Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology.

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.

Propofol disrupts alpha dynamics in functionally distinct thalamocortical networks during loss of consciousness.

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.

Initiation of an Emulsion Microinfusion: Flow Direction Influences Delivery Onset Rate.

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.

Lag times to steady state drug delivery by continuous intravenous infusion: direct comparison of peristaltic and syringe pump performance identifies contributions from infusion system dead volume and pump startup characteristics.

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.

Direct Visualization of the Dural Puncture Site During Lumbar Spine Surgery Performed Under Spinal Anesthesia: A Case Report.

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.

Ipsilateral Vocal Cord Monitoring for Carotid Endarterectomy and Concurrent Contralateral Vocal Cord Paralysis: A Case Report.

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.

Spinal anesthesia for lumbar spine surgery correlates with fewer total medications and less frequent use of vasoactive agents: A single center experience.

STUDY OBJECTIVE: Anesthesiologists 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. DESIGN: Retrospective single institutional study. SETTING: Academic medical center, operating rooms. PATIENTS: Consecutive 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. INTERVENTIONS: Spinal or general anesthesia. MEASUREMENTS: Numbers of medications administered during the case. MAIN RESULTS: Anesthesiologists 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. CONCLUSIONS: For 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.

Factors that modify the risk of intraoperative seizures triggered by electrical stimulation during supratentorial functional mapping.

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.

A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans.

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.

Drug Infusion Systems: Technologies, Performance, and Pitfalls.

This review aims to broadly describe drug infusion technologies and raise subtle but important issues arising from infusion therapy that can potentially lead to patient instability and morbidity. Advantages and disadvantages of gravity-dependent drug infusion are described and compared with electromechanical approaches for precise control of medication infusion, including large-volume peristaltic and syringe pumps. This review discusses how drugs and inert carriers interact within infusion systems and outlines several complexities and potential sources of drug error. Major topics are (1) the importance of the infusion system dead volume; (2) the quantities of coadministered fluid and the concept of microinfusion; and (3) future directions for drug infusion.The infusion system dead volume resides between the point where drug and inert carrier streams meet and the patient's blood. The dead volume is an often forgotten reservoir of drugs, especially when infusion flows slow or stop. Even with medications and carriers flowing, some mass of drug always resides within the dead volume. This reservoir of drug can be accidentally delivered into patients. When dose rate is changed, there can be a significant lag between intended and actual drug delivery. When a drug infusion is discontinued, drug delivery continues until the dead volume is fully cleared of residual drug by the carrier. When multiple drug infusions flow together, a change in any drug flow rate transiently affects the rate of delivery of all the others. For all of these reasons, the use of drug infusion systems with smaller dead volumes may be advantageous.For critically ill patients requiring multiple infusions, the obligate amount of administered fluid can contribute to volume overload. Recognition of the risk of overload has given rise to microinfusion strategies wherein drug solutions are highly concentrated and infused at low rates. However, potential risks associated with the dead volume may be magnified with microinfusion. All of these potential sources for adverse events relating to the infusion system dead volume illustrate the need for continuing education of clinical personnel in the complexities of drug delivery by infusion.This review concludes with an outline of future technologies for managing drug delivery by continuous infusion. Automated systems based on physiologic signals and smart systems based on physical principles and an understanding of dead volume may mitigate against adverse patient events and clinical errors in the complex process of drug delivery by infusion.

Novel Pump Control Technology Accelerates Drug Delivery Onset in a Model of Pediatric Drug Infusion.

BACKGROUND: Laboratory data suggest that newly initiated drug infusions reach steady-state delivery after a significant time lag. Depending on drug and carrier flow rates and the infusion system's common volume, lag times may exceed 20 or more minutes, especially in the neonatal/pediatric critical care environment. This study tested the hypothesis that a computer-executed algorithm controlling infusion pumps in a coordinated fashion predictably hastens the achievement of the intended steady-state drug delivery in a model of neonatal/pediatric drug infusion. METHODS: We constructed an in vitro model of neonatal/pediatric drug infusions through a pediatric 4-Fr central venous catheter at total system flows of 2 mL/h or 12 mL/h, representing a clinically relevant infusion range. Methylene blue served as the model infused drug for quantitative analysis. A novel algorithm, based on Taylor Dispersion Theory of fluid flow through tubes and executed by a computer, generated flow patterns that controlled and coordinated drug and carrier delivery by syringe pumps. We measured the time to achieve the intended steady-state drug delivery by conventional initiation of the drug infusion ("turning on the drug pump") and by algorithm-controlled infusion initiation. RESULTS: At 2 mL/h total system flow, application of the algorithm reduced the time to achieve half of the intended drug delivery rate (T50) from 17 minutes [17, 18] to 3 minutes [3, 3] (median, interquartile range). At 12 mL/h total system flow, application of the algorithm reduced T50 from 6 minutes [6, 7] to 3 minutes [3, 3] The bootstrapped median difference is -14 (95% confidence interval [CI], -16 to -12, adjusted P=.00192) for 2 mL/h flow and -3 (95% CI, -4 to -3, adjusted P=.02061) for 12 mL/h flow. Compared with conventional initiation, the additional fluid required by the algorithm-directed infusion was 0.43 and 1.03 mL for the low- and high-infusion rates, respectively. CONCLUSIONS: The output of infusion pumps can be predictably controlled and coordinated by a computer-executed algorithm in a model of neonatal/pediatric drug infusions. Application of an algorithm can reduce the time to achieve the intended rate of infused drug delivery with minimal incremental volume administration.

