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Objective . Over the past decade, neural electrodes have played a crucial role in bridging biological tissues with electronic and robotic devices. This study focuses on evaluating the optimal tip profile and insertion speed for effectively implanting Paradromics' high-density fine microwire arrays (F μ A) prototypes into the primary visual cortex (V1) of mice and rats, addressing the challenges associated with the 'bed-of-nails' effect and tissue dimpling. Approach . Tissue response was assessed by investigating the impact of electrodes on the blood-brain barrier (BBB) and cellular damage, with a specific emphasis on tailored insertion strategies to minimize tissue disruption during electrode implantation. Main results. Electro-sharpened arrays demonstrated a marked reduction in cellular damage within 50 μ m of the electrode tip compared to blunt and angled arrays. Histological analysis revealed that slow insertion speeds led to greater BBB compromise than fast and pneumatic methods. Successful single-unit recordings validated the efficacy of the optimized electro-sharpened arrays in capturing neural activity. Significance. These findings underscore the critical role of tailored insertion strategies in minimizing tissue damage during electrode implantation, highlighting the suitability of electro-sharpened arrays for long-term implant applications. This research contributes to a deeper understanding of the complexities associated with high-channel-count microelectrode array implantation, emphasizing the importance of meticulous assessment and optimization of key parameters for effective integration and minimal tissue disruption. By elucidating the interplay between insertion parameters and tissue response, our study lays a strong foundation for the development of advanced implantable devices with a reduction in reactive gliosis and improved performance in neural recording applications., (Creative Commons Attribution license.)

Background and Objectives: Despite decades of increasingly sophisticated neurocritical care, patient outcomes after spontaneous intracerebral hemorrhage (ICH) remain dismal. Whether this reflects therapeutic nihilism or the effects of the primary injury has been questioned. In this contemporary cohort, we determined the 30- and 90-day mortality, cause-specific mortality, functional outcome, and the effect of surgical intervention in a culture of aggressive medical and surgical support., Methods: This was a retrospective cohort study of consecutive adult patients with spontaneous ICH admitted to a tertiary neurocritical care unit. Patients with secondary ICH and those subject to limitation of care before 72 hours were excluded. For each ICH score, mortality at 30- and 90-days, and the modified Rankin Scale (mRS) within 1-year were examined. The effect of craniotomy/craniectomy ± hematoma evacuation on the outcome of supratentorial ICH was determined using propensity score matching. Median patient follow-up after discharge was 2.2 (interquartile range [IQR] 0.4-4.4) years., Results: Among 319 patients with spontaneous ICH (median age was 69 [IQR 60-77] years, 60% male), 30- and 90-day mortality were 16% and 22%, respectively, and unfavorable functional outcome (mRS score 4-6) was 50% at a median 3.1 months after ICH. Admission predictors of mortality mirrored those of the original ICH score. Unfavorable outcomes for ICH scores 3 and 4 were 73% and 86%, respectively. The most common adjudicated primary causes of mortality were direct effect or progression of ICH (54%), refractory cerebral edema (21%), and medical complications (11%). In matched analyses, lifesaving surgery for supratentorial ICH did not significantly alter mortality or unfavorable functional outcome in patients overall. In subgroup analyses restricted to (1) surgery with hematoma evacuation and (2) ICH score 3 and 4 patients, the odds of 30-day mortality were reduced by 71% (odds ratio [OR] 0.29, 95% CI 0.09-0.9, p = 0.032) and 80% (OR 0.2, 95% CI 0.04-0.91, p = 0.038), respectively, but no difference was observed for 90-day mortality or unfavorable functional outcome., Discussion: This study demonstrates that poor outcomes after ICH prevail despite aggressive treatment. Unfavorable outcomes appear related to direct effects of the primary injury and not to premature care limitations. Lifesaving surgery for supratentorial lesions delayed mortality but did not alter functional outcomes., (© 2023 American Academy of Neurology.)

