Publications

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 [Spo2]) and arterial oxygen saturation (hemoximetry arterial functional oxygen saturation [Sao2]) during stable hypoxemia (Sao2 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 Sao2 and Spo2) by skin pigment category in a multivariable mixed-effects model incorporating repeated-measures and different levels of Sao2 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.

Anemia and hypoxemia are common clinical conditions that are difficult to study and may impact pulse oximeter performance. Utilizing an in vitro circulation system, we studied performance of three pulse oximeters during hypoxemia and severe anemia. Three oximeters including one benchtop, one handheld, and one fingertip device were selected to reflect a range of cost and device types. Human blood was diluted to generate four hematocrit levels (40%, 30%, 20%, and 10%). Oxygen and nitrogen were bubbled through the blood to generate a range of oxygen saturations (OHb) and the blood was cycled through the in vitro circulation system. Pulse oximeter saturations (SpO) were paired with simultaneously-measured OHb readings from a reference CO-oximeter. Data for each hematocrit level and each device were least-squares fit to a 2nd-order equation with quality of each curve fit evaluated using standard error of the estimate. Bias and average root mean square error were calculated after correcting for the calibration difference between human and in vitro circulation system calibration. The benchtop oximeter maintained good accuracy at all but the most extreme level of anemia. The handheld device was not as accurate as the benchtop, and inaccuracies increased at lower hematocrit levels. The fingertip device was the least accurate of the three oximeters. Pulse oximeter performance is impacted by severe anemia in vitro. The use of in vitro calibration systems may play an important role in augmenting in vivo performance studies evaluating pulse oximeter performance in challenging conditions.

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.

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.

Objective

To describe the association between intraoperative tissue oxygenation and postoperative troponin elevation in patients undergoing major spine surgery. We hypothesised that a decrease in intraoperative skeletal muscle tissue oxygenation (SmO) was associated with the peak postoperative cardiac troponin value.

Design

This is a prospective cohort study.

Setting

Single-centre, University of California San Francisco Medical Center.

Participants

Seventy adult patients undergoing major elective spine surgery.

Primary and secondary outcome measures

High-sensitivity troponin T (hsTnT) was measured in plasma preoperatively and on the first and second day after surgery to assess the primary outcome of peak postoperative hsTnT. Secondary outcomes included MINS and intensive care unit (ICU) admission within 30 days. Skeletal cerebral tissue oxygenation and SmO was measured continuously with near-infrared spectroscopy during surgery. The primary exposure variable was time-weighted area under the curve (TW AUC) for SmO.

Results

Mean age was 65 (33-85) years and 59% were female. No significant association was found between TW AUC for SmO and peak hsTnT (Spearman’s correlation, r=0.17, p=0.16). A total of 28 (40%) patients had MINS. ICU admission occurred in 14 (40%) in lower vs 25 (71%) in upper half of patients based on TW AUC for SmO, p=0.008.

Conclusions

Decrease in SmO was not a statistically significant predictor for peak troponin value following major spine surgery but is a potential predictor for other postoperative complications.

Trial registration number

NCT03518372.

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. 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 Africa. 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 (SaO) 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 SaO 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 (SpO) 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 SpO measurements to support at home assessment of COVID-19 patients.

Severe hypoxemia presents variably, and sometimes silently, without subjective complaints of dyspnea. The adequacy of cardiovascular compensation for oxygen delivery to tissues should be a focus in all hypoxemic patients.

Unlabelled

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 (SO) 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.

Detecting life-threatening common dyshemoglobins such as carboxyhemoglobin (COHb, resulting from carbon monoxide poisoning) or methemoglobin (MetHb, caused by exposure to nitrates) typically requires a laboratory CO-oximeter. Because of cost, these spectrophotometer-based instrument are often inaccessible in resource-poor settings. The aim of this study was to determine if an inexpensive pocket infrared spectrometer and smartphone (SCiO®Pocket Molecular Sensor, Consumer Physics Ltd., Israel) accurately detects COHb and MetHb in single drops of blood. COHb was created by adding carbon monoxide gas to syringes of heparinized blood human or cow blood. In separate syringes, MetHb was produced by addition of sodium nitrite solution. After incubation and mixing, fractional concentrations of COHb or MetHb were measured using a Radiometer ABL-90 Flex® CO-oximeter. Fifty microliters of the sample were then placed on a microscope slide, a cover slip applied and scanned with the SCiO spectrometer. The spectrograms were used to create simple linear models predicting [COHb] or [MetHb] based on spectrogram maxima, minima and isobestic wavelengths. Our model predicted clinically significant carbon monoxide poisoning (COHb ≥15%) with a sensitivity of 93% and specificity of 88% (regression r2 = 0.63, slope P<0.0001), with a mean bias of 0.11% and an RMS error of 21%. Methemoglobinemia severe enough to cause symptoms (>20% MetHb) was detected with a sensitivity of 100% and specificity of 71% (regression r2 = 0.92, slope P<0.001) mean bias 2.7% and RMS error 21%. Although not as precise as a laboratory CO-oximeter, an inexpensive pocket-sized infrared scanner/smartphone detects >15% COHb or >20% MetHb on a single drop of blood with enough accuracy to be useful as an initial clinical screening. The SCiO and similar relatively low cost spectrometers could be developed as inexpensive diagnostic tools for developing countries.

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

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.

A number of different technologies have been developed to measure tissue oxygenation, with the goal of identifying tissue hypoxia and guiding therapy to prevent patient harm. In specific cases, tissue oximetry may provide clear indications of decreases in tissue oxygenation such as that occurring during acute brain ischemia. However, the causation between tissue hemoglobin-oxygen desaturation in one organ (eg, brain or muscle) and global outcomes such as mortality, intensive care unit length of stay, and remote organ dysfunction remains more speculative. In this review, we describe the current state of evidence for predicting clinical outcomes from tissue oximetry and identify several issues that need to be addressed to clarify the link between tissue oxygenation and outcomes. We focus primarily on the expanding use of near-infrared spectroscopy to assess a venous-weighted mixture of venous and arterial hemoglobin-oxygen saturation deep in tissues such as brain and muscle. Our analysis finds that more work is needed in several areas: establishing threshold prediction values for tissue desaturation-related injury in specific organs, defining the types of interventions required to correct changes in tissue oxygenation, and defining the effect of interventions on outcomes. Furthermore, well-designed prospective studies that test the hypothesis that monitoring oxygenation status in one organ predicts outcomes related to other organs need to be done. Finally, we call for more work that defines regional variations in tissue oxygenation and improves technology for measuring and even imaging oxygenation status in critical organs. Such studies will contribute to establishing that monitoring and imaging of tissue oxygenation will become routine in the care of high-risk patients because the monitors will provide outputs that direct therapy to improve clinical outcomes.

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.

During the last century, historians have discovered that between the 13th and 18th centuries, at least six sages discovered that the air we breathe contains something that we need and use. Ibn al-Nafis (1213-1288) in Cairo and Michael Servetus (1511-1553) in France accurately described the pulmonary circulation and its effect on blood color. Michael Sendivogius (1566-1636) in Poland called a part of air “the food of life” and identified it as the gas made by heating saltpetre. John Mayow (1641-1679) in Oxford found that one-fifth of air was a special gas he called “spiritus nitro aereus.” Carl Wilhelm Scheele (1742-1786) in Uppsala generated a gas he named “fire air” by heating several metal calcs. He asked Lavoisier how it fit the phlogiston theory. Lavoisier never answered. In 1744, Joseph Priestley (1733-1804) in England discovered how to make part of air by heating red calc of mercury. He found it brightened a flame and supported life in a mouse in a sealed bottle. He called it “dephlogisticated air.” He published and personally told Lavoisier and other chemists about it. Lavoisier never thanked him. After 9 years of generating and studying its chemistry, he couldn’t understand whether it was a new element. He still named it “principe oxigene.” He was still not able to disprove phlogiston. Henry Cavendish (1731-1810) made an inflammable gas in 1766. He and Priestley noted that its flame made a dew. Cavendish proved the dew was pure water and published this in 1778, but all scientists called it impossible to make water, an element. In 1783, on June 24th, Lavoisier was urged to try it, and, when water appeared, he realized that water was not an element but a compound of two gases, proving that oxygen was an element. He then demolished phlogiston and began the new chemistry revolution.

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.

Background

Pulse spectroscopy is a new noninvasive technology involving hundreds of wavelengths of visible and infrared light, enabling the simultaneous quantitation of multiple types of normal and dysfunctional hemoglobin. We evaluated the accuracy of a first-generation pulse spectroscopy system (V-Spec™ Monitoring System, Senspec, Germany) in measuring oxygen saturation (SpO2) and detecting carboxyhemoglobin (COHb) or methemoglobin (MetHb), alone or simultaneously, with hypoxemia.

Methods

Nineteen volunteers were fitted with V-Spec probes on the forehead and fingers. A radial arterial catheter was placed for blood sampling during (1) hypoxemia with arterial oxygen saturations (SaO2) of 100% to 58.5%; (2) normoxia with MetHb and COHb increased to approximately 10%; (3) 10% COHb or MetHb combined with hypoxemia with SaO2 of 100% to 80%. Standard measures of pulse-oximetry performance were calculated: bias (pulse spectroscopy measured value – arterial measured value) mean ± SD and root-mean-square error (Arms).

Results

The SpO2 bias for SaO2 approximately 60% to 100% was 0.06% ± 1.30% and Arms of 1.30%. COHb bias was 0.45 ± 1.63, with an Arms of 1.69% overall, and did not degrade substantially during moderate hypoxemia. MetHb bias was 0.36 ± 0.80 overall and stayed small with hypoxemia. Arms was 0.88 and was <3% at all levels of SaO2 and MetHb. Hypoxemia was also accurately detected by pulse spectroscopy at elevated levels of COHb. At elevated MetHb levels, a substantial negative bias developed, -10.3 at MetHb >10%.

Conclusions

Pulse spectroscopy accurately detects hypoxemia, MetHb, and COHb. The technology also accurately detects these dysfunctional hemoglobins during hypoxemia. Future releases of this device may have an improved SpO2 algorithm that is more robust with methemoglobinemia.

In 1875, Paul Bert linked high altitude danger to the low partial pressure of oxygen when 2 of 3 French balloonists died euphorically at about 8,600 m altitude. World War I fatal crashes of high altitude fighter pilots led to a century of efforts to use oximetry to warn pilots. The carotid body, discovered in 1932 to be the hypoxia detector, led to most current physiologic understanding of the body’s respiratory responses to hypoxia and CO2. The author describes some of his UCSF group’s work: In 1963, we reported both the brain’s ventral medullary near-surface CO2 (and pH) chemosensors and the role of cerebrospinal fluid in acclimatization to altitude. In 1966, we reported the effect of altitude on cerebral blood flow and later the changes of carotid body sensitivity at altitude and the differences in natives of high altitude. In 1973, pulse oximetry was invented when Japanese biophysicist Takuo Aoyagi read and applied to pulses a largely forgotten 35-year-old discovery by English medical student J. R. Squire of a method of computing oxygen saturation from red and infrared light passing through both perfused and blanched tissue.

Oxygen has often been called the most important discovery of science. I disagree. Over five centuries, reports by six scientists told of something in air we animals all need. Three reported how to generate it. It acquired many names, finally oxygen. After 8 years of studying it, Lavoisier still couldn’t understand its nature. No special date and no scientist should get credit for discovering oxygen. Henry Cavendish discovered how to make inflammable air (H2). When burned, it made water. This was called impossible because water was assumed to be an element. When Lavoisier repeated the Cavendish test on June 24, 1783, he realized it demolished two theories, phlogiston and water as an element, a Kuhnian paradigm shift that finally unlocked his great revolution of chemistry.