Infusion System Architecture Impacts the Ability of Intensive Care Nurses to Maintain Hemodynamic Stability in a Living Swine Simulator.

BACKGROUND: The authors have previously shown that drug infusion systems with large common volumes exhibit long delays in reaching steady-state drug delivery and pharmacodynamic effects compared with smaller common-volume systems. The authors hypothesized that such delays can impede the pharmacologic restoration of hemodynamic stability. METHODS: The authors created a living swine simulator of hemodynamic instability in which occlusion balloons in the aorta and inferior vena cava (IVC) were used to manipulate blood pressure. Experienced intensive care unit nurses blinded to the use of small or large common-volume infusion systems were instructed to maintain mean arterial blood pressure between 70 and 90 mmHg using only sodium nitroprusside and norepinephrine infusions. Four conditions (IVC or aortic occlusions and small or large common volume) were tested 12 times in eight animals. RESULTS: After aortic occlusion, the time to restore mean arterial pressure to range (t1: 2.4 ± 1.4 vs. 5.0 ± 2.3 min, P = 0.003, average ± SD), time-out-of-range (tOR: 6.2 ± 3.5 vs. 9.5 ± 3.4 min, P = 0.028), and area-out-of-range (pressure-time integral: 84 ± 47 vs. 170 ± 100 mmHg · min, P = 0.018) were all lower with smaller common volumes. After IVC occlusion, t1 (3.7 ± 2.2 vs. 7.1 ± 2.6 min, P = 0.002), tOR (6.3 ± 3.5 vs. 11 ± 3.0 min, P = 0.007), and area-out-of-range (110 ± 93 vs. 270 ± 140 mmHg · min, P = 0.003) were all lower with smaller common volumes. Common-volume size did not impact the total amount infused of either drug. CONCLUSIONS: Nurses did not respond as effectively to hemodynamic instability when drugs flowed through large common-volume infusion systems. These findings suggest that drug infusion system common volume may have clinical impact, should be minimized to the greatest extent possible, and warrants clinical investigations.

Infusion system carrier flow perturbations and dead-volume: large effects on drug delivery in vitro and hemodynamic responses in a swine model.

BACKGROUND: We have previously shown that, at constant carrier flow, drug infusion systems with large dead-volumes (V) slow the time to steady-state drug delivery in vitro and pharmacodynamic effect in vivo compared to those with smaller V. In this study, we tested whether clinically relevant alterations in carrier flow generate perturbations in drug delivery and pharmacodynamic effect, and how these might be magnified when V is large. METHODS: Drug delivery in vitro or mean arterial blood pressure (MAP) and ventricular contractility (max dP/dt) in a swine model were quantified during an infusion of norepinephrine (fixed rate 3 mL/h) with a crystalloid carrier (10 mL/h). The carrier flow was transiently halted for either 10 minutes or 20 minutes and then restarted. In separate experiments, a second drug infusion (50 mL over 10 minutes) was introduced into the same catheter lumen used by a steady-state norepinephrine infusion. The resulting perturbations in drug delivery and biologic effect were compared between drug infusion systems with large and small V. RESULTS: Halting carrier flow immediately decreased drug delivery in vitro, and MAP and max dP/dt. These returned to steady state before restarting carrier flow with the small, but not the large, V. Resuming carrier flow after 10 minutes resulted in a transient increase in drug delivery in vitro and max dP/dt in vivo, which were of longer duration and greater area under the curve (AUC) for larger V. MAP also increased for longer duration for larger V. Resuming the carrier flow after 20 minutes resulted in greater AUCs for drug delivery, MAP, and max dP/dt for the larger V. Adding a second infusion to a steady-state norepinephrine plus carrier flow initially resulted in a drug bolus in vitro and augmented contractility response in vivo, both greater with a larger V. Steady-state drug delivery resumed before the secondary infusion finished. After the end of the secondary infusion drug delivery, MAP and max dP/dt decreased over minutes. Drug delivery and max dP/dt returned to steady state more quickly with the small V. CONCLUSIONS: Stopping and resuming a carrier flow, or introducing a second medication infusion, impacts drug delivery in vitro and biologic response in vivo. Infusion systems with small dead-volumes minimize these perturbations and dampen the resulting hemodynamic instability. Alterations in carrier flow impact drug delivery, resulting in substantial effects on physiologic responses. Therefore, infusion systems for vasoactive drugs should be configured with small V when possible.