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multifactorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single-center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multicenter, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone., Competing Interests: D.Y.C. has received grant funding from the National Institutes of Health (KL2TR002542 and K08NS112601), the American Heart Association and American Stroke Association (18POST34030369), the Andrew David Heitman Foundation, the Aneurysm and AVM Foundation, and the Brain Aneurysm Foundation. S.E.N. has received grant funding from the Brain Aneurysm Foundation as well as personal fees from Springer Nature. The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective . The safe insertion of high density intracortical electrode arrays has been a long-standing practical challenge for neural interface engineering and applications such as brain-computer interfaces (BCIs). However, the pia mater can be difficult to penetrate and causes deformation of underlying cortical tissue during insertion of high-density intracortical arrays. This can lead to neuron damage or failed insertions. The development of a method to ease insertion through the pia mater would represent a significant step toward inserting high density intracortical arrays. Approach . Here we describe a surgical procedure, inspired by laser corneal ablation, that can be used in translational models to thin the pia mater. Main results . We demonstrate that controlled pia removal with laser ablation over a small area of cortex allows for microelectrode arrays to be inserted into the cortex with less force, thus reducing deformation of underlying tissue during placement of the microelectrodes. This procedure allows for insertion of high-density electrode arrays and subsequent acute recordings of spiking neuron activity in sheep cortex. We also show histological and electrophysiological evidence that laser removal of the pia does not acutely affect neuronal viability in the region. Significance . Laser ablation of the pia reduces insertion forces of high-density arrays with minimal to no acute damage to cortical neurons. This approach suggests a promising new path for clinical BCI with high-density microelectrode arrays., (© 2021 IOP Publishing Ltd.)

Objective: Decoding neural activity has been limited by the lack of tools available to record from large numbers of neurons across multiple cortical regions simultaneously with high temporal fidelity. To this end, we developed the Argo system to record cortical neural activity at high data rates., Approach: Here we demonstrate a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system, supporting simultaneous recording from 65 536 channels, sampled at 32 kHz and 12-bit resolution. This system was designed for cortical recordings, compatible with both penetrating and surface microelectrodes., Main Results: We validated this system through initial bench testing to determine specific gain and noise characteristics of bonded microwires, followed by in-vivo experiments in both rat and sheep cortex. We recorded spiking activity from 791 neurons in rats and surface local field potential activity from over 30 000 channels in sheep., Significance: These are the largest channel count microwire-based recordings in both rat and sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

Mammalian brains consist of 10s of millions to 100s of billions of neurons operating at millisecond time scales, of which current recording techniques only capture a tiny fraction. Recording techniques capable of sampling neural activity at high spatiotemporal resolution have been difficult to scale. The most intensively studied mammalian neuronal networks, such as the neocortex, show a layered architecture, where the optimal recording technology samples densely over large areas. However, the need for application-specific designs as well as the mismatch between the three-dimensional architecture of the brain and largely two-dimensional microfabrication techniques profoundly limits both neurophysiological research and neural prosthetics. Here, we discuss a novel strategy for scalable neuronal recording by combining bundles of glass-ensheathed microwires with large-scale amplifier arrays derived from high-density CMOS in vitro MEA systems or high-speed infrared cameras. High signal-to-noise ratio (<25 μV RMS noise floor, SNR up to 25) is achieved due to the high conductivity of core metals in glass-ensheathed microwires allowing for ultrathin metal cores (down to <1 μm) and negligible stray capacitance. Multi-step electrochemical modification of the tip enables ultra-low access impedance with minimal geometric area, which is largely independent of the core diameter. We show that the microwire size can be reduced to virtually eliminate damage to the blood-brain-barrier upon insertion and we demonstrate that microwire arrays can stably record single-unit activity. Combining microwire bundles and CMOS arrays allows for a highly scalable neuronal recording approach, linking the progress in electrical neuronal recordings to the rapid progress in silicon microfabrication. The modular design of the system allows for custom arrangement of recording sites. Our approach of employing bundles of minimally invasive, highly insulated and functionalized microwires to extend a two-dimensional CMOS architecture into the 3rd dimension can be translated to other CMOS arrays, such as electrical stimulation devices., (Copyright © 2020 Kollo, Racz, Hanna, Obaid, Angle, Wray, Kong, Müller, Hierlemann, Melosh and Schaefer.)

