Evidence Against Use of Nitrogen for the Death Penalty.

This Viewpoint discusses the recent use of forced nitrogen inhalation as capital punishment in Alabama and describes the body of evidence indicating that forced nitrogen inhalation is an inhumane practice.

Low Perfusion and Missed Diagnosis of Hypoxemia by Pulse Oximetry in Darkly Pigmented Skin: A Prospective Study.

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.

Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming: Mechanisms and Proposed Standards for Clinical Assessment.

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.

A novel approach for the detection of cognitive impairment and delirium risk in older patients undergoing spine surgery.

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.

Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes.

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.

Neuroanatomical Basis for the Orexinergic Modulation of Anesthesia Arousal and Pain Control.

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.

Pulse Oximeter Performance, Racial Inequity, and the Work Ahead.

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.

Extremes of age are associated with differences in the expression of selected pattern recognition receptor genes and ACE2, the receptor for SARS-CoV-2: implications for the epidemiology of COVID-19 disease.

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.

Accuracy of Samsung Smartphone Integrated Pulse Oximetry Meets Full FDA Clearance Standards for Clinical Use.

Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes.1,2,3,4 The pandemic highlights the need for accurate pulse oximetry, particularly at home, as infection rates increase in multiple global regions including the UK, USA and South Africa5. Over 100 million Samsung smartphones containing dedicated biosensors (Maxim Integrated Inc, San Jose, CA) and preloaded Apps to perform pulse oximetry, are in use globally. We performed detailed in human hypoxia testing on the Samsung S9 smartphone to determine if this integrated hardware meets full FDA/ISO requirements for clinical pulse oximetry. Methods: The accuracy of integrated pulse oximetry in the Samsung 9 smartphone during stable arterial oxygen saturations (SaO2) between 70% and 100% was evaluated in 12 healthy subjects. Inspired oxygen, nitrogen, and carbon dioxide partial pressures were monitored and adjusted via a partial rebreathing circuit to achieve stable target SaO2 plateaus between 70% and 100%. Arterial blood samples were taken at each plateau and saturation measured on each blood sample using ABL-90FLEX blood gas analyzer. Bias, calculated from smartphone readings minus the corresponding arterial blood sample, was reported as root mean square deviation (RMSD). Findings: The RMSD of the over 257 data points based on blood sample analysis obtained from 12 human volunteers tested was 2.6%. Interpretation: Evaluation of the smartphone pulse oximeter performance is within requirements of <3.5% RMSD blood oxygen saturation (SpO2) value for FDA/ISO clearance for clinical pulse oximetry. This is the first report of smartphone derived pulse oximetry measurements that meet full FDA/ISO accuracy certification requirements. Both Samsung S9 and S10 contain the same integrated pulse oximeter, thus over 100 million smartphones in current global circulation could be used to obtain clinically accurate spot SpO2 measurements to support at home assessment of COVID-19 patients.

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways.

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 (svPLA2) 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 PLA2s 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 svPLA2-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA2 activation, arachidonic acid, increases in intracellular Ca2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLA2s 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 PLA2 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.

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom.

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.

Activation of orexin system facilitates anesthesia emergence and pain control.

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.

Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom.

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 sPLA2S 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.

Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite.

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 (sPLA2) inhibitors with brief exploration of other potential drug targets on venom molecules.

Increased Cytokines at High Altitude: Lack of Effect of Ibuprofen on Acute Mountain Sickness, Physiological Variables, or Cytokine Levels.

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 (SpO2) was 84.5% ± 5.4% (mean ± standard deviation). Increase in blood interleukin-1ß (IL-1ß), 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.

Four Types of Pulse Oximeters Accurately Detect Hypoxia during Low Perfusion and Motion.

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.

Effects of Changes in Arterial Carbon Dioxide and Oxygen Partial Pressures on Cerebral Oximeter Performance.

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.