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Background: Mild hypothermia is neuroprotective after cerebral ischemia but surgery involving profound hypothermia (PH, temperature less than 18°C) is associated with neurologic complications. Rewarming (RW) from PH injures hippocampal neurons by glutamate excitotoxicity, N-methyl-D-aspartate receptors, and intracellular calcium. Because neurons are protected from hypoxia-ischemia by anesthetic agents that inhibit N-methyl-D-aspartic acid receptors, we tested whether anesthetics protect neurons from damage caused by PH/RW.Methods: Organotypic cultures of rat hippocampus were used to model PH/RW injury, with hypothermia at 4°C followed by RW to 37°C and assessment of cell death 1 or 24 h later. Cell death and intracellular Ca were assessed with fluorescent dye imaging and histology. Anesthetic agents were present in the culture media during PH and RW or only RW.Results: Injury to hippocampal CA1, CA3, and dentate neurons after PH and RW involved cell swelling, cell rupture, and adenosine triphosphate (ATP) loss; this injury was similar for 4 through 10 h of PH. Isoflurane (1% and 2%), sevoflurane (3%) and xenon (60%) reduced cell loss but propofol (3 μM) and pentobarbital (100 μM) did not. Isoflurane protection involved reduction in N-methyl-D-aspartate receptor-mediated Ca influx during RW but did not involve γ-amino butyric acid receptors or KATP channels. However, cell death increased over the next day.Conclusion: Anesthetic protection of neurons rewarmed from 4°C involves suppression of N-methyl-D-aspartate receptor-mediated Ca overload in neurons undergoing ATP loss and excitotoxicity. Unlike during hypoxia/ischemia, anesthetic agents acting predominantly on γ-aminobutyric acid receptors do not protect against PH/RW. The durability of anesthetic protection against cold injury may be limited. [ABSTRACT FROM AUTHOR]

The OpenOximetry Repository is a structured database storing clinical and lab pulse oximetry data, serving as a centralized repository and data model for pulse oximetry initiatives. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). Data contributions are encouraged. All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters. The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available., Competing Interests: Competing Interests The UCSF Hypoxia Research Laboratory receives funding from pulse oximeter manufacturers/sponsors to test the sponsors’ devices for the purposes of product development and regulatory performance testing. Data submitted by the UCSF Hypoxia Lab for this repository do not include Hypoxia Lab sponsors’ study devices unless the sponsor provides consent to include these data. Otherwise, all UCSF Hypoxia Lab data are collected from devices procured by the Hypoxia Lab for the purposes of independent research. At the time of this publication, no pulse oximeter company provides direct funding for the Open Oximetry Project, participates in study design or analysis, or is involved in the creation of this data repository. None of the investigators who maintain this database own stock or equity interests in any pulse oximeter device companies. AIW holds equity and management roles in Ataia Medical. Atia Medical was not involved in study design, funding, or any portion of the study. There are no other conflicts of interest to declare.

Background: Retrospective clinical trials of pulse oximeter accuracy report more frequent missed diagnoses of hypoxemia in hospitalized Black patients than White patients, differences that may contribute to racial disparities in health and health care. Retrospective studies have limitations including mistiming of blood samples and oximeter readings, inconsistent use of functional versus fractional saturation, and self-reported race used as a surrogate for skin color. Our objective was to prospectively measure the contributions of skin pigmentation, perfusion index (PI), sex, and age on pulse oximeter errors in a laboratory setting., Methods: We enrolled 146 healthy subjects, including 25 with light skin (Fitzpatrick class I and II), 78 with medium (class III and IV), and 43 with dark (class V and VI) skin. We studied 2 pulse oximeters (Nellcor N-595 and Masimo Radical 7) in prevalent clinical use. We analyzed 9763 matched pulse oximeter readings (pulse oximeter measured functional saturation [Sp o2 ]) and arterial oxygen saturation (hemoximetry arterial functional oxygen saturation [Sa o2 ]) during stable hypoxemia (Sa o2 68%-100%). PI was measured as percent infrared light modulation by the pulse detected by the pulse oximeter probe, with low perfusion categorized as PI < 1%. The primary analysis was to assess the relationship between pulse oximeter bias (difference between Sa o2 and Sp o2 ) by skin pigment category in a multivariable mixed-effects model incorporating repeated-measures and different levels of Sa o2 and perfusion., Results: Skin pigment, PI, and degree of hypoxemia significantly contributed to errors (bias) in both pulse oximeters. For PI values of 1.0% to 1.5%, 0.5% to 1.0%, and <0.5%, the P value of the relationship to mean bias or median absolute bias was <.00001. In lightly pigmented subjects, only PI was associated with positive bias, whereas in medium and dark subjects bias increased with both low perfusion and degree of hypoxemia. Sex and age was not related to pulse oximeter bias. The combined frequency of missed diagnosis of hypoxemia (pulse oximeter readings 92%-96% when arterial oxygen saturation was <88%) in low perfusion conditions was 1.1% for light, 8.2% for medium, and 21.1% for dark skin., Conclusions: Low peripheral perfusion combined with darker skin pigmentation leads to clinically significant high-reading pulse oximeter errors and missed diagnoses of hypoxemia. Darkly pigmented skin and low perfusion states are likely the cause of racial differences in pulse oximeter performance in retrospective studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block.

