Effects of Acute, Profound Hypoxia on Healthy Humans: Implications for Safety of Tests Evaluating Pulse Oximetry or Tissue Oximetry Performance.

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.

The Most Important Discovery of Science.

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.

Eight sages over five centuries share oxygen's discovery.

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.

Crediting six discoverers of oxygen.

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.

Monitoring oxygenation.

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.

Unfinished physiology.

The following was an invited pre-dinner commentary to the standing group waiting for supper, light heartedly suggesting several still unsettled physiologic problems in need of study.

History of measuring O2 and CO2 responses.

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.

Takuo Aoyagi: discovery of pulse oximetry.

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.

Dark skin decreases the accuracy of pulse oximeters at low oxygen saturation: the effects of oximeter probe type and gender.

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.

HIGH LIFE: High altitude fatalities led to pulse oximetry.

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.

L-arginine supplementation enhances exhaled NO, breath condensate VEGF, and headache at 4,342 m.

We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4,342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.

Fire-air and dephlogistication. Revisionisms of oxygen's discovery.

Americans are taught that Joseph Priestley discovered oxygen in 1774 and promptly brought that news to Lavoisier. Lavoisier proved that air contained a new element, oxygen, which combined with hydrogen to make water. He disproved the phlogiston theory but Priestley called it dephlogisticated air until his death 30 years later. Scandanavians learn that a Swedish apothecary Carl Wilhelm Scheele beat Priestley by 2 years but was deprived of credit because Lavoisier denied receiving a letter Scheele later claimed to have sent in September 1774 describing his 1772 discovery of "fire air". His claim was unconfirmed because Scheele first published his work in 1777. However, Scheele's missing letter was made public in 1992 in Paris, 218 years late, and now resides at the French Academie de Sciences. Lavoisier received it on Oct 15, 1774. His guilt was kept secret in the effects of Madame Lavoisier. He failed on several occasions to credit either Priestley or Scheele for contributing to the most important discovery in the history of science. Priestley was a teacher, political philosopher, essayist, Unitarian minister and pioneer in chemical and electrical science. He discovered 9 gases including nitrous oxide. He invented soda water, refrigeration, and gum erasers for which he coined the term "rubber". He discovered photosynthesis. He was humorless, argumentative, brilliant and passionate, called a "furious free-thinker". While his liberal colleagues Josiah Wedgwood, Erasmus Darwin, James Watts, and others of the Lunar Society were celebrating the 2nd anniversary of the French revolution, a Birmingham mob, supported by the royalists and the established church, destroyed Priestley's home, laboratory and church. Driven from England, he emigrated to Pennsylvania where he built a home and laboratory and collected a 1600 volume library, then among the largest in America. He is regarded as a founder of liberal Unitarian thinking. He was friend and correspondent of Thomas Jefferson. His philosophy and insight persuaded Jefferson to initiate what Americans call a liberal arts education. Scheele was later recognized as a brilliant and productive pioneer in chemistry although he died at age 44 of tasting his own arsenic compounds. In the new time-lapse play "Oxygen" set in Stockholm in both 18th and 21st centuries, in 1774, blame falls on Lavoisier's wife who hid Scheele's letter in hopes of giving her husband sole credit for discovering oxygen. In 2001, four Nobel committee panelists cannot agree which should receive the first "Retro-Nobel Prize" for the greatest discovery of all time: Priestley, Scheele or Lavoisier or all three. The audience is asked to choose.

Career perspective: John W. Severinghaus.

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.

Effects of skin pigmentation on pulse oximeter accuracy at low saturation.

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 invention and development of blood gas analysis apparatus.

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.