Objective: Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty., Methods: The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm., Results: The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III-V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01-112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0-2) assessed at a median of 4 months (interquartile range 2-8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512)., Conclusions: The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Objective: Health care-associated infections (HAIs) after subarachnoid hemorrhage (SAH) are prevalent; however, data describing epidemiology of infection are limited. This study reports incidence rates, risk factors, and the resulting SAH patient-related outcomes., Methods: We studied the incidence of HAIs acquired in the intensive care unit (ICU) over a 6-year period. We used Bayesian Model Averaging to identify risk factors associated with an increased risk of HAIs, particularly urinary tract infections (UTI), pneumonia, and ventriculostomy-associated infections (VAI). We also examined the impact of HAIs on risk of vasospasm, ICU and hospital length of stay, and discharge disposition and adjusted for other risk factors., Results: Of 419 patients with SAH, 66 (15.8%) developed 79 HAI episodes. Mean HAI incidence rates (per 1000 ICU-days) were UTI, 7.1; pneumonia, 4.3; and VAI, 2.4. The admission characteristic associated with increased risk of overall HAI, UTI, and VAI was diabetes mellitus. Hunt and Hess grades III-V were associated with increased risk of overall HAI and VAI. Male gender, intraventricular hemorrhage, and blood glucose level (>10) were associated with increased risk of pneumonia, whereas the incidence was lower in the presence of steroids. HAI was associated with increased length of stay of 10 ICU-days and 22 hospital-days, but not vasospasm or poor discharge disposition., Conclusions: HAIs are serious complications after SAH associated with prolonged ICU and hospital length of stay. Additional rigorous infection control measures aimed at patients with identifiable risk factors should trigger prevention, and early detection of nosocomial infections is warranted to further reduce the prevalence of HAIs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Healthcare-associated infections (HAIs) occur frequently in neurological intensive care units (neuro-ICUs); however, data differentiating associations with various diagnostic categories and resulting burdens are limited. This prospective cohort study reported incidence rates, pathogen distribution, and patient-related outcomes of HAIs in a neuro-ICU population from April 2010 to March 2016., Methods: Laboratory results and specific clinical indicators were used to categorize infections as per National Healthcare Safety Network nosocomial infection surveillance definitions. Patient outcomes studied included length of stay and mortality., Results: There were 6,033 neuro-ICU admissions resulting in 20,800 neuro-ICU days over the 6-year study period. A total of 227 HAIs were identified for a rate of 10.9/1,000 ICU days. Device-associated infections accounted for 80.6% of HAIs, with incidence rates (per 1,000 device days) being 18.4 for ventilator-associated pneumonia; 4.9 for catheter-associated urinary tract infections (CAUTIs); 4.0 for ventriculostomy-associated infections; and 0.6 for central line-associated blood stream infections (CLABSIs). Of the various diagnostic categories, subdural hematoma and intracerebral/intraventricular hemorrhage were associated with the highest pooled HAIs, with incidence rates of 21.3 and 21.1 per 1,000 neuro-ICU days, respectively. Prolonged neuro-ICU length of stay was strongly associated with all HAIs., Conclusions: This large-scale surveillance study provides estimates of the risk of common HAIs in neurocritical care patients and their effect on hospitalization. Preventive strategies kept rates of infection very low, in particular CAUTI, CLABSI, and Clostridium difficile infections, and inhibited the emergence of resistant organisms., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate primary causes of death after spontaneous subarachnoid hemorrhage (SAH) and externally validate the HAIR score, a prognostication tool, in a single academic institution., Methods: We reviewed all patients with SAH admitted to our neuro-intensive care unit between 2010 and 2016. Univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality. The HAIR score predictors were Hunt and Hess grade at treatment decision, age, intraventricular hemorrhage, and rebleeding within 24 hours. Validation of the HAIR score was characterized with the receiver operating curve, the area under the curve, and a calibration plot., Results: Among 434 patients with SAH, in-hospital mortality was 14.1%. Of the 61 mortalities, 54 (88.5%) had a neurologic cause of death or withdrawal of care and 7 (11.5%) had cardiac death. Median time from SAH to death was 6 days. The main causes of death were effect of the initial hemorrhage (26.2%), rebleeding (23%) and refractory cerebral edema (19.7%). Factors significantly associated with in-hospital mortality in the multivariate analysis were age, Hunt and Hess grade, and intracerebral hemorrhage. Maximum lumen size was also a significant risk factor after aneurysmal SAH. The HAIR score had a satisfactory discriminative ability, with an area under the curve of 0.89., Conclusions: The in-hospital mortality is lower than in previous reports, attesting to the continuing improvement of our institutional SAH care. The major causes are the same as in previous reports. Despite a different therapeutic protocol, the HAIR score showed good discrimination and could be a useful tool for predicting mortality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neuroscience would be revolutionized by a technique to measure intracellular electrical potentials that would not disrupt cellular physiology and could be massively parallelized. Though such a technology does not yet exist, the technical hurdles for fabricating minimally disruptive, solid-state electrical probes have arguably been overcome in the field of nanotechnology. Nanoscale devices can be patterned with features on the same length scale as biological components, and several groups have demonstrated that nanoscale electrical probes can measure the transmembrane potential of electrogenic cells. Developing these nascent technologies into robust intracellular recording tools will now require a better understanding of device-cell interactions, especially the membrane-inorganic interface. Here we review the state-of-the art in nanobioelectronics, emphasizing the characterization and design of stable interfaces between nanoscale devices and cells., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nanoscale devices have been proposed as tools for measuring and controlling intracellular activity by providing electrical and/or chemical access to the cytosol. Unfortunately, nanostructures with diameters of 50-500 nm do not readily penetrate the cell membrane, and rationally optimizing nanoprobes for cell penetration requires real-time characterization methods that are capable of following the process of membrane penetration with nanometer resolution. Although extensive work has examined the rupture of supported synthetic lipid bilayers, little is known about the applicability of these model systems to living cell membranes with complex lipid compositions, cytoskeletal attachment, and membrane proteins. Here, we describe atomic force microscopy (AFM) membrane penetration experiments in two parallel systems: live HEK293 cells and stacks of synthetic lipid bilayers. By using the same probes in both systems, we were able to clearly identify membrane penetration in synthetic bilayers and compare these events with putative membrane penetration events in cells. We examined membrane penetration forces for three tip geometries and 18 chemical modifications of the probe surface, and in all cases the median forces required to penetrate cellular and synthetic lipid bilayers with nanoprobes were greater than 1 nN. The penetration force was sensitive to the probe's sharpness, but not its surface chemistry, and the force did not depend on cell surface or cytoskeletal properties, with cells and lipid stacks yielding similar forces. This systematic assessment of penetration under various mechanical and chemical conditions provides insights into nanoprobe-cell interactions and informs the design of future intracellular nanoprobes.