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.

Recent events have called long-overdue attention to one of the first investigators to discover the roles of something in air changing the color of the pulmonary blood flowing through the lung.

Mild hypothermia (33°C-34°C) after cerebral ischemia in intact animals or ischemia-like conditions 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 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.

After training in physics during World War II, I spent 2 years designing radar at Massachusetts Institute of Technology and then switched to biophysics. After medical school and a residency, I was doctor drafted to National Institutes of Health where I studied blood gas transport in hypothermia and developed the carbon dioxide electrode and the blood gas analyzer (pH, partial pressure of O2, and partial pressure of CO2). I joined the University of California San Francisco in 1958 in a new anesthesia department and new Cardiovascular Research Institute. My research aims were anesthesia patient monitoring, respiratory physiology, blood gas transport, and high-altitude acclimatization and pathology.

Neurotoxic snake envenomation can result in respiratory failure and death. Early treatment is considered important to survival. Inexpensive, heat-stable, needle-free, antiparalytics could facilitate early treatment of snakebite and save lives, but none have been developed. An experiment using aerosolized neostigmine to reverse paralysis suggests how early interventions could be developed.

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

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

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.

Background

Anemia is associated with morbidity and mortality and frequently leads to transfusion of erythrocytes. The authors sought to directly compare the effect of high inspired oxygen fraction versus transfusion of erythrocytes on the anemia-induced increased heart rate (HR) in humans undergoing experimental acute isovolemic anemia.

Methods

The authors combined HR data from healthy subjects undergoing experimental isovolemic anemia in seven studies performed by the group. HR changes associated with breathing 100% oxygen by nonrebreathing facemask versus transfusion of erythrocytes at their nadir hemoglobin concentration of 5 g/dl were examined. Data were analyzed using a mixed-effects model.

Results

HR had an inverse linear relationship to hemoglobin concentration with a mean increase of 3.9 beats per min per gram of hemoglobin (beats/min/g hemoglobin) decrease (95% CI, 3.7-4.1 beats/min/g hemoglobin), P < 0.0001. Return of autologous erythrocytes significantly decreased HR by 5.3 beats/min/g hemoglobin (95% CI, 3.8-6.8 beats/min/g hemoglobin) increase, P < 0.0001. HR at nadir hemoglobin of 5.6 g/dl (95% CI, 5.5-5.7 g/dl) when breathing air (91.4 beats/min; 95% CI, 87.6-95.2 beats/min) was reduced by breathing 100% oxygen (83.0 beats/min; 95% CI, 79.0-87.0 beats/min), P < 0.0001. The HR at hemoglobin 5.6 g/dl when breathing oxygen was equivalent to the HR at hemoglobin 8.9 g/dl when breathing air.

Conclusions

High arterial oxygen partial pressure reverses the heart rate response to anemia, probably because of its usability rather than its effect on total oxygen content. The benefit of high arterial oxygen partial pressure has significant potential clinical implications for the acute treatment of anemia and results of transfusion trials.

Cyanosis was used for a century after dentists began pulling teeth under 100% N(2)O in 1844 because brief (2 min) severe hypoxia is harmless. Deaths came with curare and potent anesthetic respiratory arrest. Leland Clark’s invention of a polarographic blood oxygen tension electrode (1954) was introduced for transcutaneous PO2 monitoring to adjust PEEP and CPAP PO2 to prevent premature infant blindness from excess O2 (1972). Oximetry for warning military aviators was tried after WW II but not used for routine monitoring until Takuo Aoyagi (1973) discovered an equation to measure SaO2 by the ratio of ratios of red and IR light transmitted through tissue as it changed with arterial pulses. Pulse oximetry (1982) depended on simultaneous technology improvements of light emitting red and IR diodes, tiny cheap solid state sensors and micro-chip computers. Continuous monitoring of airway anesthetic concentration and oxygen also became very common after 1980. Death from anesthesia fell 10 fold between 1985 and 2000 as pulse oximetry became universally used, but no proof of a causative relationship to pulse oximetry exists. It is now assumed that all anesthesiologist became much more aware of the dangers of prolonged hypoxia, perhaps by using the pulse oximeters.

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.

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%.

Antifreeze proteins (AFP) are associated with protection from freezing. We measured the effect of type I antifreeze protein on spontaneous bursting of mixed neuronal/glial cultures using a multi-electrode array culture system. Antifreeze protein (10mg/ml) reversibly depressed bursting activity without inhibiting mitochondrial oxidative capacity. The effect of antifreeze protein on cold/re-warming injury was investigated in rat hippocampal slice cultures. Compared to bovine serum albumin at a similar concentration, antifreeze protein protected hippocampal neurons from 8h of profound hypothermia at (4 degrees C) followed by re-warming. The protection observed is believed to be associated with the inhibitory effect of antifreeze protein.

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%.

Neurons preconditioned with non-injurious hypoxia or the anesthetic isoflurane express different genes but are equally protected against severe hypoxia/ischemia. We hypothesized that neuroprotection would be augmented when preconditioning with isoflurane and hypoxic preconditioning are combined. We also tested if preconditioning requires intracellular Ca(2+) and the inositol triphosphate receptor, and if gene expression is similar in single agent and combined preconditioning. Hippocampal slice cultures prepared from 9 day old rats were preconditioned with hypoxia (95% N(2), 5% CO(2) for 15 min, HPC), 1% isoflurane for 15 min (APC) or their combination (CPC) for 15 min. A day later cultures were deprived of O(2) and glucose (OGD) to produce neuronal injury. Cell death was assessed 48 h after OGD. mRNA encoding 119 signal transduction genes was quantified with cDNA micro arrays. Intracellular Ca(2+) in CA1 region was measured with fura-2 during preconditioning. The cell-permeable Ca(2+) buffer BAPTA-AM, the IP(3) receptor antagonist Xestospongin C and RNA silencing were used to investigate preconditioning mechanisms. CPC decreased CA1, CA3 and dentate region death by 64-86% following OGD, more than HPC or APC alone (P<0.01). Gene expression following CPC was an amalgam of gene expression in HPC and APC, with simultaneous increases in growth/development and survival/apoptosis regulation genes. Intracellular Ca(2+) chelation and RNA silencing of IP(3) receptors prevented preconditioning neuroprotection and gene responses. We conclude that combined isoflurane-hypoxia preconditioning augments neuroprotection compared to single agents in immature rat hippocampal slice cultures. The mechanism involves genes for growth, development, apoptosis regulation and cell survival as well as IP(3) receptors and intracellular Ca(2+).

Oxygen-glucose deprivation (OGD) initiates a cascade of intracellular responses that culminates in cell death in sensitive species. Neurons from Arctic ground squirrels (AGS), a hibernating species, tolerate OGD in vitro and global ischemia in vivo independent of temperature or torpor. Regulation of energy stores and activation of mitogen-activated protein kinase (MAPK) signaling pathways can regulate neuronal survival. We used acute hippocampal slices to investigate the role of ATP stores and extracellular signal-regulated kinase (ERK)1/2 and Jun NH(2)-terminal kinase (JNK) MAPKs in promoting survival. Acute hippocampal slices from AGS tolerated 30 mins of OGD and showed a small but significant increase in cell death with 2 h OGD at 37 degrees C. This tolerance is independent of hibernation state or season. Neurons from AGS survive OGD despite rapid ATP depletion by 3 mins in interbout euthermic AGS and 10 mins in hibernating AGS. Oxygen-glucose deprivation does not induce JNK activation in AGS and baseline ERK1/2 and JNK activation is maintained even after drastic depletion of ATP. Surprisingly, inhibition of ERK1/2 or JNK during OGD had no effect on survival, whereas inhibition of JNK increased cell death during normoxia. Thus, protective mechanisms promoting tolerance to OGD by AGS are downstream from ATP loss and are independent of hibernation state or season. Journal of Cerebral Blood Flow & Metabolism (2008) 28, 1307-1319; doi:10.1038/jcbfm.2008.20; published online 9 April 2008.

Quantitative analysis of the chemical interactions of CO2 and O2 on ventilation from early 20th century to the present start with the amazingly steep CO2 response found by Haldane and his pupils, proceed through discovery of the prime role of the H+ ion and the discovery of carotid body chemoreception. The interaction of central and peripheral drives and changes with time and acute and chronic altitude exposure are still under investigation.

In the 1930s and 1940s, photo cells permitted German, English, and American physiologists to construct ear oximeters with red and infrared light, requiring calibration. In 1940 Squire recognized that changes of red and infrared light transmission caused by pneumatic tissue compression permitted saturation to be computed. In 1949 Wood used this idea to compute absolute saturation continuously from the ratios of optical density changes with pressure in an ear oximeter. In 1972 Takuo Aoyagi, an electrical engineer at Nihon Kohden company in Tokyo, was interested in measuring cardiac output noninvasively by the dye dilution method using a commercially available ear oximeter. He balanced the red and infrared signals to cancel the pulse noise which prevented measuring the dye washout accurately. He discovered that changes of oxygen saturation voided his pulse cancellation. He then realized that these pulsatile changes could be used to compute saturation from the ratio of ratios of pulse changes in the red and infrared. His ideas, equations and instrument were adapted, improved and successfully marketed by Minolta about 1978, stimulating other firms to further improve and market pulse oximeters worldwide in the mid 1980s. Dr. Aoyagi and associates provided a detailed history for this paper.

Introduction

Pulse oximetry may overestimate arterial oxyhemoglobin saturation (Sao2) at low Sao2 levels in individuals with darkly pigmented skin, but other factors, such as gender and oximeter probe type, remain less studied.

Methods

We studied the relationship between skin pigment and oximeter accuracy in 36 subjects (19 males, 17 females) of a range of skin tones. Clip-on type sensors and adhesive/disposable finger probes for the Masimo Radical, Nellcor N-595, and Nonin 9700 were studied. Semisupine subjects breathed air-nitrogen-CO2 mixtures via a mouthpiece to rapidly achieve 2- to 3-min stable plateaus of Sao2. Comparisons of Sao2 measured by pulse oximetry (Spo2) with Sao2 (by Radiometer OSM-3) were used in a multivariate model to assess the source of errors.

Results

The mean bias (Spo2 – Sao2) for the 70%-80% saturation range was 2.61% for the Masimo Radical with clip-on sensor, -1.58% for the Radical with disposable sensor, 2.59% for the Nellcor clip, 3.6% for the Nellcor disposable, -0.60% for the Nonin clip, and 2.43% for the Nonin disposable. Dark skin increased bias at low Sao2; greater bias was seen with adhesive/disposable sensors than with the clip-on types. Up to 10% differences in saturation estimates were found among different instruments in dark-skinned subjects at low Sao2.

Conclusions

Multivariate analysis indicated that Sao2 level, sensor type, skin color, and gender were predictive of errors in Spo2 estimates at low Sao2 levels. The data suggest that clinically important bias should be considered when monitoring patients with saturations below 80%, especially those with darkly pigmented skin; but further study is needed to confirm these observations in the relevant populations.

The ability of fishes, amphibians, and reptiles to survive extremes of oxygen availability derives from a core triad of adaptations: profound metabolic suppression, tolerance of ionic and pH disturbances, and mechanisms for avoiding free-radical injury during reoxygenation. For long-term anoxic survival, enhanced storage of glycogen in critical tissues is also necessary. The diversity of body morphologies and habitats and the utilization of dormancy have resulted in a broad array of adaptations to hypoxia in lower vertebrates. For example, the most anoxia-tolerant vertebrates, painted turtles and crucian carp, meet the challenge of variable oxygen in fundamentally different ways: Turtles undergo near-suspended animation, whereas carp remain active and responsive in the absence of oxygen. Although the mechanisms of survival in both of these cases include large stores of glycogen and drastically decreased metabolism, other mechanisms, such as regulation of ion channels in excitable membranes, are apparently divergent. Common themes in the regulatory adjustments to hypoxia involve control of metabolism and ion channel conductance by protein phosphorylation. Tolerance of decreased energy charge and accumulating anaerobic end products as well as enhanced antioxidant defenses and regenerative capacities are also key to hypoxia survival in lower vertebrates.

