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See also ANALYTICAL METHODS, AUTOMATED; PHARMACOKINETICS AND
PHARMACODYNAMICS; TRACER KINETICS.
CO2 ELECTRODES
JOHN W. SEVERINGHAUS
University of California in San
Francisco
San Francisco, California
METHODS OF MEASURING BLOOD pCO2 BEFORE
DISCOVERY OF THE pCO2 ELECTRODE
Bubble Equilibration Methods
Carbon dioxide in blood is largely in the form of the
bicarbonate ion, which could be converted to CO2 gas by
adding acid and extracting the gas in a vacuum. The
concept of partial pressures gradually stimulated interest
in measuring pCO2 in the late nineteenth century. Gas
analysis had been developed earlier, so the first method
was to equilibrate a small gas bubble with a large volume of
blood sample at body temperature, and then remove the
bubble for gas analysis. Pflüger developed a tonometer for
this purpose in the 1870s, and August Krogh used this
110 CO2 ELECTRODES

method in fish in the early twentieth century. It was

developed into a clinical and laboratory method by Richard
Riley, using a specially adapted syringe with a capillary
attached, which was invented by F. J. W. Roughton and
P. Scholander during World War II. Riley’s bubble method
worked well for pCO2, but poorly for pO2 especially when
blood was saturated with oxygen.

The Henderson–Hasselbalch Method

The most accurate early method was made possible by L. J.
Henderson’s discovery of buffering and his equation in
1908, its logarithmic modification by K. A. Hasselbalch
in 1916, and P. T. Courage’s design of a glass pH electrode
(1925) in which blood could be measured with little loss of Figure 1. Equilibration method for measuring arterial pCO2
CO2 to air. Blood pH was determined, usually at room introduced by Astrup during the Copenhagen polio epidemic,
temperature, there being no thermostated electrodes, and 1952–1954. Log pCO2 plotted versus pH results in straight lines
the Rosenthal temperature correction (0.0147 pH units/ with varying pCO2, and shifts of pH and slope when blood is acidified
8C) was used to compute pH at 37 8C. Plasma CO2 content or alkalinized. The shift gave rise to the concept of base excess.
was determined in the Van Slyke manometric apparatus
that used 1 mL of plasma (after carefully centrifuging blood
THE CO2 ELECTRODE
under a gas tight seal, a floating cork). This method
reached a precision of 0.3 mmHg pCO2 in studies of the
History
arterial to alveolar pCO2 difference during surgical
hypothermia at The National Institute of Health (NIH) (5). A carbon dioxide (CO2) electrode was first described by
physiologists Gesell and McGinty at the University of
Astrup and The Equilibration Method Michigan in 1926, for use in expired air, but not in blood
(8). It used the effect of CO2 on the pH of a film of peritoneal
Hundreds of patients with polio needed artificial ventila-
membrane wet with a salt solution. Their paper was redis-
tion in the communicable disease hospital in Copenhagen
covered 40 years later by M. Laver at Massachusetts General
during epidemics in 1950–1952. Poul Astrup, M.D. (Pro-
Hospital who informed Trubohovich of this effect (9).
fessor of Clinical Chemistry, University of Copenhagen,
In August 1954, Richard W. Stow, Ph.D. (Associate
Copenhagen, Denmark, and Director of the Clinical
Professor of Physical Medicine, Ohio State University,
Laboratory, Rigshospitalet, Copenhagen, Denmark) and
Columbus, Ohio) (Fig. 2), a physical chemist, reported
his associates, particularly Ole Siggaard Andersen,
the design of a CO2 electrode at the fall meeting of the
Ph.D., M.D. (Professor of Clinical Chemistry, University
American Physiologic Society in Madison, Wisconsin (10).
of Copenhagen, and Director, Clinical Chemistry Labora-
tory, Herlev Hospital, Copenhagen, Denmark), devised a
way of determining blood pCO2 using only a pH electrode to
measure pH before and after equilibration of a blood sam-
ple with two known concentrations of pCO2(6). Astrup
made use of the little known fact that, as pCO2 is changed,
the relationship of pH to pCO2 in a given blood sample is
semilogarithmic (Fig. 1). By plotting the two measured values
of pH at the known equilibrated pCO2, he could graphically
interpolate the pCO2 from the original sample pH.
From 1954 until the mid-1960s, Astrup’s method was
made widely available by the Radiometer Co. of Copenhagen.
The device had a thermostated capillary pH electrode, refer-
ence electrode, and tiny shaking equilibrator through which
humidified gas flowed. Astrup’s apparatus and method
became obsolete with the introduction of the CO2 electrode.
Ole Siggaard Andersen, Astrup, and others used the
values obtained for pH and pCO2 to calculate bicarbonate,
total CO2, and base excess, a term they introduced as a
quantitative measure of the nonrespiratory or metabolic
abnormality in a whole blood sample. Base excess proved to
be the first accurate index of the nonrespiratory component
of acid–base balance (7). Its first application was only for
blood, but by 1966, it was shown to apply to the extra-
cellular fluid of the entire body if one assumed an average Figure 2. Richard Stow, invented the CO2 electrode in 1954 to
extracellular fluid hemoglobin concentration of 5 g/dL. assist in managing polio patients on ventilators (10).