Computer control of drug delivery by continuous intravenous infusion: bridging the gap between intended and actual drug delivery.

BACKGROUND: Intravenous drug infusion driven by syringe pumps may lead to substantial temporal lags in achieving steady-state delivery at target levels when using very low flow rates ("microinfusion"). This study evaluated computer algorithms for reducing temporal lags via coordinated control of drug and carrier flows. METHODS: Novel computer control algorithms were developed based on mathematical models of fluid flow. Algorithm 1 controlled initiation of drug infusion and algorithm 2 controlled changes to ongoing steady-state infusions. These algorithms were tested in vitro and in vivo using typical high and low dead volume infusion system architectures. One syringe pump infused a carrier fluid and a second infused drug. Drug and carrier flowed together via a manifold through standard central venous catheters. Samples were collected in vitro for quantitative delivery analysis. Parameters including left ventricular max dP/dt were recorded in vivo. RESULTS: Regulation by algorithm 1 reduced delivery delay in vitro during infusion initiation by 69% (low dead volume) and 78% (high dead volume). Algorithmic control in vivo measuring % change in max dP/dt showed similar results (55% for low dead volume and 64% for high dead volume). Algorithm 2 yielded greater precision in matching the magnitude and timing of intended changes in vivo and in vitro. CONCLUSIONS: Compared with conventional methods, algorithm-based computer control of carrier and drug flows can improve drug delivery by pump-driven intravenous infusion to better match intent. For norepinephrine infusions, the amount of drug reaching the bloodstream per time appears to be a dominant factor in the hemodynamic response to infusion.

Cost analysis of spinal and general anesthesia for the surgical treatment of lumbar spondylosis.

Lumbar spine surgery is typically performed under general anesthesia, although spinal anesthesia can also be used. Given the prevalence of lumbar spine surgery, small differences in cost between the two anesthetic techniques have the potential to make a large impact on overall healthcare costs. We sought to perform a cost comparison analysis of spinal versus general anesthesia for lumbar spine operations. Following Institutional Review Board approval, a retrospective cohort study was performed from 2009-2012 on consecutive patients undergoing non-instrumented, elective lumbar spine surgery for spondylosis by a single surgeon. Each patient was evaluated for both types of anesthesia, with the decision for anesthetic method being made based on a combination of physical status, anatomical considerations, and ultimately a consensus agreement between patient, surgeon, and anesthesiologist. Patient demographics and clinical characteristics were compared between the two groups. Operating room costs were calculated whilst blinded to clinical outcomes and reported in percentage difference. General anesthesia (n=319) and spinal anesthesia (n=81) patients had significantly different median operative times of 175 ± 39.08 and 158 ± 32.75 minutes, respectively (p<0.001, Mann-Whitney U test). Operating room costs were 10.33% higher for general anesthesia compared to spinal anesthesia (p=0.003, Mann-Whitney U test). Complications of spinal anesthesia included excessive movement (n=1), failed spinal attempt (n=3), intraoperative conversion to general anesthesia (n=2), and a high spinal level (n=1). In conclusion, spinal anesthesia can be performed safely in patients undergoing lumbar spine surgery. It has the potential to reduce operative times, costs, and possibly, complications. Further prospective evaluation will help to validate these findings.

Application of process improvement principles to increase the frequency of complete airway management documentation.

BACKGROUND: Process improvement in healthcare delivery settings can be difficult, even when there is consensus among clinicians about a clinical practice or desired outcome. Airway management is a medical intervention fundamental to the delivery of anesthesia care. Like other medical interventions, a detailed description of the management methods should be documented. Despite this expectation, airway documentation is often insufficient. The authors hypothesized that formal adoption of process improvement methods could be used to increase the rate of "complete" airway management documentation. METHODS: The authors defined a set of criteria as a local practice standard of "complete" airway management documentation. The authors then employed selected process improvement methodologies over 13 months in three iterative and escalating phases to increase the percentage of records with complete documentation. The criteria were applied retrospectively to determine the baseline frequency of complete records, and prospectively to measure the impact of process improvements efforts over the three phases of implementation. RESULTS: Immediately before the initial intervention, a retrospective review of 23,011 general anesthesia cases over 6 months showed that 13.2% of patient records included complete documentation. At the conclusion of the 13-month improvement effort, documentation improved to a completion rate of 91.6% (P<0.0001). During the subsequent 21 months, the completion rate was sustained at an average of 90.7% (SD, 0.9%) across 82,571 general anesthetic records. CONCLUSION: Systematic application of process improvement methodologies can improve airway documentation and may be similarly effective in improving other areas of anesthesia clinical practice.