Background: Postoperative delirium is a common postsurgical complication in older patients and is associated with high morbidity and mortality. The objective of this study was to determine whether a digital cognitive assessment and patient characteristics could identify those at-risk., Methods: Patients 65 years and older undergoing spine surgeries ≥3 h were evaluated as part of a single-center prospective observational cohort study at an academic medical center, from January 1, 2019, to December 31, 2020. Of 220 eligible patients, 161 were enrolled and 152 completed the study. The primary outcome of postoperative delirium was measured by the Confusion Assessment Method for the Intensive Care Unit or the Nursing Delirium Screening Scale, administered by trained nursing staff independent from the study protocol. Baseline cognitive impairment was identified using the tablet-based TabCAT Brain Health Assessment., Results: Of the 152 patients included in this study, 46% were women. The mean [SD] age was 72 [5.4] years. Baseline cognitive impairment was identified in 38% of participants, and 26% had postoperative delirium. In multivariable analysis, impaired Brain Health Assessment Cognitive Score (OR 2.45; 95% CI, 1.05-5.67; p = 0.037), depression (OR 4.54; 95% CI, 1.73-11.89; p = 0.002), and higher surgical complexity Tier 4 (OR 5.88; 95% CI, 1.55-22.26; p = 0.009) were associated with postoperative delirium. The multivariate model was 72% accurate for predicting postoperative delirium, compared to 45% for the electronic medical record-based risk stratification model currently in use., Conclusion: In this prospective cohort study of spine surgery patients, age, cognitive impairment, depression, and surgical complexity identified patients at high risk for postoperative delirium. Integration of scalable digital assessments into preoperative workflows could identify high-risk patients, automate decision support for timely interventions that can improve patient outcomes and lower hospital costs, and provide a baseline cognitive assessment to monitor for postoperative cognitive change., (© 2022 The American Geriatrics Society.)

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.

Hypothalamic orexin (hypocretin) neurons play crucial roles in arousal control. Their involvement in anesthesia and analgesia remains to be better understood. In order to enhance our view on the neuroanatomy, we systematically mapped the projections of orexin neurons with confocal microscope and light sheet microscope. We specifically expressed optogenetic opsins tagged with fluorescence markers in orexin neurons through adeno-associated viral infection in the mouse brain. The imaging results revealed fine details and novel features of the orexin projections throughout the brain, particularly related to the nuclei regulating arousal and pain. We then optogenetically activated orexin neurons in the lateral hypothalamus to study the effects on anesthesia-related behaviors. cFos staining showed that optogenetic stimulation can activate orexin neurons in the ChR2-mCherry group, but not the control mCherry group (62.86 ± 3.923% vs. 7.9 ± 2.072%; P < 0.0001). In behavior assays, optogenetic stimulation in the ChR2-mCherry group consistently elicited robust arousal from light isoflurane anesthesia (9.429 ± 3.804 s vs. 238.2 ± 17.42 s; P < 0.0001), shortened the emergence time after deep isoflurane anesthesia (109.5 ± 13.59 s vs. 213.8 ± 21.77 s; P = 0.0023), and increased the paw withdrawal latency in a hotplate test (11.45 ± 1.185 s vs. 8.767 ± 0.7775; P = 0.0317). The structural details of orexin fibers established the neuroanatomic basis for studying the role of orexin in anesthesia and analgesia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiang, Chen, Li, Fang, Bickler, Guan and Zhou.)

It has long been known that many pulse oximeters function less accurately in patients with darker skin. Reasons for this observation are incompletely characterized and potentially enabled by limitations in existing regulatory oversight. Based on decades of experience and unpublished data, we believe it is feasible to fully characterize, in the public domain, the factors that contribute to missing clinically important hypoxemia in patients with darkly pigmented skin. Here we propose 5 priority areas of inquiry for the research community and actionable changes to current regulations that will help improve oximeter accuracy. We propose that leading regulatory agencies should immediately modify standards for measuring accuracy and precision of oximeter performance, analyzing and reporting performance outliers, diversifying study subject pools, thoughtfully defining skin pigmentation, reporting data transparently, and accounting for performance during low-perfusion states. These changes will help reduce bias in pulse oximeter performance and improve access to safe oximeters., Competing Interests: The UCSF Hypoxia Research Laboratory, Clinimark, and Physio Monitor, LLC charge pulse oximeter manufacturers for performing validation studies, but no companies were involved with the writing or data analysis presented in this paper., (Copyright © 2022 by Daedalus Enterprises.)

Background: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes., Methods: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2., Results: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins., Conclusions: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA 2 ) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLA 2 s and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA 2 -induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA 2 activation, arachidonic acid, increases in intracellular Ca 2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLA 2 s and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA 2 and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom., Competing Interests: The author owns equity in Ophirex, Inc., a public benefit corporation.

Objective: There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake's bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use., Methods: The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013., Results: 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming., Conclusions: Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius . These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.

Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep-wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin-DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin-DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery., Competing Interests: The authors declare no conflict of interest.

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A₂ (sPLA₂) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan ( Oxyuranus scutellatus ) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA 2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA₂ inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.