Direct access into cells' interiors is essential for biomolecular delivery, gene transfection, and electrical recordings yet is challenging due to the cell membrane barrier. Recently, molecular delivery using vertical nanowires (NWs) has been demonstrated for introducing biomolecules into a large number of cells in parallel. However, the microscopic understanding of how and when the nanowires penetrate cell membranes is still lacking, and the degree to which actual membrane penetration occurs is controversial. Here we present results from a mechanical continuum model of elastic cell membrane penetration through two mechanisms, namely through "impaling" as cells land onto a bed of nanowires, and through "adhesion-mediated" penetration, which occurs as cells spread on the substrate and generate adhesion force. Our results reveal that penetration is much more effective through the adhesion mechanism, with NW geometry and cell stiffness being critically important. Stiffer cells have higher penetration efficiency, but are more sensitive to NW geometry. These results provide a guide to designing nanowires for applications in cell membrane penetration.

Management of intracranial hypertension is a major cornerstone of neurocritical care. Apart from traumatic brain injury, there are no clear guidelines for intracranial pressure (ICP) monitoring. The insertion of ICP monitors is an invasive procedure with inherent risks and could be contraindicated in case of severe coagulopathy. The transcranial Doppler (TCD) pulsatility index (PI) has emerged as a surrogate marker for ICP. This is a technical report with illustrative cases on the use of PI in the management of high ICP, as a guide for optimal dosing of hyperosmolar agents we use in our institution. The use of TCD PI is a useful adjunct to guide the use of hyperosmolar therapy in various conditions with raised intracranial hypertension. We will discuss the combination of the PI determination with an anatomical evaluation of the optic nerve diameter to eliminate confounding factors in PI determination.

Direct electrical recording of the neuronal transmembrane potential has been crucial to our understanding of the biophysical mechanisms subserving neuronal computation. Existing intracellular recording techniques, however, limit the accuracy and duration of such measurements by changing intracellular biochemistry and/or by damaging the plasma membrane. Here we demonstrate that nanoengineered electrodes can be used to record neuronal transmembrane potentials in brain tissue without causing these physiological perturbations. Using focused ion beam milling, we have fabricated Solid-Conductor Intracellular NanoElectrodes (SCINEs), from conventional tungsten microelectrodes. SCINEs have tips that are <300 nm in diameter for several micrometers, but can be easily handled and can be inserted into brain tissue. Performing simultaneous whole-cell patch recordings, we show that SCINEs can record action potentials (APs) as well as slower, subthreshold neuronal potentials without altering cellular properties. These results show a key role for nanotechnology in the development of new electrical recording techniques in neuroscience.