Background

Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h.

Methods

Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit-symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h (“fresh”) or 3 weeks (“stored”) to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion.

Results

Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion-induced DSST improvement did not differ between groups (P = 0.96).

Conclusion

Erythrocytes stored for 3 weeks are as efficacious as are erythrocytes stored for 3.5 h in reversing the neurocognitive deficit of acute anemia. Requiring fresh rather than stored erythrocytes for augmentation of oxygen delivery does not seem warranted.

Background

Isoflurane preconditions neurons to improve tolerance of subsequent ischemia in both intact animal models and in in vitro preparations. The mechanisms for this protection remain largely undefined. Because isoflurane increases intracellular Ca2+ concentrations and Ca2+ is involved in many processes related to preconditioning, the authors hypothesized that isoflurane preconditions neurons via Ca2+-dependent processes involving the Ca2+- binding protein calmodulin and the mitogen-activated protein kinase-ERK pathway.

Methods

The authors used a preconditioning model in which organotypic cultures of rat hippocampus were exposed to 0.5-1.5% isoflurane for a 2-h period 24 h before an ischemia-like injury of oxygen-glucose deprivation. Survival of CA1, CA3, and dentate neurons was assessed 48 later, along with interval measurements of intracellular Ca2+ concentration (fura-2 fluorescence microscopy in CA1 neurons), mitogen-activated protein kinase p42/44, and the survival associated proteins Akt and GSK-3beta (in situ immunostaining and Western blots).

Results

Preconditioning with 0.5-1.5% isoflurane decreased neuron death in CA1 and CA3 regions of hippocampal slice cultures after oxygen-glucose deprivation. The preconditioning period was associated with an increase in basal intracellular Ca2+ concentration of 7-15%, which involved Ca2+ release from inositol triphosphate-sensitive stores in the endoplasmic reticulum, and transient phosphorylation of mitogen-activated protein kinase p42/44 and the survival-associated proteins Akt and GSK-3beta. Preconditioning protection was eliminated by the mitogen-activated extracellular kinase inhibitor U0126, which prevented phosphorylation of p44 during preconditioning, and by calmidazolium, which antagonizes the effects of Ca2+-bound calmodulin.

Conclusions

Isoflurane, at clinical concentrations, preconditions neurons in hippocampal slice cultures by mechanisms that apparently involve release of Ca2+ from the endoplasmic reticulum, transient increases in intracellular Ca2+ concentration, the Ca2+ binding protein calmodulin, and phosphorylation of the mitogen-activated protein kinase p42/44.

Objective

Acute anemia slows the responses to clinical tests of cognitive function. We tested the hypothesis that these slowed responses during acute severe isovolemic anemia in healthy unmedicated humans result from impaired central processing.

Methods

A blinded operator measured the latency of the P300 peak in nine healthy volunteers at each volunteer’s baseline hemoglobin concentration (Hb), and again after isovolemic hemodilution to Hb 5 g/dL. At both Hb concentrations, the P300 latency was measured twice: with the blinded subject breathing air or 100% oxygen, administered in random order.

Results

Anemia increased P300 latency significantly from baseline values (P < 0.05). Breathing oxygen during induced anemia resulted in a P300 latency not different from that at baseline when breathing air (P = 0.5) or oxygen (P = 0.8).

Conclusions

Impaired central processing is, at least in part, responsible for the slowed responses and deficits of cognitive function that occur during acute isovolemic anemia at Hb 5-6 g/dL.

Significance

The P300 latency appears to be a potential measure of inadequate central oxygenation. In healthy young adults with acute anemia, erythrocytes should be transfused to produce Hb>5-6 g/dL. As a temporizing measure, administration of oxygen can reverse the cognitive deficits and impaired central processing associated with acute anemia.

Background

It is uncertain whether skin pigmentation affects pulse oximeter accuracy at low HbO2 saturation.

Methods

The accuracy of finger pulse oximeters during stable, plateau levels of arterial oxygen saturation (Sao2) between 60 and 100% were evaluated in 11 subjects with darkly pigmented skin and in 10 with light skin pigmentation. Oximeters tested were the Nellcor N-595 with the OxiMax-A probe (Nellcor Inc., Pleasanton, CA), the Novametrix 513 (Novametrix Inc., Wallingford, CT), and the Nonin Onyx (Nonin Inc., Plymouth, MN). Semisupine subjects breathed air-nitrogen-carbon dioxide mixtures through a mouthpiece. A computer used end-tidal oxygen and carbon dioxide concentrations determined by mass spectrometry to estimate breath-by-breath Sao2, from which an operator adjusted inspired gas to rapidly achieve 2- to 3-min stable plateaus of desaturation. Comparisons of oxygen saturation measured by pulse oximetry (Spo2) with Sao2 (by Radiometer OSM3) were used in a multivariate model to determine the interrelation between saturation, skin pigmentation, and oximeter bias (Spo2 – Sao2).

Results

At 60-70% Sao2, Spo2 (mean of three oximeters) overestimated Sao2 (bias +/- SD) by 3.56 +/- 2.45% (n = 29) in darkly pigmented subjects, compared with 0.37 +/- 3.20% (n = 58) in lightly pigmented subjects (P < 0.0001). The SD of bias was not greater with dark than light skin. The dark-light skin differences at 60-70% Sao2 were 2.35% (Nonin), 3.38% (Novametrix), and 4.30% (Nellcor). Skin pigment-related differences were significant with Nonin below 70% Sao2, with Novametrix below 90%, and with Nellcor at all ranges. Pigment-related bias increased approximately in proportion to desaturation.

Conclusions

The three tested pulse oximeters overestimated arterial oxygen saturation during hypoxia in dark-skinned individuals.

The frog brain survives hypoxia with a slow loss of energy charge and ion homeostasis. Because hypoxic death in most neurons is associated with increases in intracellular calcium ([Ca2+]i), we examined the relationship between [Ca2+]i and survival of a mixed population of isolated cells from the forebrain of North American bullfrog Rana catesbeiana tadpoles. Forebrain cells from stage V-XV tadpoles were isolated by enzymatic digestion and loaded with one of three different calcium indicators (Fura-2, Fura 2-FF and BTC) to provide estimates of [Ca2+]i accurate at low and high [Ca2+]i. Propidium iodide (PI) fluorescence was used as an indicator of cell viability. Cells were exposed to anoxia (100% N2) and measurements of [Ca2+]i and cell survival made from 1 h to 18 h. Intracellular [Ca2+] increased significantly after 3-6 h anoxia (P<0.05), regardless of the type of Ca2+ indicator used; however, there were substantial differences in the measurements of [Ca2+]i with the different indicators, reflecting their varying affinities for Ca2+. Resting [Ca2+]i was approximately 50 nmol l(-1) and increased to about 9-30 micromol l(-1) after 4-6 h anoxia. The significant increase in [Ca2+]i during anoxia was not associated with significant increases in cell death, with 85-95% survival over this time period. Cells exposed to anoxia for 18 h, or those made anoxic for 4-6 and reoxygenated for 12 h to 16 h, had survival rates greater than 70%, but survival was significantly less than normoxic controls. These results indicate that large increases in [Ca2+]i are not necessarily associated with hypoxic cell death in vertebrate brain cells.

Objective

To investigate an unexpectedly high initial skin CO2 pressure with a new small earlobe probe* heated to 42 degrees C containing both transcutaneous (tcPCO2) and pulse oximeter saturation (SpO2) sensors.

Methods

The probe was mounted on the ear lobe of six patients during abdominal or thoracic surgery and on several awake volunteers. The probe was mounted on a cheek or forearm in two other volunteers. Patients were artificially ventilated under general anesthesia at constant end-expiratory PCO2.

Results

In patients, at 8 +/- 3 min after mounting, tcPCO2 peaked 5 mmHg higher than its final value (p = 0.0067, n = 6, paired t-test). After 25 min, tcPCO2 was not different from PaCO2 (arterial). Similar overshoots were recorded with this device when mounted on the arm or cheek and with a standard transcutaneous PCO2 probe set to 42 degrees C, mounted on the ear lobe, arm or chest of awake volunteers. In two volunteers, we found that heating the sensor to 45 degrees C for the first 15 min on the ear, and then decreasing it to 42 degrees C prevented overshoot, and provided valid tcPCO2 data 3 – 5 min after application of the sensor.

Conclusions

A temperature of 42 degrees C may increase local skin temperature and metabolism before vasodilating more remote arteriolar control of sub-sensor capillary flow. We suggest that transcutaneous PCO2 probes be initially set to 44 – 45 degrees C for 5 – 15 min to induce prompt vasodilation to prevent this overshoot and then reduced to 42 degrees C to avoid skin thermal injury in case of long-term application.

Acute mountain sickness (AMS) is a common condition in individuals who travel to altitudes over 2000 m. While AMS is an important public health problem, no measurements can reliably support or predict the diagnosis with any degree of confidence. We therefore set out to study whether pulse oximetry data are associated with AMS. We studied 169 subjects who had recently arrived by foot at 3080 m. Subjects completed a demographic survey, which collected data on ascent profiles and AMS symptoms. Resting arterial oxygen saturation and pulse rate were then measured using finger pulse oximetry. Forty-six subjects (27%) had AMS, using the Lake Louise score. Only pulse rate was significantly associated with the presence of AMS (OR: 1.4; 95% CI, 1.1 to 1.9; p < 0.05, backwards stepwise logistical regression). A trend showed worse AMS diagnoses were associated with higher mean pulse rates (p < 0.05, ANOVA linear weighted analysis). While some previous studies have shown an association between decreased oxygen saturation and acute mountain sickness at altitude, our results did not demonstrate such an association. The utility of pulse oximetry remains limited in the diagnosis of AMS. We recommend further study to determine the possible utility of pulse rate in the diagnosis and prediction of AMS.

Background

Previous studies have found subtle slowing of responses in tests of addition and digit-symbol substitution during acute severe isovolemic anemia to a hemoglobin concentration of 5 g/dl in healthy unmedicated humans. In this study, the authors tested the hypothesis that such changes relate to the slowing of afferent neural traffic.

Methods

The median nerve was stimulated at the wrist in seven healthy unmedicated volunteers before and after induction of acute isovolemic anemia to a nadir hemoglobin concentration of 5.1 +/- 0.3 g/dl (mean +/- SD). Times for neural impulses to travel from the stimulus site to the brachial plexus, cervical spinal cord, and cerebral cortex were measured using somatosensory evoked potentials. Tests were repeated during acute anemia with the subject breathing oxygen. As a control for time and intrasubject variation, the testing was repeated on a separate day when anemia was not produced at times equivalent to those on the experimental day.

Results

Induced acute severe isovolemic anemia decreased nerve conduction latencies from the wrist to the contralateral cerebral cortex (i.e., to the N20 peak) by 2.3 +/- 1.6% compared with values at a mean hemoglobin concentration of 12.7 g/dl (P < 0.01). These decreased latencies were due solely to an increased peripheral conduction velocity, from the wrist to the brachial plexus (P < 0.05), and were not altered when subjects breathed oxygen (P > 0.05). Conduction velocity from the brachial plexus or cervical spinal cord to the cerebral cortex did not change with acute anemia (P > 0.05). Latencies did not differ on the control day among the times of testing (all P > 0.05), nor did they differ at baseline between the control and experimental days (all P > 0.05).