Drug infusion system manifold dead-volume impacts the delivery response time to changes in infused medication doses in vitro and also in vivo in anesthetized swine.

BACKGROUND: IV infusion systems can be configured with manifolds connecting multiple drug infusion lines to transcutaneous catheters. Prior in vitro studies suggest that there may be significant lag times for drug delivery to reflect changes in infusion rates set at the pump, especially with low drug and carrier flows and larger infusion system dead-volumes. Drug manifolds allow multiple infusions to connect to a single catheter port but add dead-volume. We hypothesized that the time course of physiological responses to drug infusion in vivo reflects the impact of dead-volume on drug delivery. METHODS: The kinetic response to starting and stopping epinephrine infusion ([3 mL/h] with constant carrier flow [10 mL/h]) was compared for high- and low-dead-volume manifolds in vitro and in vivo. A manifold consisting of 4 sequential stopcocks with drug entering at the most upstream port was contrasted with a novel design comprising a tube with separate coaxial channels meeting at the downstream connector to the catheter, which virtually eliminates the manifold contribution to the dead-volume. The time to 50% (T50) and 90% (T90) increase or decrease in drug delivery in vitro or contractile response in a swine model in vivo were calculated for initiation and cessation of drug infusion. RESULTS: The time to steady state after initiation and cessation of drug infusion both in vitro and in vivo was much less with the coaxial low-dead-volume manifold than with the high-volume design. Drug delivery after initiation in vitro reached 50% and 90% of steady state in 1.4 ± 0.12 and 2.2 ± 0.42 minutes with the low-dead-volume manifold and in 7.1 ± 0.58 and 9.8 ± 1.6 minutes with the high-dead-volume manifold, respectively. The contractility in vivo reached 50% and 90% of the full response after drug initiation in 4.3 ± 1.3 and 9.9 ± 3.9 minutes with the low-dead-volume manifold and 11 ± 1.2 and 17 ± 2.6 minutes with the high-dead-volume manifold, respectively. Drug delivery in vitro decreased by 50% and 90% after drug cessation in 1.9 ± 0.17 and 3.5 ± 0.61 minutes with the low-dead-volume manifold and 10.0 ± 1.0 and 17.0 ± 2.8 minutes with the high-dead-volume manifold, respectively. The contractility in vivo decreased by 50% and 90% with drug cessation in 4.1 ± 1.1 and 14 ± 5.2 with the low-dead-volume manifold and 12 ± 2.7 and 23 ± 5.6 minutes with the high-dead-volume manifold, respectively. CONCLUSIONS: The architecture of the manifold impacts the in vivo biologic response, and the drug delivery rate, to changes in drug infusion rate set at the pump.

Local cortical dynamics of burst suppression in the anaesthetized brain.

Burst suppression is an electroencephalogram pattern that consists of a quasi-periodic alternation between isoelectric 'suppressions' lasting seconds or minutes, and high-voltage 'bursts'. It is characteristic of a profoundly inactivated brain, occurring in conditions including hypothermia, deep general anaesthesia, infant encephalopathy and coma. It is also used in neurology as an electrophysiological endpoint in pharmacologically induced coma for brain protection after traumatic injury and during status epilepticus. Classically, burst suppression has been regarded as a 'global' state with synchronous activity throughout cortex. This assumption has influenced the clinical use of burst suppression as a way to broadly reduce neural activity. However, the extent of spatial homogeneity has not been fully explored due to the challenges in recording from multiple cortical sites simultaneously. The neurophysiological dynamics of large-scale cortical circuits during burst suppression are therefore not well understood. To address this question, we recorded intracranial electrocorticograms from patients who entered burst suppression while receiving propofol general anaesthesia. The electrodes were broadly distributed across cortex, enabling us to examine both the dynamics of burst suppression within local cortical regions and larger-scale network interactions. We found that in contrast to previous characterizations, bursts could be substantially asynchronous across the cortex. Furthermore, the state of burst suppression itself could occur in a limited cortical region while other areas exhibited ongoing continuous activity. In addition, we found a complex temporal structure within bursts, which recapitulated the spectral dynamics of the state preceding burst suppression, and evolved throughout the course of a single burst. Our observations imply that local cortical dynamics are not homogeneous, even during significant brain inactivation. Instead, cortical and, implicitly, subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice.