Managing delivery of complex multidrug infusions in anesthesia and critical care presents a significant clinical challenge. Current practices relying on manual control of infusion pumps often result in unpredictable drug delivery profiles and dosing errors-key issues highlighted by the United States Food and Drug Administration (FDA). To address these issues, we introduce the SMART (synchronized-pump management algorithms for reliable therapies) framework, a novel approach that leverages low Reynolds number drug transport physics and machine learning to accurately manage multidrug infusions in real-time. SMART is activated based on the Shafer number ( Sh ), a novel non-dimensional number that quantifies the relative magnitude of a drug's therapeutic action timescale to its transport timescale within infusion manifolds. SMART is useful when Sh < 1 , where drug transport becomes the rate limiting step in achieving the desired therapeutic effects. When activated, SMART monitors multidrug concentrations within infusion manifolds and leverages this information to perform end-to-end management of drug delivery using an ensemble of deterministic and deep reinforcement learning (RL) decision networks. Notably, SMART RL networks employ differentially sampled split buffer architecture that accelerates learning and improves performance by seamlessly combining deterministic predictions with RL experience during training. SMART deployed in standalone infusion pumps under simulated clinical conditions outperformed state-of-the-art manual control protocols. This framework has the potential to revolutionize critical care by enhancing accuracy of medication delivery and reducing cognitive workloads. Beyond critical care, the ability to accurately manage multi-liquid delivery via complex manifolds will have important bearings for manufacturing and process control.

Goal: To develop a compact, real-time microfluidic spectroscopy system capable of simultaneously measuring the concentrations of multiple solutes flowing together through a single fluid pathway with high temporal resolution. Methods: The measurement system integrates a Z-flow cell and dual-wavelength LED light sources with a compact spectrophotometer. The experimental setup consisted of two clinical infusion pumps delivering distinct marker dyes through a common fluid pathway composed of a clinical manifold and a single lumen of a clinical intravascular catheter, while a third pump delivered an inert carrier fluid. Concentration measurements of the mixed dyes were performed at high-frequency sampling intervals, with dynamic pump rate adjustments to evaluate the system's ability to detect real-time changes in solute concentration. A MATLAB-based control application enabled automated data acquisition, processing, and system control to enhance experimental efficiency. Results: The system accurately measured solute concentrations, capturing temporal variations with high precision. It demonstrated high reproducibility with a standard error of the mean no larger than [Formula: see text] for Erioglaucine and [Formula: see text] for Tartrazine at steady state, and high accuracy with a maximum deviation of [Formula: see text] for Erioglaucine and [Formula: see text] for Tartrazine from the expected steady-state concentrations. Conclusions: This system enables continuous, real-time monitoring of multiple solutes in dynamic flow conditions, offering a portable solution with high sensitivity to temporal concentration changes-advancing beyond traditional static fluid measurement methods.

Critically ill or anesthetized patients commonly receive pump-driven intravenous infusions of potent, fast-acting, short half-life medications for managing hemodynamics. Stepwise dosing, e.g. over 3-5 min, adjusts physiologic responses. Flow rates range from < 0.1 to > 30 ml/h, depending on pump type (large volume, syringe) and drug concentration. Most drugs are formulated in aqueous solutions. Hydrophobic drugs are formulated as lipid emulsions. Do the physical and chemical properties of emulsions impact delivery compared to aqueous solutions? Does stepwise dose titration by the pump correlate with predicted plasma concentrations? Precise, gravimetric, flow rate measurement compared delivery of a 20% lipid emulsion (LE) and 0.9% saline (NS) using different pump types and flow rates. We measured stepwise delivery and then computed predicted plasma concentrations following stepwise dose titration. We measured the pharmacokinetic coefficient of short-term variation, (PK-CV), to assess pump performance. LE and NS had similar mean flow rates in stepwise rate increments and decrements between 0.5 and 32 ml/h and continuous flows 0.5 and 5 ml/h. Pharmacokinetic computation predictions suggest delayed achievement of intended plasma levels following dose titrations. Syringe pumps exhibited smaller variations in PK-CV than large volume pumps. Pump-driven deliveries of lipid emulsion and aqueous solution behave similarly. At low flow rates we observed large flow rate variability differences between pump types showing they may not be interchangeable. PK-CV analysis provides a quantitative tool to assess infusion pump performance. Drug plasma concentrations may lag behind intent of pump dose titration.

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

Companion resources associated with the publication, "Propofol disrupts alpha dynamics in functionally distinct thalamocortical networks during loss of consciousness" (in press) (DOI: 10.1073/pnas.2207831120) https://www.biorxiv.org/content/10.1101/2022.04.05.487190v1.full.pdf Contents: 1. 10-Hz cross-spectral matrices computed from pre- and post-loss of consciousness epochs (see manuscript for details) 2. Channel labels of matrix rows and columns 3. Channel coordinates and Freesurfer structural labels in MNI space. 4. Structural segmentations of thalamic nuclei in MNI152 space. (Thanks to Fischl Lab, Martinos Center.) Patient demographics are listed in Supporting Information for the PNAS publication. For diffusion images used in the publication, please refer to the WU-Minn Human Connectome Project, using matches listed in the manuscript's Supporting Information.

During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.

Critically ill and anesthetized patients commonly receive life-sustaining medications by pump-driven continuous intravenous infusion. Microinfusion refers to delivering concentrated drugs with low flow carriers to conserve fluid administration. Most infused medications are water-soluble. Delivery onset lag times have been identified for microinfusions of water-soluble drugs or experimental surrogates. Drugs may be formulated as emulsions. Initiation of emulsion microinfusions has not been described. We tested in vitro the hypothesis that an emulsion's physical characteristics would influence its microinfusion delivery onset. We adapted an established in vitro model of pump-driven continuous intravenous microinfusion to compare the delivery of methylene blue as a surrogate for water-soluble drugs and a 10% lipid emulsion as a surrogate for a drug formulated as an emulsion. The drug surrogates joined the carrier with carrier flow vertically upwards, vertically downwards or horizontally. We measured the times to 5%, 50% and 95% of plateau delivery. Emulsion entry into a vertical (upwards) carrier flow resulted in a rapid initial emulsion delivery exceeding predictions of delivery models. Emulsion entry into both horizontal and vertical (downwards) carrier flows resulted in long lag times to steady state. Methylene blue delivery was unaffected by carrier flow orientation. Initiating microinfusion emulsion delivery with upward flow can result in a relative bolus, whereas long delivery lags would be expected with horizontal or downwards flow. An emulsion might carry a high potency drug having significant physiologic effects, e. g. clevidipine. Unrecognized, differences in initial emulsion delivery kinetics depending on carrier flow orientation may have clinical implications for both efficacy and safety.

Time lags between the initiation of a continuous drug infusion and achievement of a steady state delivery rate present an important safety concern. At least 3 factors contribute to these time lags: (1) dead volume size, (2) the ratio between total system flow and dead volume, and (3) startup delay. While clinicians employ both peristaltic pumps and syringe pumps to propel infusions, there has been no head-to-head comparison of drug delivery between commercially available infusion pumps with these distinct propulsion mechanisms. We quantified the delivery of a model drug by peristaltic and syringe pumps at clinically relevant flow rates using spectrophotometric absorbance. Delivery curves were modeled and compared, and the time required to reach 5% (T5), 50% (T50), and 95% (T95) of the intended delivery rate was reported. The ability to overcome the combined effects of startup delay and dead volume differed between syringe and peristaltic pumps. T5, T50, and T95 were shorter for the peristaltic pump at higher flow rates. T50 and T95 were shorter for the syringe pump at lower flow rates. The ability to overcome the effects of dead volume was overall similar between the syringe and peristaltic pumps, as was the response to consecutive changes in drug infusion rates. Startup delay and dead volume in carrier-based infusion systems cause substantial time lags to reaching intended delivery rates. Peristaltic and syringe pumps are similarly susceptible to dead volume effects. Startup performance differed between peristaltic and syringe pumps; their relative performance may be dependent on flow rate.

SummarySubanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

Spinal anesthesia (SA) has been utilized for lumbar surgical procedures; however, postdural puncture headache (PDPH) and subdural hemorrhage (SDH) are potential consequences. We present the case of a 76-year-old with progressive neurogenic claudication secondary to lumbar spinal stenosis who received SA for a 2-level lumbar posterior decompression. After decompression, the site of dural puncture from a 24-gauge Sprotte spinal needle was identified. Our intraoperative image demonstrates the submillimeter dural defect that can potentially engender complications as significant as PDPH and/or SDH. We recommend searching for, and preemptively sealing, the dural puncture site when SA is used for lumbar spine surgery.

Vagus nerve injury may complicate carotid endarterectomy (CEA). The recurrent laryngeal nerve (RLN) branches from the vagus nerve, innervating the ipsilateral vocal cord. Vagus nerve injury can cause vocal cord dysfunction. Intraoperative vocal cord monitoring can detect vagus nerve injury during CEA. A patient with distorted neck anatomy from radiotherapy to treat oropharyngeal cancer and resultant right vocal cord paralysis required left CEA. Anticipating difficult neck dissection risking vagus nerve damage with associate RLN malfunction, we added vocal cord electromyography (EMG) to routine CEA electroencephalography (EEG). We recommend vocal cord EMG in anatomically complex CEA to avoid vagus nerve injury.

Study objectiveAnesthesiologists at our hospital commonly administer spinal anesthesia for routine lumbar spine surgeries. Anecdotal impressions suggested that patients received fewer anesthesia-administered intravenous medications, including vasopressors, during spinal versus general anesthesia. We hypothesized that data review would confirm these impressions. The objective was to test this hypothesis by comparing specific elements of spinal versus general anesthesia for 1-2 level open lumbar spine procedures.DesignRetrospective single institutional study.SettingAcademic medical center, operating rooms.PatientsConsecutive patients (144 spinal and 619 general anesthesia) identified by automatic structured query of our electronic anesthesia record undergoing lumbar decompression, foraminotomy or microdiscectomy by one surgeon under general or spinal anesthesia.InterventionsSpinal or general anesthesia.MeasurementsNumbers of medications administered during the case.Main resultsAnesthesiologists administered in the operating room a total of 10 ± 2 intravenous medications for general anesthetics and 5 ± 2 medications for spinal anesthetics (-5, 95% CI -5 to -4, p<0.001, univariate analysis). Multivariable analysis supported this finding (spinal versus general anesthesia: -4, 95% CI -5 to -4, p<0.001). Spinal anesthesia patients were less likely to receive ephedrine, or phenylephrine (by bolus or by infusion) (all p<0.001, Chi-squared test). Spinal anesthesia patients were also less likely to receive labetolol or esmolol (both p = 0.002, Fishers' Exact test). No neurologic injuries were attributed to, or masked by, spinal anesthesia. Three spinal anesthetics failed.ConclusionsFor routine lumbar surgery in our cohort, spinal compared to general anesthesia was associated with significantly fewer drugs administered during a case and less frequent use of vasoactive agents. Safety implications include greater hemodynamic stability with spinal anesthesia along with reduced risks for medication error and transmission of pathogens associated with medication administration.

During awake consciousness, the brain intrinsically maintains a dynamical state in which it can coordinate complex responses to sensory input. How the brain reaches this state spontaneously is not known. General anesthesia provides a unique opportunity to examine how the human brain recovers its functional capabilities after profound unconsciousness. We used intracranial electrocorticography and scalp EEG in humans to track neural dynamics during emergence from propofol general anesthesia. We identify a distinct transient brain state that occurs immediately prior to recovery of behavioral responsiveness. This state is characterized by large, spatially distributed, slow sensory-evoked potentials that resemble the K-complexes that are hallmarks of stage two sleep. However, the ongoing spontaneous dynamics in this transitional state differ from sleep. These results identify an asymmetry in the neurophysiology of induction and emergence, as the emerging brain can enter a state with a sleep-like sensory blockade before regaining responsivity to arousing stimuli.

Objective: Intraoperative mapping via electrical stimulation is the gold standard technique for surgeries close to the eloquent cortex. However, it can trigger seizures which immediately impact patient's safety. We studied whether administration of antiepileptic drugs (AED) prior to and/or at the beginning of the surgery decreases the probability of triggering seizures, while adjusting for other risk factors. Methods: 544 consecutive intraoperative mapping cases performed at a tertiary care center for epilepsy and brain tumor surgery were included in the study. Using a multivariate logistic regression analysis, we analyzed the independent impacts of AED loading at time of surgery, preoperative AED maintenance, history of seizures, type of stimulation paradigm, lobar location of stimulation, age, opioid administration and pathology on the probability of triggering seizures. Results: Seizures were identified in 135 patients. Intravenous loading with AED decreased the odds of triggering seizures by 45% (OR = 0.55, p = 0.01), Penfield (versus multipulse train) stimulation and diffuse (versus well circumscribed) pathology increased it twice (OR = 1.97, p = 0.01) and 2.4 times (OR = 2.42, p = 0.003) respectively. No other factors had a significant impact. Conclusions: Seizures triggered during mapping occur frequently and are multifactorial. Significance: Loading with AED independently reduces the risk of their occurrence. (C) 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.