Closed-loop automated critical care as proof-of-concept study for resuscitation in a swine model of ischemia-reperfusion injury.

BACKGROUND: Volume expansion and vasopressors for the treatment of shock is an intensive process that requires frequent assessments and adjustments. Strict blood pressure goals in multiple physiologic states of shock (traumatic brain injury, sepsis, and hemorrhagic) have been associated with improved outcomes. The availability of continuous physiologic data is amenable to closed-loop automated critical care to improve goal-directed resuscitation. METHODS: Five adult swine were anesthetized and subjected to a controlled 30% estimated total blood volume hemorrhage followed by 30 min of complete supra-celiac aortic occlusion and then autotransfusion back to euvolemia with removal of aortic balloon. The animals underwent closed-loop critical care for 255 min after removal of the endovascular aortic balloon. The closed-loop critical care algorithm used proximal aortic pressure and central venous pressure as physiologic input data. The algorithm had the option to provide programmatic control of pumps for titration of vasopressors and weight-based crystalloid boluses (5 ml/kg) to maintain a mean arterial pressure between 60 and 70 mmHg. RESULTS: During the 255 min of critical care the animals experienced hypotension (< 60 mmHg) 15.3% (interquartile range: 8.6-16.9%), hypertension (> 70 mmHg) 7.7% (interquartile range: 6.7-9.4%), and normotension (60-70 mmHg) 76.9% (interquartile range: 76.5-81.2%) of the time. Excluding the first 60 min of the critical care phase the animals experienced hypotension 1.0% (interquartile range: 0.5-6.7%) of the time. Median intervention rate was 8.47 interventions per hour (interquartile range: 7.8-9.2 interventions per hour). The proportion of interventions was 61.5% (interquartile range: 61.1-66.7%) weight-based crystalloid boluses and 38.5% (interquartile range: 33.3-38.9%) titration of vasopressors. CONCLUSION: This autonomous critical care platform uses critical care adjuncts in an ischemia-reperfusion injury model, utilizing goal-directed closed-loop critical care algorithm and device actuation. This description highlights the potential for this approach to deliver nuanced critical care in the ICU environment, thereby optimizing resuscitative efforts and expanding capabilities through cognitive offloading. Future efforts will focus on optimizing this platform through comparative studies of inputs, therapies, and comparison to manual critical care.

The association of modifiable mechanical ventilation settings, blood gas changes and survival on extracorporeal membrane oxygenation for cardiac arrest.

RESEARCH QUESTION: Given the relative independence of ventilator settings from gas exchange and plasticity of blood gas values during extracorporeal cardiopulmonary resuscitation (ECPR), do mechanical ventilation parameters and blood gas values influence survival? METHODS: Observational cohort study of 7488 adult patients with ECPR from the Extracorporeal Life Support Organization (ELSO) Registry. We performed case-mix adjustment for severity of illness and patient type using generalized estimating equation logistic regression to determine factors associated with hospital survival accounting for clustering by center, standardizing variables by 1 standard deviation (SD) of their values. We examined non-linear relationships between ventilatory and blood gas values with hospital survival. RESULTS: Hospital survival was decreased with higher PaO2 on ECMO (OR 0.69, per 1SD increase [95% CI 0.64, 0.74]; p < 0.001) and with any relative changes in PaCO2 (pre-arrest to on-ECMO) in a non-linear fashion. Survival was worsened with any peak inspiratory pressure >20 cmH20 (OR 0.69, per 1SD [0.64, 0.75]; p < 0.001) and above 40% fraction of inspired oxygen (OR 0.75, per 1SD [0.69, 0.82]; p < 0.001), and with higher dynamic driving pressure (OR 0.72, per 1 SD increase [0.65, 0.79]; <0.001). Ventilation settings and blood gas values varied widely across hospitals, but were not associated with annual hospital ECPR case volume. CONCLUSION: Lower ventilatory pressures, avoidance of hyperoxia, and relatively unchanged CO2 (pre- to on-ECMO) were all associated with survival in patients after ECPR, yet varied across hospitals. Our findings represent potential targets for prospective trials for this rapidly growing therapy to test if these associations have causality.

Developmental regulation of human embryonic stem cell-derived neurons by calcium entry via transient receptor potential channels.

Spontaneous calcium (Ca(2+)) transients in the developing nervous system can affect proliferation, migration, neuronal subtype specification, and neurite outgrowth. Here, we show that telencephalic human neuroepithelia (hNE) and postmitotic neurons (PMNs) generated from embryonic stem cells display robust Ca(2+) transients. Unlike previous reports in animal models, transients occurred by a Gd(3+)/La(3+)-sensitive, but thapsigargin- and Cd(2+)-insensitive, mechanism, strongly suggestive of a role for transient receptor potential (Trp) channels. Furthermore, Ca(2+) transients in PMNs exhibited an additional sensitivity to the canonical Trp (TrpC) antagonist SKF96365 and shRNA-mediated knockdown of the TrpC1 subunit. Functionally, inhibition of Ca(2+) transients in dividing hNE cells led to a significant reduction in proliferation, whereas either pharmacological inhibition or shRNA-mediated knockdown of the TrpC1 and TrpC4 subunits significantly reduced neurite extension in PMNs. Primary neurons cultured from fetal human cortex displayed nearly identical Ca(2+) transients and pharmacological sensitivities to Trp channel antagonists. Together these data suggest that Trp channels present a novel mechanism for controlling Ca(2+) transients in human neurons and may offer a target for regulating proliferation and neurite outgrowth when engineering cells for therapeutic transplantation.