Conclusion

Somatosensory evoked potential latencies were not increased by acute severe isovolemic anemia, making it unlikely that the afferent portion of the neural system is responsible for slowing of cognitive responses previously observed during acute anemia. Because severe isovolemic anemia did not increase somatosensory evoked potential latencies, etiologies other than anemia should be sought if latencies are increased during intraoperative monitoring.

Background

The cardiovascular response to acute isovolemic anemia in humans is thought to differ from that of other species. Studies of anesthetized humans have found either no change or a decreased heart rate. A previous study showed that in 32 healthy unmedicated humans, heart rate increased during acute isovolemic anemia. The hypothesis that heart rate in humans increases in response to acute isovolemic anemia and that the increase is affected by gender was tested.

Study design and methods

Acute isovolemic anemia to a Hb concentration of approximately 5 g per dL in 95 unmedicated healthy humans was produced by simultaneous withdrawal of blood and IV replacement with 5-percent HSA and autologous platelet-rich plasma. The relationship between heart rate and Hb concentration was examined using a mixed-effects linear regression model that allowed each person to have a fitted line with its own slope and intercept. Cubic and quadratic terms were added to determine if these improved the goodness of fit. The effect of gender was tested by including it and its interactions with Hb in the mixed model.

Results

The relationship between heart rate and Hb concentration was linear (p < 0.001) and consistent among the population studied: heart rate = 116.0-4.0 [Hb] (slope 95% CI: -4.2 to -3.8 beats/min/g Hb). Adding a cubic or quadratic term did not significantly improve the goodness of fit of the mathematical expression to the data, confirming the linear nature of the relationship between heart rate and Hb concentration. For women, the slope of the heart rate response was significantly greater than it was for males (difference +/- SE: 0.70 +/- 0.23, p < 0.005).

Conclusion

In 95 unmedicated, healthy humans, heart rate was a linear function of Hb during acute isovolemic anemia. Females had a significantly greater slope of increase in heart rate with decreasing Hb concentration than did males. The relationship is consistent among individuals, is similar to that reported for conscious dogs, and differs from that found previously in anesthetized humans.

In 1953, the doctor draft interrupted Dr. Severinghaus’ anesthesia and physiology training and sent him to the National Institutes of Health as director of anesthesia research at the newly opened Clinical Center. He developed precise laboratory partial pressure of carbon dioxide (PCO(2)) and pH analysis to investigate lung blood gas exchange during hypothermia. Constants for carbon dioxide solubility and pK’ were more accurately determined. In August 1954, he heard Richard Stow describe invention of a carbon dioxide electrode and immediately built one, improved its stability, and tested its response characteristics. In April 1956, he also heard Leland Clark reveal his invention of an oxygen electrode. Dr. Severinghaus obtained one and constructed a stirred cuvette in which blood partial pressure of oxygen (PO(2)) could be accurately measured. Technician Bradley and Dr. Severinghaus combined these, making the first blood gas analysis system in 1957 and 1958, and shortly thereafter, they added a pH electrode. Blood gas analyzers rapidly developed commercially. Dr. Severinghaus collaborated with Astrup and other Danes on the Haldane and Bohr effects and their concepts of base excess during two sabbaticals in Copenhagen. Work with both Astrup and Roughton on the oxygen dissociation curve led Dr. Severinghaus to devise a modified Hill equation that closely fit their new, better human oxygen dissociation curve and a blood gas slide rule that solved oxygen dissociation curve, PCO(2), pH, and acid-base questions. Blood gas analysis revolutionized both clinical medicine and cardiorespiratory and metabolic physiology.

Background

Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2-3 g/dl and thus reverse the effects of acute anemia.

Methods

Thirty-one healthy volunteers, aged 28 +/- 4 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 +/- 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test.

Results

Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 +/- 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 +/- 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia.

Conclusion

The authors confirmed that acute isovolemic anemia subtly slows human reaction time, degrades memory, increases heart rate, and decreases energy level. The findings of this study support the hypothesis that increasing Pao2 to 350 mmHg or greater by breathing oxygen reverses all of these effects of acute anemia except for decreased energy.

Background

Because of the rapid recovery of neuromuscular function after succinylcholine administration, there is a belief that patients will start breathing sufficiently rapidly to prevent significant oxygen desaturation. The authors tested whether this belief was valid.

Methods

Twelve healthy volunteers aged 18-45 yr participated in the study. After preoxygenation to an end-tidal oxygen concentration greater than 90%, each subject received 5 mg/kg thiopental and 1 mg/kg succinylcholine. Oxygen saturation (SaO2) was measured at both a finger and an ear lobe (beat to beat). During the period of apnea and as they were recovering, the volunteers received continuous verbal reassurance by the investigators. If the SaO2 decreased below 80%, the volunteers received chin lift and, if necessary, assisted ventilation. The length of time the subject was apneic and level of desaturation were related by linear regression analysis. One hour after recovery and again 1 week later, subjects were asked a series of questions regarding their emotional experience.

Results

In six volunteers, SaO2 decreased below 95% during apnea; in four, SaO2 decreased below 80%, necessitating chin lift and assisted ventilation in three. Apnea time was significantly longer in volunteers who reached SaO2 less than 80% than in those who did not (7.0+/-0.4 and 4.1+/-0.3 min, respectively), and there was a significant correlation between the length of time the subject was apneic and the magnitude of desaturation.

Conclusions

Spontaneous recovery from succinylcholine-induced apnea may not occur sufficiently quickly to prevent hemoglobin desaturation in subjects whose ventilation is not assisted.

Hypothesis

Acute severe isovolemic anemia (to a hemoglobin [Hb] concentration of 50 g/L) does not decrease subcutaneous wound tissue oxygen tension (PsqO(2)).

Setting

University hospital operating room and inpatient general clinical research center ward.

Subjects

Twenty-five healthy, paid volunteers.

Methods

Subcutaneous oxygen tension and subcutaneous temperature (Tsq) were measured continuously during isovolemic hemodilution to an Hb level of 50 g/L. In 14 volunteers (initially well-perfused), “normal” perfusion (Tsq >34.4 degrees C) was achieved by hydration and systemic warming prior to starting isovolemic hemodilution, while in 11 volunteers (perfusion not controlled [PNC]), no attempt was made to control perfusion prior to hemodilution.

Main outcome measures

Measurements of PsqO(2), Tsq, and relative subcutaneous blood flow (flow index).

Results

While PsqO(2), Tsq, and flow index were significantly lower in PNC vs well-perfused subjects at baseline, there was no significant difference between them at the Hb of 50 g/L (nadir). Subcutaneous PO(2) did not decrease significantly in either group. Arterial PO(2) was not different between the groups, and did not change significantly over time; Tsq and flow index increased significantly from baseline to nadir Hb in both groups.

Conclusions

The level of PsqO(2) was maintained at baseline levels during hemodilution to Hb 50 g/L in healthy volunteers, whether they were initially well-perfused or mildly underperfused peripherally. Given the significant increase in Tsq and flow index, this resulted from a compensatory increase in subcutaneous blood flow sufficient to maintain oxygen delivery. Wound healing depends to a large extent on tissue oxygen delivery, and these data suggest that even severe anemia by itself would not be sufficient to impair wound healing. Thus, transfusion of autologous packed red blood cells solely to improve healing in surgical patients with no other indication for transfusion is not supported by these results.

Background

Controversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia.

Methods

Fifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 +/- 1.2 to 5.2 +/- 0.5 g/dl (mean +/- SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia.

Results

During hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5-7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values.

Conclusion

With acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.

Background

Erythrocytes are transfused to prevent or treat inadequate oxygen delivery resulting from insufficient hemoglobin concentration. Previous studies failed to find evidence of inadequate systemic oxygen delivery at a hemoglobin concentration of 5 g/dl. However, in those studies, sensitive, specific measures of critical organ function were not used. This study tested the hypothesis that acute severe decreases of hemoglobin concentration alters human cognitive function.

Methods

Nine healthy volunteers, age 29 +/- 5 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dl and again after transfusion of their autologous erythrocytes to return their hemoglobin concentration to 7 g/dl. To control for duration of the experiment, each volunteer also completed the same tests on a separate day, without alteration of hemoglobin, at times of the day approximately equivalent to those on the experimental day.

Results

No test showed any change in reaction time or error rate at hemoglobin concentration of 7 g/dl compared with the data at the baseline hemoglobin concentration of 14 g/dl. Reaction time, but not error rate, for horizontal addition and digit-symbol substitution test (DSST) increased at hemoglobin 6 g/dl (mean horizontal addition, 19%; 95% confidence interval [CI], 4-34%; mean DSST, 10%; 95% CI, 4-17%) and further at 5 g/dl (mean horizontal addition, 43%; 95% CI, 6-79%; mean DSST, 18%; 95% CI, 4-31%). Immediate and delayed memory was degraded at hemoglobin 5 g/dl but not at 6 g/dl. Return of hemoglobin to 7 g/dl returned all tests to baseline, except for the DSST, which significantly improved, and returned to baseline the following morning after transfusion of all autologous erythrocytes.

Conclusion

Acute reduction of hemoglobin concentration to 7 g/dl does not produce detectable changes in human cognitive function. Further reduction of hemoglobin level to 6 and 5 g/dl produces subtle, reversible increases in reaction time and impaired immediate and delayed memory. These are the first prospective data to demonstrate subtle degraded human function with acute anemia of hemoglobin concentrations of 6 and 5 g/dl. This reversibility of these decrements with erythrocyte transfusion suggests that our model can be used to test the efficacy of erythrocytes, oxygen therapeutics, or other treatments for acute anemia.

Background

Transfusion guidelines recommend that clinicians assess patients for signs and symptoms of anemia before the transfusion of RBCs. However, studies of signs and symptoms associated with acute isovolemic anemia are limited. The objective of this study was to determine whether acute reduction of Hb concentration to 5 g per dL would result in fatigue, tachycardia, or hypotension in resting, young, healthy, isovolemic humans, and whether changes were reversible with RBC transfusion.

Study design and methods

Conscious, resting, healthy adults less than 35 years old (n = 8) underwent acute isovolemic hemodilution to Hb of 5 g per dL and self-scored their energy level at various Hb concentrations. Heart rate and blood pressure were also measured. For controls, measurements of each subject were made during a comparable period of rest without hemodilution.

Results

During acute isovolemic hemodilution, energy levels decreased progressively and were lower at Hb of 7, 6, and 5 g per dL than at baseline (p<0.01) or in control sessions (p<0.05). The energy level was lower at Hb 7 g per dL than at 14 ( p = 0.005), lower at Hb 6 g per dL than at 7 (p = 0.01), and lower at Hb 5 g per dL than at 6 (p =0.01). Energy levels rose and were not different from baseline or control levels after transfusion of all autologous RBCs. Similarly, median heart rate increased with hemodilution to Hb of 7, 6, and 5 g per dL and decreased with transfusion of autologous RBCs. Supine blood pressure did not decrease with isovolemic hemodilution.

Conclusion

In resting, young, healthy humans, acute isovolemic anemia to Hb levels of 7, 6, and 5 g per dL results in decreased self-scored energy levels and in an increase in heart rate but not in hypotension. Changes in energy and heart rate are reversible with the transfusion of autologous RBCs.

Background

The “critical” level of oxygen delivery (DO2) is the value below which DO2 fails to satisfy the metabolic need for oxygen. No prospective data in healthy, conscious humans define this value. The authors reduced DO2 in healthy volunteers in an attempt to determine the critical DO2.

Methods

With Institutional Review Board approval and informed consent, the authors studied eight healthy, conscious volunteers, aged 19-25 yr. Hemodynamic measurements were obtained at steady state before and after profound acute isovolemic hemodilution with 5% albumin and autologous plasma, and again at the reduced hemoglobin concentration after additional reduction of DO2 by an infusion of a beta-adrenergic antagonist, esmolol.

Results

Reduction of hemoglobin from 12.5+/-0.8 g/dl to 4.8+/-0.2 g/dl (mean +/- SD) increased heart rate, stroke volume index, and cardiac index, and reduced DO2 (14.0+/-2.9 to 9.9+/-20 ml O2 x kg(-1) x min(-1); all P<0.001). Oxygen consumption (VO2; 3.0+/-0.5 to 3.4+/-0.6 ml O2 x kg(-1) x min(-1); P<0.05) and plasma lactate concentration (0.50+/-0.10 to 0.62+/-0.16 mM; P<0.05; n = 7) increased slightly. Esmolol decreased heart rate, stroke volume index, and cardiac index, and further decreased DO2 (to 7.3+/-1.4 ml O2 x kg(-1) x min(-1); all P<0.01 vs. before esmolol). VO2 (3.2+/-0.6 ml O2 x kg(-1) x min(-1); P>0.05) and plasma lactate (0.66+/-0.14 mM; P>0.05) did not change further. No value of plasma lactate exceeded the normal range.

Conclusions

A decrease in DO2 to 7.3+/-1.4 ml O2 x kg(-1) min(-1) in resting, healthy, conscious humans does not produce evidence of inadequate systemic oxygenation. The critical DO2 in healthy, resting, conscious humans appears to be less than this value.

Context

Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment.

Objective

To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport.

Design

Before and after interventional study.

Setting

Academic tertiary care medical center.

Participants

Conscious healthy patients (n =11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21).

Interventions

Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously.

Main outcome measures

“Critical” oxygen delivery (TO2) as assessed by oxygen consumption (VO2), plasma lactate concentration, and ST changes on electrocardiogram.

Results

Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO2 and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: VO2 increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O2 x kg(-1) x min[-1]) to 3.42 (0.54) mL O2 x kg(-1) x min(-1) (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L; P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae.

Conclusions

Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO2, as assessed by lack of change of VO2 and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.

Individuals with a prior history of (susceptible to high altitude pulmonary edema (HAPE-S) have high resting pulmonary arterial pressures, but little data are available on their vascular response to exercise. We studied the pulmonary vascular response to exercise in seven HAPE-S and nine control subjects at sea level and at 3,810 m altitude. At each location, both normoxic (inspired PO2 = 148 Torr) and hypoxic (inspired PO2 = 91 Torr) studies were conducted. Pulmonary hemodynamic measurements included pulmonary arterial and pulmonary arterial occlusion pressures. A multiple regression analysis demonstrated that the pulmonary arterial pressure reactivity to exercise was significantly greater in the HAPE-S group. This reactivity was not influenced by altitude or oxygenation, implying that the response was intrinsic to the pulmonary circulation. Pulmonary arterial occlusion pressure reactivity to exercise was also greater in the HAPE-S group, increasing with altitude but independent of oxygenation. These findings suggest an augmented flow-dependent pulmonary vasoconstriction and/or a reduced vascular cross-sectional area in HAPE-S subjects.

Ventilation-perfusion (VA/Q) mismatch has been shown to increase during exercise, especially in hypoxia. A possible explanation is subclinical interstitial edema due to high pulmonary capillary pressures. We hypothesized that this may be pathogenetically similar to high-altitude pulmonary edema (HAPE) so that HAPE-susceptible people with higher vascular pressures would develop more exercise-induced VA/Q mismatch. To examine this, seven healthy people with a history of HAPE and nine with similar altitude exposure but no HAPE history (control) were studied at rest and during exercise at 35, 65, and 85% of maximum 1) at sea level and then 2) after 2 days at altitude (3,810 m) breathing both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) gas at both locations. We measured cardiac output and respiratory and inert gas exchange. In both groups, VA/Q mismatch (assessed by log standard deviation of the perfusion distribution) increased with exercise. At sea level, log standard deviation of the perfusion distribution was slightly higher in the HAPE-susceptible group than in the control group during heavy exercise. At altitude, these differences disappeared. Because a history of HAPE was associated with greater exercise-induced VA/Q mismatch and higher pulmonary capillary pressures, our findings are consistent with the hypothesis that exercise-induced mismatch is due to a temporary extravascular fluid accumulation.

The fractional increase in cerebral blood flow (CBF) velocity (VCBF) from the control value with 5-min steps of isocapnic hypoxia and hyperoxic hypercapnia was measured by transcranial Doppler in six sea-level native men before and during a 5-day sojourn at 3,810 m altitude to determine whether cerebral vasoreactivity to low arterial O2 saturation (SaO2) gradually increased [as does the hypoxic ventilatory response (HVR)] or diminished (adapted, in concert with known slow fall of CBF) at altitude. A control resting PCO2 value was chosen each day during preliminary hyperoxia to set ventilation at 140 ml.kg-1.min-1 for this and the parallel HVR study, attempting to establish control cerebrospinal fluid (CSF) and brain extracellular fluid pH values unaltered by acclimatization. The relationship of CBF to SaO2 was nonlinear, steepening at a lower SaO2. A hyperbolic equation was used to describe hypoxic cerebrovascular reactivity: fractional VCBF = x[60/ (SaO2-40)-1], where X is the fractional increase of VCBF at 70%.X rose from 0.346 +/- 0.104 (SD) at sea level to 0.463 +/- 0.084 on altitude day 5 (P < 0.05 by paired t-test, justified by the a priori experimental plan). For comparison with CO2 sensitivity, from these X values, we estimate the rise in CBF in response to a 1% fall in SaO2 at 80% to be 1.30% at sea level and 1.74% after 5 days at altitude. CBF sensitivity to increased end-tidal PCO2 rose from 4.01 +/- 0.62%/Torr at sea level to 5.12 +/- 0.79%/Torr on day 5 (P < 0.05), as expected, at the lower PCO2 due to the logarithmic relationship of PCO2 to CSF pH. This change was not significant after correction to log PCO2. We conclude that the cerebral vascular response to acute isocapnic hypoxia may increase during acclimatization at high altitude. The mechanism is unknown but is presumably unrelated to the parallel carotid chemosensitization that, in these subjects, increased the HVR by 60% in the same 5-day period from 0.91 +/- 0.38 to 1.46 +/- 0.59 l.min-1.% fall in SaO2-1).

To understand the factors influencing breath-holding performance, we tested whether the hypoxic (HVR) and hypercapnic ventilatory responses (HCVR) were predictors of the extent of maximal breath-holds as measured by breath-hold duration, the lowest oxyhemoglobin saturation (SpO2min), lowest calculated PaO2 (PaO2min) and highest end-tidal PCO2 (PETCO2max) reached. Steady state isocapnic HVR and hyperoxic HCVR were measured in 17 human volunteers. Breath-holds were made at total lung capacity (TLC), at TLC following hyperventilation, at functional residual capacity, and at TLC with FIO2 = 0.15. SpO2 was measured continuously by pulse oximetry, and alveolar gas was measured at the end of breath-holds by mass spectrometry. PaO2min was calculated from SpO2min and PETCO2max. HVR was a significant predictor of both SpO2min and PaO2min. HVR and forced vital capacity were predictors of breath-hold duration by multiple linear regression. HCVR had no significant predictive value. We conclude that HVR, but not HCVR, is a significant predictor of breath-holding performance.

By re-examining the results of various studies of HVD, of the localization of medullary CO2 chemosensory cells, and of their acid secretion, an hypothesis has been developed suggesting that the neurones which detect increased CO2 or CSF acid respond to decreased transmembrane H+ gradient, i.e. a greater fall in ECF than in ICF pH. Hypoxic lactic acid generated within these cells depresses activity, which can be restored by an appropriate rise of Paco2, disclosing both normal peripheral chemoreceptor hypoxic sensitivity and normal medullary integrative response.

Hypoxic ventilatory response (HVR) and hypoxic ventilatory depression (HVD) were measured in six subjects before, during, and after 12 days at 3,810-m altitude (barometric pressure approximately 488 Torr) with and without 15 min of preoxygenation. HVR was tested by 5-min isocapnic steps to 75% arterial O2 saturation measured by pulse oximetry (Spo2) at an isocapnic PCO2 (P*CO2) chosen to set hyperoxic resting ventilation to 140 ml.kg-1.min-1. Hypercapnic ventilatory response (HCVR, 1.min-1.Torr-1) was tested at ambient and high SPO2 6-8 min after a 6- to 10-Torr step increase of end-tidal PCO2 (PETCO2) above P*CO2. HCVR was independent of preoxygenation and was not significantly increased at altitude (when corrected to delta logPCO2). Preoxygenated HVR rose from -1.13 +/- 0.23 (SE) l.min-1.%SPO2(-1) at sea level to -2.17 +/- 0.13 by altitude day 12, without reaching a plateau, and returned to control after return to sea level for 4 days. Ambient HVR was measured at P*CO2 by step reduction of SPO2 from its ambient value (86-91%) to approximately 75%. Ambient HVR slope was not significantly less, but ventilation at equal levels of SPO2 and PCO2 was lower by 13.3 +/- 2.4 l/min on day 2 (SPO2 = 86.2 +/- 2.3) and by 5.9 +/- 3.5 l/min on day 12 (SPO2 = 91.0 +/- 1.5; P < 0.05). This lower ventilation was estimated (from HCVR) to be equivalent to an elevation of the central chemoreceptor PCO2 set point of 9.2 +/- 2.1 Torr on day 2 and 4.5 +/- 1.3 on day 12.(ABSTRACT TRUNCATED AT 250 WORDS)

To honour Siggaard-Andersen’s role in the development of accurate blood oximetry, this paper was abstracted from a recent review and survey of over 750 publications of pulse oximetry. Pulse oximetry usage has become nearly universal during anesthesia and related critical care in the developed world during the last decade. More than 35 manufacturers offer pulse oximetry. Costs of some have fallen to less than $1500 per device, with no necessary on-going charges. Pulse oximeters are remarkable: Accuracy is +/- 2% down to 70% SaO2 without any user calibration, no drift, instantaneous readout, and almost no maintenance or safety problems. New developments include better understanding of management of premature infants, beginning use for fetal SaO2 during labor, sophisticated methods of ignoring motion artifacts and room light interference, and awareness of sources of error. Oximetry use has caused anesthesiologists and most critical care physicians to become far more able to avoid severe hypoxia in patients. Malpractice insurance rates for anesthesiologists have dropped in the USA, and other evidence suggests, although failing to prove, that anesthesia and critical care is now safer, probably due to oximetry.

The topographic relationship between previously identified medullary ventral surface respiratory chemosensitive regions and brain surface extracellular fluid (ECF) acid production during acute hypoxia was explored in anesthetized, paralyzed, and artificially ventilated cats. Glass pH electrodes (0.8-mm diam, sheathed in stainless steel tubing) were mounted in mechanical contact with surfaces of medullary surface or adjacent pyramids, pons, spinal cord, or parietal cortex. Isocapnic hypoxia of 5 min [at arterial O2 saturation (SaO2) = 48 +/- 10%] reduced pH over rostral (Mitchell) and caudal (Loeschcke) areas by 0.12 +/- 0.09 and 0.07 +/- 0.04, respectively (n = 10, P < 0.05). Change in pH (delta pH) was proportional to desaturation with slopes 100 delta pH/delta SaO2 of 0.45 (rostral) and 0.20 (caudal) (R = 0.91 and 0.88, respectively). pH drop usually began within 3 min of hypoxia, became stable between 5 and 15 min, began to rise within 2 min of reoxygenation, and returned to control within 10 min. During equally hypoxic tests, intermediate area (Schläfke), pons, and spinal cord surfaces showed no significant acid shift. Parietal cortex ECF pH dropped more slowly but steadily by 0.079 +/- 0.034 during 20 min at SaO2 = 50% after a small but significant initial alkaline shift, and acidification of cortical surface continued for > 5 min after reoxygenation. We conclude that medullary ventral chemosensitive regions produce more lactic acid during hypoxia than neighboring brain surfaces.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that the hypoxic ventilatory response (HVR) of an individual is a constant unaffected by acclimatization, isocapnic 5-min step HVR, as delta VI/delta SaO2 (l.min-1.%-1, where VI is inspired ventilation and SaO2 is arterial O2 saturation), was tested in six normal males at sea level (SL), after 1-5 days at 3,810-m altitude (AL1-3), and three times over 1 wk after altitude exposure (PAL1-3). Equal medullary central ventilatory drive was sought at both altitudes by testing HVR after greater than 15 min of hyperoxia to eliminate possible ambient hypoxic ventilatory depression (HVD), choosing for isocapnia a P’CO2 (end tidal) elevated sufficiently to drive hyperoxic VI to 140 ml.kg-1.min-1. Mean P’CO2 was 45.4 +/- 1.7 Torr at SL and 33.3 +/- 1.8 Torr on AL3, compared with the respective resting control end-tidal PCO2 of 42.3 +/- 2.0 and 30.8 +/- 2.6 Torr. SL HVR of 0.91 +/- 0.38 was unchanged on AL1 (30 +/- 18 h) at 1.04 +/- 0.37 but rose (P less than 0.05) to 1.27 +/- 0.57 on AL2 (3.2 +/- 0.8 days) and 1.46 +/- 0.59 on AL3 (4.8 +/- 0.4 days) and remained high on PAL1 at 1.44 +/- 0.54 and PAL2 at 1.37 +/- 0.78 but not on PAL3 (days 4-7). HVR was independent of test SaO2 (range 60-90%). Hyperoxic HCVR (CO2 response) was increased on AL3 and PAL1. Arterial pH at congruent to 65% SaO2 was 7.378 +/- 0.019 at SL, 7.44 +/- 0.018 on AL2, and 7.412 +/- 0.023 on AL3.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of elevated intracranial pressure (ICP) on intracellular oxygenation and cerebrocortical blood volume (CBV) were studied in rabbits. Intracellular oxygen (O2) concentration was assessed as the level of pyridine nucleotide concentration ([NADH]) oxidation/reduction balance and relative cerebrocortical blood volume (CBV) were measured with a fibreoptic fluororeflectometer probe placed on the cerebrocortical surface. Experiments were conducted in six urethane anaesthetized, normocarbic animals at different fractions of inspired O2 (FIO2). During gradual increases in ICP, [NADH] began to increase (representing decreased intracellular mitochondrial PO2) for all values of FIO2 as ICP exceeded a threshold of 18 +/- 2.2 cmH2O (P less than 0.05). The decline in intracellular oxygenation with elevated ICP was inversely related to FIO2 (P less than 0.05). With ICP greater than 18 +/- 2.2 cmH2O, intracellular mitochondrial oxygenation showed an improvement between an FIO2 of 0.21 and 0.5 (P less than 0.05) but increasing FIO2 from 0.5 to 1.0 resulted in no statistically significant improvement in tissue redox balance. The CBV, largely representing tissue capillary blood, increased when ICP reached greater 18 +/- 1.2 cmH2O probably reflecting local autoregulation or venous distension (P less than 0.05). However, above 30 +/- 1.1 cmH2O, CBV decreased (P less than 0.05). The results demonstrate the interdependence of inspired oxygen concentration, elevated ICP, and brain intracellular oxygenation, and suggest that brain oxygen utilization deteriorates above an ICP of about 18 cmH2O.

We have measured the ventilatory responses to increased inspired carbon dioxide and to hypoxia in four goats awake and at 0.5%, 1.0% and 1.25% end-tidal halothane concentration. While maintaining PE’CO2 constant at each of three values (means 5.86, 6.45 and 7.2 kPa), PE’O2 was reduced rapidly from more than 25 kPa to 5.3-6 kPa for 3 min to record the increase in ventilation. Eleven sets of these 24 steady state points were obtained (2 PO2 x 3 PCO2 x 4 anaes. = 24). The mean isocapnic hypoxic ventilatory response (HVR) was 6.52 (SD 2.58) litre min-1 (n = 33) when awake, 5.62 (3.48) litre min-1 at 0.5% end-tidal halothane (ns), 3.05 (2.02) litre min-1 at 1% and 2.91 (2.12) litre min-1 at 1.25%, the last two being reduced significantly from awake and 0.5% halothane (P less than 0.05). With 1.25% halothane, HVR was reduced to 44.5 (18.6)% of the awake HVR. However, when HVR was expressed as % increase in ventilation produced by isocapnic hypoxia, it was 71 (19)% awake but 124 (65)% with 1.25% halothane, a significant increase with halothane (P less than 0.05). With 1.25% halothane, the carbon dioxide response slope decreased to 36.4 (26.4)% of control; hypoxia did not increase the slope significantly. Whereas previous studies in man have shown that halothane preferentially depresses hypoxic chemosensitivity and has a significant effect at 0.1 MAC, in the goat the hypoxic and carbon dioxide chemosensitivities were depressed equally. At 0.5% end-tidal concentration (about 0.5 MAC), halothane did not significantly depress hypoxic response.

The degree of systolic hypotension causing failure and recovery were tested simultaneously with three oximeters (CSI 504US, Nellcor N-200, and Ohmeda 3740) in nine normal male volunteers. Perfusion of the right hand was slowly reduced and restored by 1) elevation of the hand plus systemic hypotension with nitroprusside if needed (EL); 2) clamp compression of the brachial artery (CL); 3) brachial cuff inflation (CU); and 4) intraarterial norepinephrine (NE). With EL, pulse pressure was normal whereas right radial arterial systolic pressure (SP) was 25.3 +/- 12.4 mmHg at failure and 34.1 +/- 13.3 at recovery (mean of three oximeters, n = 189). With CL, pulse pressure fell more than did mean pressure, and failure occurred at 37.3 +/- 9.8 and recovery at 46.8 +/- 17.6 mmHg, n = 84. With CL, threshold of function, defined as the average of failure SP and recovery SP, was 47.1 +/- 13.5, n = 41 for Nellcor, higher than for either CSI (38.7 +/- 14.5, n = 17) or Ohmeda (36.0 +/- 3.4, n = 26) (P less than 0.05). With EL, no difference among instruments was found (mean 29.7 +/- 12.8, n = 189). Threshold was 58.2 +/- 8.4, n = 17 with CU if cuff inflation was slow (filling veins), but recovery was similar to EL after rapid cuff occlusion. With NE, SP threshold was increased to 58.3 +/- 21.0 with CL but only to 41.0 +/- 13.8 with EL.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter study used 756 samples from 251 patients in 12 institutions to compare arterial (PaO2, PaCO2) with transcutaneous (PsO2, PsCO2) oxygen and carbon dioxide tensions, measured usually at 44 degrees C. Of these samples, 336 were obtained from 116 neonates, 27 from 25 children with cystic fibrosis, and 140 from 40 patients under general anesthesia. Ninety-one patients were between 4 weeks and 18 years of age, 32 were between 18 and 60 years, and 12 were over 60. The ratio of transcutaneous to arterial P(s/a)CO2 was 1.01 +/- 0.11 with PaCO2 less than 30 mm Hg, increasing to 1.04 +/- 0.08 at PaCO2 greater than 40 mm Hg. Mean bias and its standard deviation (PsCO2 – PaCO2) were + 1.3 +/- 3.9 mm Hg in the entire group, + 1.8 +/- 4.2 mm Hg in neonates (NS). Bias was + 0.2 +/- 2.7 mm Hg when PaCO2 was less than 30 mm Hg (N = 175, NS), 1.0 +/- 3.4 with 30 less than PaCO2 less than 40 (n = 329, p less than 0.001), and + 2.04 +/- 4.00 mm Hg with 40 less than PaCO2 less than 70 (n = 229, p less than 0.001). These data suggest that, using transcutaneous PCO2 monitors with inbuilt temperature correction of 4.5%/degrees C, the skin metabolic offset should be set to 6 mm Hg. The linear regression was PsCO2 = 1.052(PaCO2) – 0.56, Sy.x = 3.92, R = 0.929 (n = 756); and PsCO2 = 1.09(PaCO2) – 1.57, Sy.x = 4.17, R = 0.928 in neonates (n = 336).(ABSTRACT TRUNCATED AT 250 WORDS)

A retrospective evaluation of simultaneous tests of oximeters of various manufacturers in volunteer subjects disclosed greater errors at low saturations in subjects with low hemoglobin (Hb) concentrations. Forty-three pulse oximeters of 12 manufacturers studied over a period of 10 months showed that, at a mean arterial oxygen saturation (SaO2) level of 54.5%, as Hb concentration fell, average pulse oximeter (SpO2) bias increased approximately linearly from 0 at Hb greater than 14 g/dl to about -14% at 8 less than Hb less than 9 g/dl. At SaO2 = 53.6%, the mean bias (SaO2–SpO2) of 13 oximeters of 5 manufacturers averaged -15.0% (n = 43) in a subject with Hb = 8 g/dl, but -6.4% (n = 390) in nonanemic subjects. The additional bias in the anemic subject increased with desaturation. It was 0.13% at SaO2 = 98.5% (n = 13), -1.31% at 87.5% (n = 38), -2.71% at 75.1% (n = 38), -5.18% at 61.3% (n = 26), and -9.95% at 53.6% (n = 41); n is the product of the number of oximeters and number of tests in each saturation range. The instruments that showed the greatest errors at low saturations in nonanemic subjects also showed the greatest additional errors associated with anemia (the range between manufacturers of anemic incremental error at about 53% being from -3.2 to -14.5%) and conformed well to the relationship bias (anemic) = 1.35 x bias (normal) -8.18% (r = 0.94; Sy.x = 3.3%). The error due to anemia was zero at 97% SaO2 and became evident when SaO2 fell below 75%.

Low arterial CO2 tension (PaCO2) experienced by birds during high-altitude flight may result in cerebral vasoconstriction with reduced cerebral O2 delivery. To test this, brain redox balance and blood volume were studied during severe hypocapnia (PaCO2 11-20 mmHg) in ducks. Cerebrocortical redox balance, measured as relative [NADH], and blood volume were measured simultaneously with a fiber-optic fluorometer-reflectometer. Cerebrocortical blood volume (an index of blood flow) fell nearly linearly with PaCO2 during severe hypocapnia, even during severe hypoxemia. Cerebrocortical redox balance was shifted toward reduction of NADH ([NADH] increased) by both hypoxemia and hypocapnia. If hypocapnia causes similar changes in brain blood flow during high-altitude flight, tissue hypoxia will be exacerbated. Tolerance of brain tissue hypoxia during flight may be an important adaptation in high-flying birds.

