefits within these subgroups.

Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding.

An animal's evolutionary success depends on the ability to seek and consume foods while avoiding environmental threats. However, how evolutionarily conserved threat detection circuits modulate feeding is unknown. In mammals, feeding and threat assessment are strongly influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits feeding. Here, we report that the PBN receives dense inputs from two discrete neuronal populations in the bed nucleus of the stria terminalis (BNST), an extended amygdala structure that encodes affective information. Using a series of complementary approaches, we identify opposing BNST-PBN circuits that modulate neuropeptide-expressing PBN neurons to control feeding and affective states. These previously unrecognized neural circuits thus serve as potential nodes of neural circuitry critical for the integration of threat information with the intrinsic drive to feed.

Dose-response relationship between local anesthetic volume and hemidiaphragmatic paresis following ultrasound-guided supraclavicular brachial plexus blockade.

BACKGROUND: There is no consensus regarding what volume of local anesthetic should be used to achieve successful supraclavicular block while minimizing hemidiaphragmatic paresis (HDP). This study investigated the dose-response relationship between local anesthetic volume and HDP after ultrasound-guided supraclavicular brachial plexus block. METHODS: A dose escalation design was used to define the dose response curve for local anesthetic volume and incidence of HDP in subjects undergoing upper extremity surgery with supraclavicular block as the primary anesthetic. Dosing levels of 5, 10, 15, 20, 25, 30, 35 and 40 mL of local anesthetic were administered in cohorts of three subjects per dose. Diaphragm function was assessed with M-mode ultrasound before and after block. Secondary objectives included assessment of negative inspiratory force (NIF), oxygen saturation, subjective dyspnea and extent of sensory and motor blockade. RESULTS: Twenty-one subjects completed the study. HDP was present at all doses, with an incidence of 33% at 5 mL to 100% at 30-35 mL. There was a significant decrease in NIF (7.5 cmH2O, IQR (22,0); p=0.01) and oxygen saturation on room air (1%, IQR (2,0); p=0.01) 30 min postblock in subjects experiencing HDP but not in those without HDP. There was no increase in dyspnea in subjects with or without HDP. No subject required respiratory intervention. Motor and sensory block improved with increasing dose, and subjects with HDP exhibited denser blocks than those without (p<0.01). CONCLUSIONS: There is no clinically relevant volume of local anesthetic at which HDP can be avoided when performing a supraclavicular block. In our subject population free of respiratory disease, HDP was well tolerated. TRIAL REGISTRATION NUMBER: NCT03138577.