Lundeberg, Jenny, John R. Feiner, Andrew Schober, Jeffrey W. Sall, Helge Eilers, and Philip E. Bickler. Increased cytokines at high altitude: lack of effect of ibuprofen on acute mountain sickness, physiological variables or cytokine levels. High Alt Med Biol. 19:249-258, 2018., Introduction: There is no consensus on the role of inflammation in high-altitude acclimatization., Aims: To determine the effects of a nonsteroidal anti-inflammatory drug (ibuprofen 400 mg every 8 hours) on blood cytokines, acclimatization, acute mountain sickness (AMS, Lake Louise Score), and noninvasive oxygenation in brain and muscle in healthy volunteers., Materials and Methods: In this double-blind study, 20 volunteers were randomized to receive ibuprofen or placebo at sea level and for 48 hours at 3800 m altitude. Arterial, brain, and leg muscle saturation with near infrared spectroscopy, pulse oximetry, and heart rate were measured. Blood samples were collected for cytokine levels and cytokine gene expression., Results: All of the placebo subjects and 8 of 11 ibuprofen subjects developed AMS at altitude (p = 0.22, comparing placebo and ibuprofen). On arrival at altitude, the oxygen saturation as measured by pulse oximetry (S p O 2 ) was 84.5% ± 5.4% (mean ± standard deviation). Increase in blood interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels occurred comparably in the placebo and ibuprofen groups (all not significant, univariate test by Wilcoxon rank sum). Increased IL-6 was associated with higher AMS scores (p = 0.002 by Spearman rank correlation). However, we found no difference or association in AMS score and blood or tissue oxygenation between the ibuprofen and placebo groups., Conclusions: We found that ibuprofen, at the package-recommended adult dose, did not have a significant effect on altitude-related increases in cytokines, AMS scores, blood, or tissue oxygenation in a population of healthy subjects with a high incidence of AMS.

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential prereferral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses, and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA 2 ) inhibitors with brief exploration of other potential drug targets on venom molecules.

Background: Pulse oximeter performance is degraded by motion artifacts and low perfusion. Manufacturers developed algorithms to improve instrument performance during these challenges. There have been no independent comparisons of these devices., Methods: We evaluated the performance of four pulse oximeters (Masimo Radical-7, USA; Nihon Kohden OxyPal Neo, Japan; Nellcor N-600, USA; and Philips Intellivue MP5, USA) in 10 healthy adult volunteers. Three motions were evaluated: tapping, pseudorandom, and volunteer-generated rubbing, adjusted to produce photoplethsmogram disturbance similar to arterial pulsation amplitude. During motion, inspired gases were adjusted to achieve stable target plateaus of arterial oxygen saturation (SaO2) at 75%, 88%, and 100%. Pulse oximeter readings were compared with simultaneous arterial blood samples to calculate bias (oxygen saturation measured by pulse oximetry [SpO2] - SaO2), mean, SD, 95% limits of agreement, and root mean square error. Receiver operating characteristic curves were determined to detect mild (SaO2 < 90%) and severe (SaO2 < 80%) hypoxemia., Results: Pulse oximeter readings corresponding to 190 blood samples were analyzed. All oximeters detected hypoxia but motion and low perfusion degraded performance. Three of four oximeters (Masimo, Nellcor, and Philips) had root mean square error greater than 3% for SaO2 70 to 100% during any motion, compared to a root mean square error of 1.8% for the stationary control. A low perfusion index increased error., Conclusions: All oximeters detected hypoxemia during motion and low-perfusion conditions, but motion impaired performance at all ranges, with less accuracy at lower SaO2. Lower perfusion degraded performance in all but the Nihon Kohden instrument. We conclude that different types of pulse oximeters can be similarly effective in preserving sensitivity to clinically relevant hypoxia.

Background: Currently, no reliable method exists for continuous, noninvasive measurements of absolute cerebral blood flow (CBF). We sought to determine how changes measured by ultrasound-tagged near-infrared spectroscopy (UT-NIRS) compare with changes in CBF as measured by transcranial Doppler (TCD) in healthy volunteers during profound hypocapnia and hypercapnia., Methods: Ten healthy volunteers were monitored with a combination of TCD, UT-NIRS (c-FLOW, Ornim Medical), as well as heart rate, blood pressure, end-tidal PCO2 (PEtCO2), end-tidal O2, and inspired O2. Inspired CO2 and minute ventilation were controlled to achieve 5 stable plateau goals of EtCO2 at 15-20, 25-30, 35-40, 45-50, and 55-60 mm Hg, for a total of 7 measurements per subject. CBF was assessed at a steady state, with the TCD designated as the reference standard. The primary analysis was a linear mixed-effect model of TCD and UT-NIRS flow with PEtCO2, which accounts for repeated measures. Receiver operating characteristic curves were determined for detection of changes in CBF., Results: Hyperventilation (nadir PEtCO2 17.1 ± 2.4) resulted in significantly decreased mean flow velocity of the middle cerebral artery from baseline (to 79% ± 22%), but not a consistent decrease in UT-NIRS cerebral flow velocity index (n = 10; 101% ± 6% of baseline). Hypercapnia (peak PEtCO2 59.3 ± 3.3) resulted in a significant increase from baseline in both mean flow velocity of the middle cerebral artery (153% ± 25%) and UT-NIRS (119% ± 11%). Comparing slopes versus PEtCO2 as a percent of baseline for the TCD (1.7% [1.5%-2%]) and UT-NIRS (0.4% [0.3%-0.5%]) shows that the UT-NIRS slope is significantly flatter, P < .0001. Area under the receiver operating characteristic curve was significantly higher for the TCD than for UT-NIRS, 0.97 (95% confidence interval, 0.92-0.99) versus 0.75 (95% confidence interval, 0.66-0.82)., Conclusions: Our data indicate that UT-NIRS cerebral flow velocity index detects changes in CBF only during hypercarbia but not hypocarbia in healthy subjects and with much less sensitivity than TCD. Additional refinement and validation are needed before widespread clinical utilization of UT-NIRS.

Background: Cerebral oximetry (cerebral oxygen saturation; ScO2) is used to noninvasively monitor cerebral oxygenation. ScO2 readings are based on the fraction of reduced and oxidized hemoglobin as an indirect estimate of brain tissue oxygenation and assume a static ratio of arterial to venous intracranial blood. Conditions that alter cerebral blood flow, such as acute changes in PaCO2, may decrease accuracy. We assessed the performance of two commercial cerebral oximeters across a range of oxygen concentrations during normocapnia and hypocapnia., Methods: Casmed FORE-SIGHT Elite (CAS Medical Systems, Inc., USA) and Covidien INVOS 5100C (Covidien, USA) oximeter sensors were placed on 12 healthy volunteers. The fractional inspired oxygen tension was varied to achieve seven steady-state levels including hypoxic and hyperoxic PaO2 values. ScO2 and simultaneous arterial and jugular venous blood gas measurements were obtained with both normocapnia and hypocapnia. Oximeter bias was calculated as the difference between the ScO2 and reference saturation using manufacturer-specified weighting ratios from the arterial and venous samples., Results: FORE-SIGHT Elite bias was greater during hypocapnia as compared with normocapnia (4 ± 9% vs. 0 ± 6%; P < 0.001). The INVOS 5100C bias was also lower during normocapnia (5 ± 15% vs. 3 ± 12%; P = 0.01). Hypocapnia resulted in a significant decrease in mixed venous oxygen saturation and mixed venous oxygen tension, as well as increased oxygen extraction across fractional inspired oxygen tension levels (P < 0.0001). Bias increased significantly with increasing oxygen extraction (P < 0.0001)., Conclusions: Changes in PaCO2 affect cerebral oximeter accuracy, and increased bias occurs with hypocapnia. Decreased accuracy may represent an incorrect assumption of a static arterial-venous blood fraction. Understanding cerebral oximetry limitations is especially important in patients at risk for hypoxia-induced brain injury, where PaCO2 may be purposefully altered.

Background: Repeated episodes of reduced glucose availability can precondition the brain against damage caused by severe hypoglycemia. Because N-methyl-D-aspartate (NMDA) receptor activation may contribute to neuronal loss in the hippocampus following glucose deprivation, we tested the hypothesis that preconditioning with reduced glucose decreased NMDA receptor-mediated cell death in hippocampal neurons., Methods: Hippocampal slice cultures from 7-day old rats were used to study glucose reduction preconditioning and N-methyl-D-aspartate receptor (NMDAR)-mediated cell death. Preconditioning involved reductions in glucose to the following levels: 0.1 mM, 0.5, or 1.0 mM for 30 minutes, 60 minutes, or 90 minutes on 3 consecutive days. Cell death following 1-hour total glucose deprivation was measured with a vital dye technique (SYTOX fluorescence). As an index of NMDAR activity, cell death following application of 1 mM NMDA, was also measured., Results: A preconditioning protocol of 30 minutes of 0.1 mM glucose per day for 3 days reduced cell death following 1-hour total glucose by 65% to 70%, depending on cellular region. No reduction in NMDAR-mediated cell death was seen following any of the preconditioning treatments. However, when NMDAR-mediated cell death was assessed following preconditioning combined with subsequent total glucose deprivation, cell death was reduced in the cultures that had been preconditioned with 0.1 mM glucose for 30 minutes×3 days., Conclusions: We found that that glucose reduction preconditioning protects hippocampal neurons against severe glucose deprivation-induced neuronal damage. This preconditioning was not associated with reductions in NMDAR-mediated cell death except when the preconditioning was combined with an additional exposure to a period of total glucose deprivation.

Implanted electronic medical devices. or stimulators such as pacemakers and nerve stimulators have grown enormously in diversity and complexity over recent decades. The function and potential interaction of these devices with the perioperative environment is of increasing concern for anesthesiologists and surgeons. Because of the innate electromagnetic environment of the hospital (operating room, gastrointestinal procedure suite, and imaging suite), implanted device malfunction, reprogramming, or destruction may occur and cause physical harm (including nerve injury, blindness, deafness, burn, stroke, paralysis, or coma) to the patient. It is critical for the anesthesiologist and surgeon to be aware of the function and interaction of implanted devices, both with other implanted devices and procedures (such as magnetic resonance imaging and cardioversion) in the hospital environment. Because of these interactions, it is imperative that proper device function is assessed when the surgical procedure is complete. This review article will discuss these important issues for 12 different types of "little black boxes," or noncardiac implantable electronic medical devices.

Extended periods of oxygen deprivation can produce acidosis, inflammation, energy failure, cell stress, or cell death. However, brief profound hypoxia (here defined as SaO2 50%-70% for approximately 10 minutes) is not associated with cardiovascular compromise and is tolerated by healthy humans without apparent ill effects. In contrast, chronic hypoxia induces a suite of adaptations and stresses that can result in either increased tolerance of hypoxia or disease, as in adaptation to altitude or in the syndrome of chronic mountain sickness. In healthy humans, brief profound hypoxia produces increased minute ventilation and increased cardiac output, but little or no alteration in blood chemistry. Central nervous system effects of acute profound hypoxia include transiently decreased cognitive performance, based on alterations in attention brought about by interruptions of frontal/central cerebral connectivity. However, provided there is no decrease in cardiac output or ischemia, brief profound hypoxemia in healthy humans is well tolerated without evidence of acidosis or lasting cognitive impairment.

Background: Universal access to pulse oximetry worldwide is often limited by cost and has substantial public health consequences. Low-cost pulse oximeters have become increasingly available with limited regulatory agency oversight. The accuracy of these devices often has not been validated, raising questions about performance., Methods: The accuracy of 6 low-cost finger pulse oximeters during stable arterial oxygen saturations (SaO2) between 70% and 100% was evaluated in 22 healthy subjects. Oximeters tested were the Contec CMS50DL, Beijing Choice C20, Beijing Choice MD300C23, Starhealth SH-A3, Jumper FPD-500A, and Atlantean SB100 II. Inspired oxygen, nitrogen, and carbon dioxide partial pressures were monitored and adjusted via a partial rebreathing circuit to achieve 10 to 12 stable target SaO2 plateaus between 70% and 100% and PaCO2 values of 35 to 45 mm Hg. Comparisons of pulse oximeter readings (SpO2) with arterial SaO2 (by Radiometer ABL90 and OSM3) were used to calculate bias (SpO2 - SaO2) mean, precision (SD of the bias), and root mean square error (ARMS)., Results: Pulse oximeter readings corresponding to 536 blood samples were analyzed. Four of the 6 oximeters tested showed large errors (up to -6.30% mean bias, precision 4.30%, 7.53 ARMS) in estimating saturation when SaO2 was reduced <80%, and half of the oximeters demonstrated large errors when estimating saturations between 80% and 90%. Two of the pulse oximeters tested (Contec CMS50DL and Beijing Choice C20) demonstrated ARMS of <3% at SaO2 between 70% and 100%, thereby meeting International Organization for Standardization (ISO) criteria for accuracy., Conclusions: Many low-cost pulse oximeters sold to consumers demonstrate highly inaccurate readings. Unexpectedly, the accuracy of some low-cost pulse oximeters tested here performed similarly to more expensive, ISO-cleared units when measuring hypoxia in healthy subjects. None of those tested here met World Federation of Societies of Anaesthesiologists standards, and the ideal testing conditions do not necessarily translate these findings to the clinical setting. Nonetheless, further development of accurate, low-cost oximeters for use in clinical practice is feasible and, if pursued, could improve access to safe care, especially in low-income countries.

The state of protein folding in the endoplasmic reticulum (ER), via the unfolded protein response (UPR), regulates a pro- or anti-apoptotic cell fate. Hypoxic preconditioning (HPC) is a potent anti-apoptotic stimulus, wherein ischemic neural injury is averted by a non-damaging exposure to hypoxia. We tested if UPR modulation contributes to the pro-survival/anti-apoptotic phenotype in neurons preconditioned with hypoxia, using organotypic cultures of rat hippocampus as a model system. Pharmacologic induction of the UPR with tunicamycin increased mRNA of 79 of 84 UPR genes and replicated the pro-survival phenotype of HPC, whereas only small numbers of the same mRNAs were upregulated at 0, 6 and 24h after HPC. During the first 24h after HPC, protein signals in all 3 UPR pathways increased at various times: increased ATF4, phosphorylation of eif2α and IRE1, cleavage of xbb1 mRNA and cleavage of ATF6. Pharmacologic inhibition of ATF6 and IRE1 blocked HPC. Ischemia-like conditions (oxygen/glucose deprivation, OGD) caused extensive neuron cell damage and involved some of the same UPR protein signals as HPC. In distinction to HPC and tunicamycin, OGD caused widespread suppression of UPR genes: 55 of 84 UPR gene mRNAs were numerically downregulated. We conclude that although HPC and ischemic cell death in hippocampal neurons involve protein-based signaling in all 3 UPR pathways, these processes co-opt only a subset of the genomic response elicited by agents known to cause protein misfolding, possibly because of persistent transcription/translation arrest induced by hypoxia and especially OGD., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Mild hypothermia (33°C-34°C) after cerebral ischemia in intact animals or ischemia-like conditions in vitro reduces neuron death. However, it is now clear that more profound hypothermia or delayed hypothermia may not provide significant protection. To further define the limitations of hypothermia after cerebral ischemia, we used hippocampal slice cultures to examine the effects of various degrees, durations, and delays of hypothermia on neuron death after an ischemia-like insult. Organotypic cultures of the hippocampus from 7- to 8 day-old rat pups were cooled to 32°C, 23°C, 17°C, or 4°C immediately or after a 2-4 hour delay from an injurious insult of oxygen and glucose deprivation (OGD). Cell death in CA1, CA3 and dentate regions of the cultures was assessed 24 hours later with SYTOX ® or propidium iodide, both of which are fluorescent markers labeling damaged cells. OGD caused extensive cell death in CA1, CA3, and dentate regions of the hippocampal cultures. Hypothermia (32°C, 23°C and 17°C) for 4-6 hours immediately after OGD was protective at 24 hours, but when hypothermia was applied for longer periods or delayed after OGD, no protection or increased death was seen. Ultra-profound hypothermia (4°C) increased cell death in all cell areas of the hippocampus even when after a milder insult of only hypoxia. In an in vitro model of recovery after an ischemia-like insult, mild to profound hypothermia is protective only when applied without delay and for limited periods of time (6-8 hours). Longer durations of hypothermia, or delayed application of the hypothermia can increase neuron death. These findings may have implications for clinical uses of therapeutic hypothermia after hypoxic or ischemic insults, and suggest that further work is needed to elucidate the limitations of hypothermia as a protective treatment after ischemic stress.