Background: Pial arteriolar responses to flow contribute to regulation of cerebral perfusion and vary according to the transmural pressure to which the vessel is exposed. This study determined the effect of increased glucose concentration on the flow responses of pial arterioles at low and high levels of transmural pressure., Methods: Pial arterioles from Sprague-Dawley rats were mounted in a perfusion myograph. In some arterioles, the endothelium was removed by perfusion with air. Diameters were recorded at transmural pressures of 60 and 120 mmHg during superfusion with physiologic saline containing 5 mm D-glucose, 20 mm D-glucose, or 5 mm D-glucose and 15 mm L-glucose. Diameters during superfusion with saline containing 44 mm D-glucose were measured at an intraluminal pressure of 60 mmHg. Flow-diameter relationships (5-30 microl/min) were recorded during perfusion with the same solutions., Results: Increasing D-glucose concentration caused constriction (P < 0.05) in endothelium-denuded but not in endothelium-intact arterioles. Addition of L-glucose caused constriction in endothelium-intact and -denuded vessels (P < 0.05 for both). At a D-glucose concentration of 5 mm and at low intraluminal pressure, flow elicits endothelium-dependent dilation such that shear stress remains constant. At a D-glucose concentration of 20 or 44 mm, after addition of L-glucose (15 mm), and at high intraluminal pressures, flow elicits constriction and shear stress is unregulated., Conclusions: High glucose concentrations elicit increased basal arteriolar smooth muscle tone that is counteracted by release of endothelium-derived relaxing factors. Endothelium-dependent relaxation to flow (shear stress) is inhibited at high glucose concentrations.

Background: Cerebral arteriolar tone is modulated in response to changes in transmural pressure and luminal flow. The effect of flow on the relation between pressure and diameter has not been fully evaluated in these vessels. This study was conducted to investigate this interaction and to determine the role of the endothelium in mediating it., Methods: Rat pial arterioles from the territory of the posterior cerebral artery were mounted in a perfusion myograph. In some arterioles, the endothelium was removed by air perfusion. Diameters were recorded at pressures from 20 to 200 mmHg in the presence and absence of flow (10 microl/min). The response to flow (0-30 microl/min) was recorded at 60 and 120 mmHg., Results: In the absence of flow, endothelium-intact arterioles demonstrated tone at distending pressures between 40 and 140 mmHg. In the presence of flow, tone did not develop until pressure exceeded 100 mmHg, and the vessels remained active at pressures up to 200 mmHg. Endothelium-denuded arterioles developed tone at the same pressure when perfused as when unperfused, but perfused vessels were able to maintain active tone at higher pressures. At 60 mmHg, flow caused dilation if the endothelium was intact and constriction if it had been removed. At 120 mmHg, flow caused constriction. Endothelium-dependent flow-relaxation was inhibited by N(G)-nitro-L-arginine methyl ester (10(-5) M) and abolished by indomethacin (10(-5) M)., Conclusion: Flow inhibits the development of pial arteriolar tone at low intraluminal pressures through endothelium-dependent mechanisms. Conversely, perfusion extends the upper limit of the myogenically regulated pressure range through endothelium-independent activation of arteriolar smooth muscle contraction.

We examined the effects of positive end-expiratory pressure (PEEP) and tidal volume on the distribution of ventilation and perfusion in a canine model of asymmetric lung injury. Unilateral right lung edema was established in 10 animals by use of a selective infusion of ethchlorvynol. Five animals were tested in the supine position (horizontal asymmetry) and five in the right decubitus position (vertical asymmetry). Raising PEEP from 5 to 12 cmH2O improved oxygenation despite a redistribution of blood flow toward the damage lung and a consistent decrease in total respiratory system compliance. This improvement paralleled a redistribution of tidal ventilation to the injured lung. This was effected primarily by a fall in the compliance of the noninjured lung due to hyperinflation. The effects of higher tidal volume were additive to those of PEEP. We propose that the major effect of PEEP in inhomogeneous lung injury is to restore tidal ventilation to a population of alveoli recruitable only at high airway pressures.

Autologous blood clot was injected into six dogs to produce a graduated decrease in cardiac output (CO). The effects of an infusion of norepinephrine, titrated to specific end points, were recorded before embolization and at two levels of pulmonary hypertension. Simultaneous measurements of systemic and renal hemodynamics were made. Sequential blood clot injection increased (p less than .01) pulmonary vascular resistance (PVR) from 1.3 to 13 to 33 mm Hg.L-1.min and reduced CO 45 percent and 75 percent (p less than .01). Norepinephrine increased both stroke volume and CO (p less than .01) in each condition and did not increase PVR. Since the biventricular filling pressures remained constant or fell slightly with norepinephrine, the increase in CO is best explained by an improvement in pump performance. There was no deterioration in renal blood flow or creatinine clearance with norepinephrine. The data suggested that in this model of right ventricular dysfunction, norepinephrine consistently improved myocardial performance without provoking further vasoconstriction in either the pulmonary or renal circulations.