The accuracy of pulse oximeters from fourteen manufacturers was tested during profound brief hypoxic plateaus in 125 subject sets using 50 normal adult volunteers, of whom 29 were studied two to nine times. A data set usually consisted of 10 subjects, and 13 sets were collected between August 1987 and July 1988. In the first 6 sets, six 30-second hypoxic plateaus were obtained per subject at 55 +/- 6% oxyhemoglobin (O2Hb) (range, 40 to 70%). In the last 7 sets, three hypoxic plateaus were obtained at each of four levels, approximately 86, 74, 62, and 50% O2Hb, for the purpose of linear regression analysis. Inspired oxygen was adjusted manually breath by breath in response to arterial oxygen saturation computed on-line from end-tidal oxygen and carbon dioxide tensions. End-plateau arterial blood O2Hb was analyzed by a Radiometer OSM-3 oximeter, and plateau pulse oximeter saturation (SpO2) was read by cursor from a computer record of the analog output. Three to 13 instruments were tested simultaneously by using 1 to 3 duplicate instruments from each of one to seven manufacturers. Variations introduced by manufacturers were tested on subsequent sets in several instruments. An index of error, “ambiguity” (alpha) of oxygen saturation, was defined as the absolute sum of bias and precision (mean and SD of SpO2 – O2Hb) at O2Hb = 55.8 +/- 4.5%, preserving the sign when bias was significant at P less than 0.05. Ambiguity values for finger probes (unless specified) with latest data were: Physio-Control, 3.9 (ear, 3.3); Puritan-Bennett, -4.4; Criticare, 5.8 (forehead, 4.7); Kontron, 5.9 (infant probe) and 6.1 (ear, 5.8; forehead, 7.1); Biochem, -6.0; Datex 6.4 (ear, 6.9; forehead, 6.8); Critikon, 8.4; SiMed, 8.6; Marquest, 9.0; Novametrix, 10.2; Invivo, -12.2 (ear, -14.3); Nellcor, -15.1; Ohmeda, -21.2; and Radiometer, -21.2 (ear, -9.6). Linear regression slopes of 36 instruments from twelve manufacturers generally deviated from 1 in proportion to alpha. The data showed substantial differences in bias and precision between pulse oximeters at low saturations, the most common problems being underestimation of saturation and failing precision.

Acetazolamide (AZ) inhibition of brain and blood carbonic anhydrase increases cerebral blood flow by acidifying cerebral extracellular fluid (ECF). This ECF acidosis was studied to determine whether it results from high PCO2, carbonic acidosis (accumulation of H2CO3), or lactic acidosis. Twenty rabbits were anesthetized with pentobarbital sodium, paralyzed, and mechanically ventilated with 100% O2. The cerebral cortex was exposed and fitted with thermostatted flat-surfaced pH and PCO2 electrodes. Control values (n = 14) for cortex ECF were pH 7.10 +/- 0.11 (SD), PCO2 42.2 +/- 4.1 Torr, PO2 107 +/- 17 Torr, HCO3- 13.8 +/- 3.0 mM. Control values (n = 14) for arterial blood were arterial pH (pHa) 7.46 +/- 0.03 (SD), arterial PCO2 (PaCO2) 32.0 +/- 4.1 Torr, arterial PO2 (PaO2) 425 +/- 6 Torr, HCO3- 21.0 +/- 2.0 mM. After intravenous infusion of AZ (25 mg/kg), end-tidal PCO2 and brain ECF pH immediately fell and cortex PCO2 rose. Ventilation was increased in nine rabbits to bring ECF PCO2 back to control. The changes in ECF PCO2 then were as follows: pHa + 0.04 +/- 0.09, PaCO2 -8.0 +/- 5.9 Torr, HCO3(-)-2.7 +/- 2.3 mM, PaO2 +49 +/- 62 Torr, and changes in cortex ECF were as follows: pH -0.08 +/- 0.04, PCO2 -0.2 +/- 1.6 Torr, HCO3(-)-1.7 +/- 1.3 mM, PO2 +9 +/- 4 Torr. Thus excess acidity remained in ECF after ECF PCO2 was returned to control values. The response of intracellular pH, high-energy phosphate compounds, and lactic acid to AZ administration was followed in vivo in five other rabbits with 31P and 1H nuclear magnetic resonance spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide (AZ), a potent carbonic anhydrase inhibitor in human and animal tissues, increases cerebral blood flow (CBF) by acidifying cerebral extracellular fluids. To demonstrate the relationship of increased CBF to brain O2 availability after AZ administration, a compensated fluorometer was used to study changes in the cerebrocortical redox balance in rabbits. Seven rabbits were anesthetized with pentobarbital sodium. Excitation light (366 nm) was conducted to the cerebrocortical surface of each animal by a 4-mm-diam fiberoptic light guide. Fluorescence emissions from cerebrocortical NADH (450 nm) were compared at different inspired O2 (FIO2) tensions. Reflected light (366 nm), which was used to determine a correction to the fluorescence signal, was separately quantitated and interpreted as an index of cerebrocortical blood volume. Reductions in FIO2 from 1.0 to 0.21, 0.14, 0.10, and 0.07 resulted in increases in both tissue blood volume and [NADH]. Intravenous AZ (25 mg/kg) increased cerebrocortical blood volume and reduced the [NADH], even during ventilation with 100% O2. The changes in brain redox balance caused by vasodilation with AZ were compared with those caused by vasodilatation with CO2. The NAD+/NADH redox state was a continuous function of FIO2 at all levels of arterial PCO2 (PaCO2), both before and after AZ administration. The improvement in cerebral O2 delivery caused by AZ-induced vasodilation was comparable to that caused by the vasodilatation that results from a PaCO2 elevation approximately equal to 12-15 Torr above normal. The slope of the relationship between [NADH] and FIO2 was similar at normal, low, and high levels of PaCO2. We conclude that AZ administration and PaCO2 elevation improve cerebral oxygenation by similar mechanisms.

The Hazinski method is an indirect, noninvasive, and maskless CO2-response test useful in infants or during sleep. It measures the classic CO2-response slope (i.e., delta VI/delta PCO2) divided by resting ventilation Sr = (VI”–VI’)/(VI’.delta PCO2) between low (‘)- and high (”)-inspired CO2 as the fractional increase of alveolar ventilation per Torr rise of PCO2. In steady states when CO2 excretion (VCO2′) = VCO2”, Hazinski CO2-response slope (Sr) may be computed from the alveolar exchange equation as Sr = (PACO2′–PICO2′)/(PACO2’–PICO2”) where PICO2 is inspired PCO2. To avoid use of a mask or mouthpiece, the subject breathes from a hood in which CO2 is mixed with inspired air and a transcutaneous CO2 electrode is used to estimate alveolar PCO2 (PACO2). To test the validity of this method, we compared the slopes measured simultaneously by the Hazinski and standard steady-state methods using a pneumotachograph, mask, and end-tidal, arterial, and four transcutaneous PCO2 samples in 15-min steady-state challenges at PICO2 23.5 +/- 4.5 and 37 +/- 4.1 Torr. Sr was computed using PACO2 and arterial PCO2 (PaCO2) as well as with the four skin PCO2 (PSCO2) values. After correction for apparatus dead space, the standard method was normalized to resting VI = 1, and its CO2 slope was designated directly measured normalized CO2 slope (Sx), permitting error to be calculated as Sr/Sx.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen saturation, SpO2%, was recorded during rapidly induced 42.5 +/- 7.2-s plateaus of profound hypoxia at 40-70% saturation by 1 or 2 pulse oximeters from each of six manufacturers (NE = Nellcor N100, OH = Ohmeda 3700, NO = Novametrix 500 versions 2.2 and 3.3 (revised instrumentation), CR = Criticare CSI 501 + version .27 and version .28 in 501 & 502 (revised instrumentation), PC = PhysioControl Lifestat 1600, and MQ = Marquest/Minolta PulseOx 7). Usually, one probe of each pair was mounted on the ear, the other on a finger. Semi-recumbent, healthy, normotensive, non-smoking caucasian or asian volunteers (age range 18-64 yr) performed the test six to seven times each. After insertion of a radial artery catheter, subjects hyperventilated 3% CO2, 0-5% O2, balance N2. Saturation ScO2, computed on-line from mass spectrometer end-tidal PO2 and PCO2, was used to manually adjust FIO2 breath by breath to obtain a rapid fall to a hypoxic plateau lasting 30-45s, followed by rapid resaturation. Arterial HbO2% (Radiometer OSM-3) sampled near the end of the plateau averaged 55.5 +/- 7.5%. ScO2% (from the mass spectrometer) and SaO2% (from pH and PO2, by Corning 178) differed from HbO2% by + 0.2 +/- 3.6% and 0.4 +/- 2.8%, respectively. The mean and SD errors of pulse oximeters (vs. HbO2%) were: (table; see text) The plateaus were always long enough to permit instruments to demonstrate a plateau with ear probes, but finger probes sometimes failed to provide plateaus in subjects with peripheral vasoconstriction. Nonetheless, SpO2 read significantly too low with finger probes at 55% mean SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulse oximetry is based on a relatively new concept, using the pulsatile variations in optical density of tissues in the red and infrared wavelengths to compute arterial oxygen saturation without need for calibration. The method was invented in 1972 by Takuo Aoyagi, a bioengineer, while he was working on an ear densitometer for recording dye dilution curves. Susumu Nakajima, a surgeon, and his associates first tested the device in patients, reporting it in 1975. A competing device was introduced and also tested and described in Japan. William New and Jack Lloyd recognized the potential importance of pulse oximetry and developed interest among anesthesiologists and others concerned with critical care in the United States. Success brought patent litigation and much competition.

Several respiratory variables were examined in 11 healthy elderly (greater than 60 years) and 12 younger (30-39 years) control subjects during all-night sleep runs, with a view to determining the effect of the aging process on breathing during sleep. O2 saturation, end-tidal PCO2, and transcutaneous PCO2 were monitored, together with standard sleep staging measures. Estimates of tidal volume (Vt) and ventilation (Ve) were obtained using a Respitrace inductive plethysmography system, from which respiratory rate (fb) was also measured. Older subjects had more sleep apnea/hypopnea than younger subjects, an incidence of 55 versus 8%, respectively. More of their arousals were associated with respiratory disturbance than those of the younger subjects, and they had more brief, but not longer, arousals. Mean O2 saturation was lower in older subjects during wakefulness but did not decrease more in older subjects than in control subjects during sleep. Mean end-tidal/transcutaneous PCO2 did not differ between groups during wakefulness or sleep. Vt and Ve estimates did not decrease during slow wave sleep in older subjects as they did in the younger subjects. It was concluded that aging by itself does not significantly alter average sleep-related changes in O2 saturation or PCO2, although the increased incidence of respiratory disturbance does produce transient swings in these variables. The lack of a decrease in ventilation estimates during sleep in spite of the usual changes in O2 saturation and PCO2 in the older group indicates a possible decrease in effective gas exchange.

Oximetry, the measurement of hemoglobin oxygen saturation in either blood or tissue, depends on the Lambert-Beer relationship between light transmission and optical density. Shortly after Bunsen and Kirchhoff invented the spectrometer in 1860, the oxygen transport function of hemoglobin was demonstrated by Stokes and Hoppe-Seyler, who showed color changes produced by aeration of hemoglobin solutions. In 1932 in Göttingen, Germany, Nicolai optically recorded the in vivo oxygen consumption of a hand after circulatory occlusion. Kramer showed that the Lambert-Beer law applied to hemoglobin solutions and approximately to whole blood, and measured saturation by the transmission of red light through unopened arteries. Matthes in Leipzig, Germany, built the first apparatus to measure ear oxygen saturation and introduced a second wavelength (green or infrared) insensitive to saturation to compensate for blood volume and tissue pigments. Millikan built a light-weight ear “oximeter” during World War II to train pilots for military aviation. Wood added a pneumatic cuff to obtain a bloodless zero. Brinkman and Zijlstra in Groningen, The Netherlands, showed that red light reflected from the forehead could be used to measure oxygen saturation. Zijlstra initiated cuvette and catheter reflection oximetry. Instrumentation Laboratory used multiple wavelengths to measure blood carboxyhemoglobin and methemoglobin is cuvette oximeters. Shaw devised an eight-wavelength ear oximeter. Nakajima and co-workers invented the pulse oximeter, which avoids the need for calibration with only two wavelengths by responding only to the pulsatile changes in transmitted red and infrared light. Lübbers developed catheter tip and cuvette fiberoptic sensors for oxygen tension, carbon dioxide tension, and pH.