Pulse oximetry is a standard of care during anaesthesia in high-income countries. However, 70% of operating environments in low- and middle-income countries have no pulse oximeter. The 'Lifebox' oximetry project set out to bridge this gap with an inexpensive oximeter meeting CE (European Conformity) and ISO (International Organization for Standardization) standards. To date, there are no performance-specific accuracy data on this instrument. The aim of this study was to establish whether the Lifebox pulse oximeter provides clinically reliable haemoglobin oxygen saturation (Sp O2 ) readings meeting USA Food and Drug Administration 510(k) standards. Using healthy volunteers, inspired oxygen fraction was adjusted to produce arterial haemoglobin oxygen saturation (Sa O2 ) readings between 71% and 100% measured with a multi-wavelength oximeter. Lifebox accuracy was expressed using bias (Sp O2 - Sa O2 ), precision (SD of the bias) and the root mean square error (Arms). Simultaneous readings of Sa O2 and Sp O2 in 57 subjects showed a mean (SD) bias of -0.41% (2.28%) and Arms 2.31%. The Lifebox pulse oximeter meets current USA Food and Drug Administration standards for accuracy, thus representing an inexpensive solution for patient monitoring without compromising standards., (© 2013 The Association of Anaesthetists of Great Britain and Ireland.)

Background: Cerebral oximetry is a noninvasive optical technology that measures frontal cortex blood hemoglobin-oxygen saturation. Commercially available cerebral oximeters have not been evaluated independently. Unlike pulse oximeters, there are currently no Food and Drug Administration standards for performance or accuracy. We tested the hypothesis that cerebral oximeters accurately measure a fixed ratio of the oxygen saturation in cerebral mixed venous and arterial blood., Methods: We evaluated the performance of 5 commercially available cerebral oximeters: the EQUANOX® 7600 in 3- and 4-wavelength versions (Nonin Medical, Plymouth, MN), FORE-SIGHT® (Casmed, Branford, CT), INVOS® 5100C (Covidien, Boulder, CO), and the NIRO-200NX® (Hamamatsu Photonics, Hamamatsu City, Japan) during stable isocapnic hypoxia in volunteers. Twenty-three healthy adults (14 men, 9 women) had sensors placed on each side of the forehead. The subject's inspired oxygen (FIO2) was then changed to produce 6 steady-state arterial oxygen saturation (SaO2) levels between 100% and 70%, while end-tidal CO2 was maintained constant. At each plateau, simultaneous blood samples from the jugular bulb and radial artery were analyzed with a hemoximeter (OSM-3, Radiometer Medical A/S, Copenhagen, Denmark). Each cerebral oximeter's bias was calculated as the difference between the instrument's reading (cerebral saturation, ScO2) with the weighted saturation of venous and arterial blood (Sa/vO2), as specified by each manufacturer (INVOS: 25% arterial/75% venous; FORE-SIGHT, EQUANOX, and NIRO: 30% arterial/70% venous)., Results: Five hundred forty-two comparisons between paired blood samples and oximeter readings were analyzed. The pooled root mean square error was 8.06%, a value higher than for pulse oximeters, which is ±3% by Food and Drug Administration standards. The mean % bias ± SD (precision) and root mean square errors were: FORE-SIGHT 1.76 ± 3.92 and 4.28; INVOS 0.05 ± 9.72 and 9.69; NIRO-200NX -1.13 ± 9.64 and 9.68; EQUANOX-3 λ 2.48 ± 8.12 and 8.47; EQUANOX-4 λ 2.84 ± 6.27 and 6.86. The FORE-SIGHT, NIRO-200NX, and EQUANOX-3 λ had significantly more positive bias at lower SaO2. The amount of bias during hypoxia was reduced when the bias was calculated on the basis of difference between oximeter reading and the arterial and mixed venous saturation difference rather than the weighted average of blood saturation, indicating that differences in the ratio between arterial and venous blood volumes account for some of the positive bias at low saturation. Dark skin pigment tended to produce more negative bias in all instruments but bias was significantly larger than zero only for the FORE-SIGHT oximeter. Bias was significantly more negative in women for INVOS and EQUANOX devices but not for the FORE-SIGHT device., Conclusions: While responsive to desaturation, cerebral oximeters exhibited large variation in reading errors between subjects, with mean bias possibly related to variations in the ratio of arterial and venous blood in the sampling area of the brain. This ratio is probably not fixed, as assumed by the manufacturers, but dynamically changes with hypoxia. Better understanding these factors could improve the performance of cerebral oximeters and help establish saturation or blood flow thresholds for brain well-being.

Background: Carbon monoxide poisoning is a significant problem in most countries, and a reliable method of quick diagnosis would greatly improve patient care. Until the recent introduction of a multiwavelength "pulse CO-oximeter" (Masimo Rainbow SET(®) Radical-7), obtaining carboxyhemoglobin (COHb) levels in blood required blood sampling and laboratory analysis. In this study, we sought to determine whether hypoxemia, which can accompany carbon monoxide poisoning, interferes with the accurate detection of COHb., Methods: Twelve healthy, nonsmoking, adult volunteers were fitted with 2 standard pulse-oximeter finger probes and 2 Rainbow probes for COHb detection. A radial arterial catheter was placed for blood sampling during 3 interventions: (1) increasing hypoxemia in incremental steps with arterial oxygen saturations (SaO2) of 100% to 80%; (2) normoxia with incremental increases in %COHb to 12%; and (3) elevated COHb combined with hypoxemia with SaO2 of 100% to 80%. Pulse-oximeter (SpCO) readings were compared with simultaneous arterial blood values at the various increments of hypoxemia and carboxyhemoglobinemia (≈25 samples per subject). Pulse CO-oximeter performance was analyzed by calculating the mean bias (SpCO - %COHb), standard deviation of the bias (precision), and the root-mean-square error (A(rms))., Results: The Radical-7 accurately detected hypoxemia with both normal and elevated levels of COHb (bias mean ± SD: 0.44% ± 1.69% at %COHb <4%, and -0.29% ± 1.64% at %COHb ≥4%, P < 0.0001, and A(rms) 1.74% vs 1.67%). COHb was accurately detected during normoxia and moderate hypoxia (bias mean ± SD: -0.98 ± 2.6 at SaO2 ≥95%, and -0.7 ± 4.0 at SaO2 <95%, P = 0.60, and A(rms) 2.8% vs 4.0%), but when SaO2 decreased below approximately 85%, the pulse CO-oximeter always gave low signal quality errors and did not report SpCO values., Conclusions: In healthy volunteers, the Radical-7 pulse CO-oximeter accurately detects hypoxemia with both low and elevated COHb levels, and accurately detects COHb, but only reads SpCO when SaO2 is more than approximately 85%.

