Bolus Dose Epinephrine Improves Blood Pressure but is Associated with Increased Mortality in Critical Care Transport.

Objective: Hypotension in the prehospital environment is common and linked to dose-dependent mortality. Bolus dose epinephrine (BDE) may reverse hypotension. We tested if BDE use to treat profound hypotension is associated with 24-hour survival. Methods: We performed a retrospective case-cohort study of critical care transport patients with systolic blood pressure (SBP) <70 mmHg from January 2011 to January 2017. To account for baseline differences between treated and untreated patients, we used nearest neighbor matching to estimate the average treatment effect of BDE on 24-hour survival. Included covariates were age, gender, shock type (cardiogenic, distributive, obstructive or hypovolemic), weight, type of service, vitals (heart rate, SBP and diastolic blood pressure, respiratory rate, oxygen saturation, end-tidal carbon dioxide, and Glasgow Coma Scale score) at the time of the first hypotensive episode, as well as pretreatment characteristics including cardiopulmonary resuscitation, defibrillation, transcutaneous pacing, needle thoracostomy, vasopressors, intubation, or arrhythmias. After statistical analysis, we assessed for residual bias by selecting random matched patient records and asking 2 blinded physicians to rate overall illness severity on a Likert scale. We compared perceived illness severity between cases and matched controls using a rank-sum test. Results: There were 6,992 patients transported with SBP <70 mmHg at least once and 4,374 meet inclusion criteria. Of the 1,620 patients transported after protocol implementation, 574 (35%) received BDE. Overall 24-hour survival, survival to discharge and 30-day survival were 80, 57, and 54%, respectively. Survival at 24 hours differed between the BDE group (66%) and controls (82%). These differences persisted at both discharge and 30 days. Administration of BDE was associated with increased post-treatment SBP. BDE treated patients were also more likely to receive cardiopulmonary resuscitation and vasopressors after treatment than untreated hypotensive patients, but there was no association with tachydysrhythmias requiring defibrillation. Conclusions: Bolus dose epinephrine increases blood pressure in the prehospital setting. Despite robust efforts to control for confounding, BDE remained associated with increased mortality in this observational cohort. This association may be due to unmeasured confounding and a randomized controlled trial is necessary to establish a causal relationship between bolus dose vasopressors and mortality.

Modeling Neural Behavior and Pain During Bladder Distention using an Agent-based Model of the Central Nucleus of the Amygdala.

Chronic bladder pain evokes asymmetric behavior in neurons across the left and right hemispheres of the amygdala. An agent-based computational model was created to simulate the firing of neurons over time and in response to painful bladder stimulation. Each agent represents one neuron and is characterized by its location in the amygdala and response type (excited or inhibited). At each time step, the firing rates (Hz) of all neurons are stochastically updated from probability distributions estimated from data collected in laboratory experiments. A damage accumulation model tracks the damage accrued by neurons during long-term, painful bladder stimulation. Emergent model output uses neural activity to measure temporal changes in pain attributed to bladder stimulation. Simulations demonstrate the model's ability to capture acute and chronic pain and its potential to predict changes in pain similar to those observed in the lab. Asymmetric neural activity during the progression of chronic pain is examined using model output and a sensitivity analysis.

Divergent functions of the left and right central amygdala in visceral nociception.

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.