The first biologic use of a platinum cathode for oxygen monitoring was reported in 1938 by Blinks and Skow, who was studying photosynthesis. Their report led to the tissue oxygen studies of Davies, Brink, and Bronk. Clark, by covering cathode and anode with a polyethylene membrane, changed the polarographic cathode from a sensor of oxygen availability by diffusion to a measure of oxygen tension (PO2) in the solution and thereby facilitated an enormous expansion of the study of the respiratory physiology of blood oxygen after 1956. Clark’s electrode led to the development of the present commercial blood gas systems that measure pH, carbon dioxide tension (PCO2), and PO2 and calculate many derived variables. Variations on Clark’s electrode were designed for in vivo catheter-tip recording; gas phase oxygen monitoring; determining oxygen content of blood by releasing hemoglobin-bound oxygen and measuring PO2; and determining oxygen consumption in cell cultures (thus replacing Warburg manometry). By reducing the cathode diameter, Staub and others eliminated the need for stirring the blood samples. Concurrent research with amperometric or polarographic oxygen measurement led Hersch to develop the means of determining oxygen content by coulometry in large cells that consumed all the injected oxygen. Methods of applying noninsulating, but protein impermeable, membranes to cathodes and of recessing cathodes into glass permitted measurement of PO2 in tissues and fluids with microelectrodes.

The electrochemical reduction of oxygen was discovered by Heinrich Danneel and Walter Nernst in 1897. Polarography using dropping mercury was discovered accidentally by Jaroslav Heyrovsky in Prague in 1922. This method produced the first measured oxygen tension values in plasma and blood in the 1940s. Brink, Davies, and Bronk implanted platinum electrodes in tissue to study oxygen supply, or availability, from about 1940, but these bare electrodes became poisoned when immersed in blood. Leland Clark sealed a platinum cathode in glass and covered it first with cellophane; he then tested silastic and polyethylene membranes. In 1954 Clark conceived and constructed the first membrane-covered oxygen electrode having both the anode and cathode behind a nonconductive polyethylene membrane. The limited permeability of polyethylene to oxygen reduced depletion of oxygen from the sample, making possible quantitative measurements of oxygen tension in blood, solutions, or gases. This invention led to the introduction of modern blood gas apparatus.

The measurement of carbon dioxide tension (Pco2) owes its development to the 1952 polio epidemics in Copenhagen and the United States, during which artificial ventilation was first widely and effectively used and it was necessary to assess its effectiveness. Pco2 had been determined by various “bubble methods” in which carbon dioxide (CO2) was measured in gas equilibrated with blood at body temperature, or by one of two methods using the manometric apparatus of Van Slyke: interpolation on a plot of CO2 content versus equilibration gas Pco2 or use of the Henderson-Hasselbalch equation to calculate Pco2 from pH and plasma CO2 content. In 1954 Richard Stow described a CO2 electrode–a new concept–using a rubber membrane permeable to CO2 to separate a wet pH and reference electrode from the blood sample. This was the first membrane electrode, a device now used in hundreds of different ways. Severinghaus developed Stow’s electrode, stabilizing it with a bicarbonate-salt solution and a spacer. The CO2 electrode concept had occurred to Gesell in 1925, but for measurement of gas only, and to Gertz and Loeschcke, who were unaware of the Stow-Severinghaus electrode, in 1958. The development of the CO2 electrode terminated the use of bubble methods, the Van Slyke methods, and the Astrup technique and at the same time reinforced the Astrup-Siggaard-Andersen acid-base analytic theory.

31P nuclear magnetic resonance (NMR) spectroscopy was used noninvasively to measure in vivo changes in intracellular pH and intracellular phosphate metabolites in the brains of rats during supercarbia (PaCO2 greater than or equal to 400 mm Hg). Five intubated rats were mechanically ventilated with inspired gas mixtures containing 70% CO2 and 30% O2. Supercarbia in the rat was observed to cause a greater reduction in cerebral intracellular pH (pHi) and increase in PCO2 than observed in other experiments with rats after 15 min of global ischemia. Complete neurologic and metabolic recovery was observed in these animals, despite and average decrease in pHi of 0.63 +/- 0.02 pH unit during supercarbia episodes that raised PaCO2 to 490 +/- 80 mm Hg. No change was observed in cerebral intracellular ATP and only a 25% decrease was detected in phosphocreatine. The concentration of free cerebral intracellular ADP, which can be calculated if one assumes that the creatine kinase reaction is in equilibrium, decreased to approximately one-third of its control value. The calculated threefold decrease in the concentration of free ADP and twofold increase in the cytosolic phosphorylation potential suggest that there is increased intracellular oxygenation during supercarbia. Because a more than fourfold increase in intracellular hydrogen ion concentration was tolerated without apparent clinical injury, we conclude that so long as adequate tissue oxygenation and perfusion are maintained, a severe decrease in intracellular pH need not induce or indicate brain injury.

Electrometric measurement of the hydrogen ion concentration was discovered by Wilhelm Ostwald in Leipzig about 1890 and described thermodynamically by his student Walther Nernst, using the van’t Hoff concept of osmotic pressure as a kind of gas pressure, and the Arrhenius concept of ionization of acids, both of which had been formalized in 1887. Hasselbalch, after adapting the pH nomenclature of Sørensen to the carbonic-acid mass equation of Henderson, made the first actual blood pH measurements (with a hydrogen electrode) and proposed that metabolic acid-base imbalance be quantified as the “reduced” pH of blood after equilibration to a carbon dioxide tension (PCO2) of 40 mm Hg. This good idea, coming 40 years before simple blood pH measurements at 37 degrees C became widely available, was never adopted. Instead, Van Slyke developed a concept of acid-base chemistry that depended on measuring plasma CO2 content with his manometric apparatus, a standard method until the 1960s, when it was displaced by the three-electrode method of blood gas analysis. The 1952 polio epidemic in Copenhagen stimulated Astrup to develop a glass electrode in which pH could be measured in blood at 37 degrees C before and after equilibration with known PCO2. He introduced the interpolative measurement of PCO2 and bicarbonate level (later base excess) using only pH measurements and, with Siggaard-Andersen, developed clinical acid-base chemistry. Controversy arose when blood base excess was noted to be altered by acute changes in PCO2 and when abnormalities of base excess were called metabolic acidosis or alkalosis, even when they represented compensation for respiratory abnormalities in PCO2. In the 1970s it became clear that “in-vivo” or “extracellular fluid” base excess (measured at an average extracellular fluid hemoglobin concentration of 5 g) eliminated the error caused by acute changes in PCO2. Base excess is now almost universally used as the index of nonrespiratory acid-base imbalance.

In 1982 Poul Astrup, in writing a history of acid base balance and blood gases, invited me to contribute a chapter about the modern period, from 1950 to the present. Astrup’s book is scheduled for publication at the end of 1985 by Radiometer Company of Copenhagen; it will be distributed by Munksgaard (Blackwell). The story of blood gas analysis since 1950 is vast: there are some 420 references to methodology and closely related physiology. This “modern” history will appear in the Journal of Clinical Monitoring as a series of essays. This first essay centers on electrochemistry, the basis of modern blood gas analysis, and accordingly examines its roots in more detail. The 17th and 18th century exploration of electricity and gas laws led to the development of thermodynamic electrochemistry in 1887 through the collaborative efforts of van’t Hoff, Arrhenius, Ostwald, and Nernst. The importance of the hydrogen ion in biology and in the body’s buffering mechanisms was worked out by Henderson, Van Slyke, Barcroft, and many others in the first quarter of this century. The glass electrode became available after 1925, but practical blood pH measurement was introduced in the 1950s by Astrup and Siggaard Andersen. Succeeding essays will concern micro pH methods and base excess analysis, the discoveries of Stow’s CO2 electrode and Clark’s O2 electrode, the development of oximetry, and related physiology.

Using only skin surface blood gas measurements, we calculated the ventilatory response to inhaled carbon dioxide from changes in skin surface PCO2 (PSCO2). This new method is based on the fact that if CO2 elimination is nearly constant, the change in alveolar ventilation from one steady state level to another is inversely proportional to the change in PSCO2. From this we derived a ventilatory ratio (VR) for 0%, 2%, and 4% CO2 breathing. A ventilatory response slope is then calculated from the three VR values, and is similar to a standard CO2 response slope. We serially studied 20 infants (28 to 40 weeks gestation) 2 to 9 weeks of age. Ten infants had serious apnea, ten did not. The infants breathed each test gas for 8 to 10 minutes during quiet sleep with skin surface electrodes attached. Infants with apnea were studied before and after apneic spells resolved. We found that apneic infants had a significantly reduced VR slope compared with that in the nonapneic infants, regardless of age. When apnea disappeared, the ventilatory ratio slope always increased into the range measured in nonapneic infants. In nonapneic infants the ventilatory ratio slope significantly increased with postnatal age. We conclude that infants with serious apnea have a reduced ventilatory response to CO2 and that the resolution of apnea is associated with the development of a normal CO2 response.

Commercially available skin surface PCO2 sensors, when properly maintained, calibrated, and applied, report arterial PCO2 over a wide range of values and in virtually all clinical conditions to an accuracy of +/- 3 torr. Inappropriate mathematical treatment of in vivo skin surface-arterial PCO2 comparisons has led to controversy regarding the precise relationship between these variables. The proper method of calibration involves applying a temperature correction factor of 4.5%/degrees C to the calibration gas setting, and subtracting 4 torr by offsetting zero. For analysis of accuracy, the resulting corrected values should be used to determine the mean and standard deviation of the skin surface:arterial PCO2 ratio. Tests of correlation as a function of PaCO2 require deliberate wide variation of PCO2 within each subject of a test group. Skin surface PCO2 monitors record blood gas tensions continuously and noninvasively, and they can be used to study cardiorespiratory function in normal subjects, in whom arterial blood sampling would be difficult to justify–two distinct advantages of the devices.

We have prepared an algorithm describing the relationship of tcPO2 to PaO2 and used this with measured values of both tcPO2 and PaO2 under four conditions (two PO2 levels, two temperatures) to generate four equation sets that yielded unique solutions for the four unknown parameters. In adults under a 44 degree C electrode, capillary temperature averaged about 43 degrees C, O2 consumption about 0.0042 ml/gm/min, blood flow about 0.64 ml/gm/min, and diffusion gradient, D, about 32 mm Hg. We have not attempted to define these values in premature or normal newborn infants, because the method requires about one hour of exposure to 100% O2.

Transcutaneous PCO2 electrodes habe been constructed and evaluated on adults and children. Glass pH and silver reference electrodes were used at 44–45 degrees C, with either circulating water and a copper jacket, or with internal electrical heating. The skin surface PCO2 at 44 degrees C is about 1.33 times PaCO2 plus 3 mmHg when measured with electrodes calibrated in gas at 44 degrees C. Three temperature effects combine in this ratio: Heating raises blood PCO2 4.5%/degrees C, skin metabolism adds about 3 mmHg, and the cooling of the electrode active surface by skin increases electrode reading. Response time to step changes of PaCO2 was about 3 min to 63%, of which 1.2 min was sensor delay, the remainder skin CO2 washout. It was found important to use ethylene glycol-water mixtures rather than water for electrolyte to avoid bubble generation and drift. Heat transfer through the pH glass electrode has been increased by enlarging the internal silver electrode to virtually fill the entire glass electrode. Time required for initial vasodilation and stabilization is similar to that of tcPO2 electrodes, and accuracy of determination of PaCO2 appears to be better than +/- mmHg.