Background: Anesthetic neurotoxicity in the developing brain of rodents and primates has raised concern. Xenon may be a nonneurotoxic alternative to halogenated anesthetics, but its toxicity has only been studied at low concentrations, where neuroprotective effects predominate in animal models. An equipotent comparison of xenon and halogenated anesthetics with respect to neurotoxicity in developing neurons has not been made., Methods: Organotypic hippocampal cultures from 7-day-old rats were exposed to 0.75, 1, and 2 minimum alveolar concentrations (MAC) partial pressures (60% xenon at 1.2, 2.67, and 3.67 atm; isoflurane at 1.4, 1.9, and 3.8%; and sevoflurane at 3.4 and 6.8%) for 6 h, at atmospheric pressure or in a pressure chamber. Cell death was assessed 24 h later with fluorojade and fluorescent dye exclusion techniques., Results: Xenon caused death of hippocampal neurons in CA1, CA3, and dentate regions after 1 and 2 MAC exposures, but not at 0.75 MAC. At 1 MAC, xenon increased cell death 40% above baseline (P < 0.01; ANOVA with Dunnett test). Both isoflurane and sevoflurane increased neuron death at 1 but not 2 MAC. At 1 MAC, the increase in cell death compared with controls was 63% with isoflurane and 90% with sevoflurane (both P < 0.001). Pretreatment of cultures with isoflurane (0.75 MAC) reduced neuron death after 1 MAC xenon, isoflurane, and sevoflurane., Conclusion: Xenon causes neuronal cell death in an in vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations. Preconditioning with a subtoxic dose of isoflurane eliminates this toxicity.

Background: In this cadaveric study we assessed the level of the emergence of the musculocutanous nerve (MCN) relative to needle insertion site during infraclavicular block., Methods: Forty brachial plexi from 20 embalmed adult cadavers were dissected. The MCN was exposed from its origin on the lateral cord to its penetration into the coracobrachialis muscle. The point of emergence of the MCN from the lateral cord relative to a line drawn directly caudad from the anteromedial tip of the coracoid process was measured. A needle was placed predissection using our previously described technique, and the distance from the needletip to the emergence of the MCN was measured., Results: MCN often emerged distal to the coracoid process. At the needle insertion site, 80% of MCN had already emerged from the lateral cord. The distance of emergence ranged from 8.5 cm proximal to 12 cm distal to the coracoid process., Conclusion: This anatomical study suggests that MCN may be one of the factors explaining MCN block failure for the single-injection technique of infraclavicular block using lateral needle trajectory.

This study examines the causes of hypothermia and rewarming injury in CA1, CA3, and dentate neurons in rat hippocampal slice cultures. Neuronal death, assessed with propidium iodide or Sytox fluorescence, Fluoro-Jade labeling, and Cresyl Violet staining, depended on the severity and duration of hypothermia. More than 6 h at temperatures less than 12 °C followed by rewarming to 37 °C (profound hypothermia and rewarming, PH/RW) caused swelling and death in large number of neurons in CA1, CA3, and dentate. During PH, [ATP] decreased and [Ca(2+)](I) and extracellular [glutamate] increased, with neuron rupture and nuclear condensation following RW. The data support the hypothesis that neuronal death from PH/RW is excitotoxic, due to ATP loss, glutamate receptor activation and Ca(2+) influx. We found that antagonism of N-methyl-D-aspartate (NMDA) receptors, but not 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid or metabotropic glutamate receptors, decreased neuron death and prevented increases in [Ca(2+)](I) caused by PH/RW. Chelating extracellular Ca(2+) decreased PH/RW injury, but inhibiting L- and T-type voltage-gated Ca(2+) channels, K+ channels, Ca(2+) release from the endoplasmic reticulum, and reverse Na(+)/Ca(2+) exchange did not affect the Ca(2+) changes or cell death. We conclude that the mechanism of PH/RW neuronal injury in hippocampal slices primarily involves intracellular Ca(2+) accumulation mediated by NMDA receptors that activates necrotic, but not apoptotic processes., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Hypoxic preconditioning in the brain (HPC), a phenomenon whereby noninjurious hypoxia induces resistance to cell death following ischemia, requires the expression of specific genes. Declines in signal transduction pathway activity with aging may decrease the genomic response to HPC and limit its neuroprotective efficacy. To test this, we determined how signal transduction gene expression, intracellular Ca(2+) levels, and phosphorylation of the survival-associated kinase Akt differ in hippocampal slice cultures (HSCs) made from postnatal day 7-10 (P7-10) and 2-year-old rats following HPC. HPC neuroprotection decreased with increasing source animal age, and HPC could not be demonstrated in HCSs made from animals >6 months of age, despite adjusting the duration of hypoxic exposure. Preconditioning protection required the survival kinase Akt in P10 hippocampal slices cultures. In P9 cultures, HPC increased Akt phosphorylation and the expression of prosurvival genes, including Bcl-2, heat shock proteins, protein kinases, c-jun, and NfκB. Lack of increased Akt phosphorylation and a greatly diminished signaling pathway gene response were found in HSCs from aging animals. Moderate and transient increases in [Ca(2+) ](i) during HPC occurred in P7-10 HSCs, but [Ca(2+) ](i) was persistently increased at 1 and 24 hr after preconditioning in HSCs from 2-year-old rats. The intracellular Ca(2+) chelator BAPTA-AM facilitated HPC neuroprotection in 2-year-old HSCs and restored the pattern of post-HPC gene expression seen in immature animals. We conclude that age-related loss of preconditioning may be due to altered intracellular Ca(2+) homeostasis (excess and sustained increase in [Ca(2+) ](i) ) and is a lesion that prevents critical elements of neuroprotective signal transduction., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Methemoglobin in the blood cannot be detected by conventional pulse oximetry and may bias the oximeter's estimate (Spo(2)) of the true arterial functional oxygen saturation (Sao(2)). A recently introduced "pulse CO-oximeter" (Masimo Rainbow SET® Radical-7) that measures SpMet, a noninvasive measurement of the percentage of methemoglobin in arterial blood (%MetHb), was shown to read spuriously high values during hypoxia. In this study we sought to determine whether the manufacturer's modifications have improved the device's ability to detect and accurately measure methemoglobin and deoxyhemoglobin simultaneously., Methods: Twelve healthy adult volunteer subjects were fitted with sensors on the middle finger of each hand, and a radial arterial catheter was placed for blood sampling. Intravenous administration of ∼300 mg of sodium nitrite elevated subjects' methemoglobin levels to a 7% to 11% target level, and hypoxia was induced to different levels of Sao(2) (70% to 100%) by varying fractional inspired oxygen. Pulse CO-oximeter readings were compared with arterial blood values measured with a Radiometer ABL800 FLEX multi-wavelength oximeter. Pulse CO-oximeter methemoglobin reading performance was analyzed by the bias (SpMet-%MetHb), and by observing the incidence of meaningful reading errors and predictive value at the various hypoxia levels. Spo(2) bias (Spo(2)--Sao(2)), precision, and root-mean-square error were evaluated during conditions of elevated methemoglobin., Results: Observations spanned 74% to 100% Sao(2) and 0.4% to 14.4% methemoglobin with 307 blood draws and 602 values from the 2 oximeters. Masimo methemoglobin reading bias and precision over the full Sao(2) span was 0.16% and 0.83%, respectively, and was similar across the span. Masimo Spo(2) readings were biased -1.93% across the 70% to 100% Sao(2) range., Conclusions: The Rainbow's methemoglobin readings are acceptably accurate over an oxygen saturation range of 74%-100% and a methemoglobin range of 0%-14%.

Background: Methemoglobin in the blood cannot be detected by conventional pulse oximetry, although it can bias the oximeter's estimate (Spo2) of the true arterial functional oxygen saturation (Sao2). A recently introduced "Pulse CO-Oximeter" (Masimo Rainbow SET(R) Radical-7 Pulse CO-Oximeter, Masimo Corp., Irvine, CA) is intended to additionally monitor noninvasively the fractional carboxyhemoglobin and methemoglobin content in blood. The purpose of our study was to determine whether hypoxia affects the new device's estimated methemoglobin reading accuracy, and whether the presence of methemoglobin impairs the ability of the Radical-7 and a conventional pulse oximeter (Nonin 9700, Nonin Medical Inc., Plymouth, MN) to detect decreases in Sao2., Methods: Eight and 6 healthy adults were included in 2 study groups, respectively, each fitted with multiple sensors and a radial arterial catheter for blood sampling. In the first group, IV administration of approximately 300 mg sodium nitrite increased subjects' methemoglobin level to a 7% to 8% target and hypoxia was induced to different levels of Sao2 (70%-100%) by varying fractional inspired oxygen. In the second group, 15% methemoglobin at room air and 80% Sao2 were targeted. Pulse CO-oximeter readings were compared with arterial blood values measured using a Radiometer multiwavelength hemoximeter. Pulse CO-oximeter methemoglobin reading performance was analyzed by observing the incidence of meaningful reading errors at the various hypoxia levels. This was used to determine the impact on predictive values for detecting methemoglobinemia. Spo2 reading bias, precision, and root mean square error were evaluated during conditions of elevated methemoglobin., Results: Observations spanned 66.2% to 99% Sao2 and 0.6% to 14.4% methemoglobin over the 2 groups (170 blood draws). Masimo methemoglobin reading bias and precision over the full Sao2 span was 7.7% +/- 13.0%. Best accuracy was found in the 95% to 100% Sao2 range (1.9% +/- 2.5%), progressing to its worst in the 70% to 80% range (24.8% +/- 15.6%). Occurrence of methemoglobin readings in error >5% increased over each 5-point decrease in Sao2 (P < 0.05). Masimo Spo2 readings were biased -6.3% +/- 3.0% in the 95% to 100% Sao2 range with 4% to 8.3% methemoglobin. Both the Radical-7 and Nonin 9700 pulse oximeters accurately detected decreases in Sao(2) <90% with 4% to 15% methemoglobin, despite displaying low Spo2 readings when Sao2 was >95%., Conclusions: The Radical-7's methemoglobin readings become progressively more inaccurate as Sao2 decreases <95%, at times overestimating true values by 10% to 40%. Elevated methemoglobin causes the Spo2 readings to underestimate Sao2 similar to conventional 2-wavelength pulse oximeters at high saturation. Spo2 readings from both types of instruments continue to trend downward during the development of hypoxemia (Sao2 <90%) with methemoglobin levels up to 15%.