Figure 3. Stow’s sketch of his 1954 CO2 electrode. (a) Cable
connection enclosure. (b) Rubber membrane. (c) Retaining O
ring. (h) Chamber for internal pH electrolyte. (j) Reference
electrode of silver chloride, not in contact with internal
electrolyte, but opening to exterior through port K.
The polio epidemic was raging at the time, and as part of
the physical therapy faculty he had sought some way to
measure pCO2 in the victims. He read in the library about
specific ion electrodes, and conceived the electrode idea. He
had wrapped a thin rubber membrane wet with distilled
water over a homemade combined pH and reference elec-
trode (Fig. 3). When he changed gas pCO2 outside the
device, the pH inside changed as a log function of gas
pCO2. However, he was unable to get stable readings
and said he doubted it could be made useful.
After his talk, Severinghaus asked him why he did not
try adding sodium bicarbonate (NaHCO3) to the water film
in the electrode. He replied that he believed this would
abolish the signal because bicarbonate would buffer the
effect of pCO2 on pH. Severinghaus replied that he was
confident that bicarbonate would not block the sensitivity.
Stow agreed that Severinghaus would further investigate
this idea. In September, 1954, after returning from Madi-
son to the National Institutes of Health, Severinghaus
confirmed the advantage of adding bicarbonate ions. A
schematic diagram of his modification of Stow’s electrode
is shown in Fig. 4. He used a Beckman bulb-type pH
electrode, a chloride-coated silver wire reference, and a
Beckman pH meter. He tied a film of cellophane over the
CO2 ELECTRODES 111
Figure 4. The concept of a pCO2 electrode. The pH sensitive
surface of a pH glass electrode is covered by a layer of electrolyte
(here in cellophane), and then by a thin layer of a membrane
permeable to CO2, but not to hydrogen ions (here Teflon). The
pH in that film is controlled by the partial pressure of CO2 on
the outside of the outer membrane as CO2 dissolves and reacts
with water to form carbonic acid. The carbonic acid dissociates
into hydrogen and bicarbonate ions. Because the electrolyte has
5–20 mM HCO 3 ions, changes of pCO2 have no measurable effect
on HCO þ
3 . The mass law then requires H to change in direct
proportion to change in pCO2. A doubling of pCO2 doubles Hþ
concentration, which is seen as a 0.3 pH unit fall.
pH electrode soaked in 25 mM NaHCO3 and then covered
the entire tip with a thin rubber dam, later from a surgical
glove. The bicarbonate not only made the device stable, but
doubled the pCO2 sensitivity compared with an electrolyte
of distilled water (or 1% NaCl). Salt was added to help
stabilize the silver chloride reference electrode.
In 1957, Stow. Baer and Randall (11) published their
discovery of the CO2 electrode without mentioning the need
to add bicarbonate ion, and took no further interest in this
idea. Stow had no interest in a patent, thinking it would
distract him from his job, and also because his university
only allowed inventors 10% of royalties. As a U.S. govern-
ment employee, Severinghaus was not permitted to patent
it, certainly not with a reluctant coinventor.
Severinghaus and co-worker A. Freeman Bradley pro-
ceeded to investigate and optimize the electrode design and
to test its performance, linearity, drift, and response time.
They constructed electrodes for laboratory use by several
colleagues, but unfortunately made no attempt at commer-
cial development for 4 years.
Between 1958 and 1960 several other investigators
constructed and published similar CO2 electrodes, in several
instances without being aware of the Stow–Severinghaus
electrode (12–14).
CO2 ELECTRODE DESIGN DETAILS
A CO2 electrode consists of a slightly spherical surfaced
glass pH electrode and a silver chloride reference electrode.
Both are mounted in a glass or plastic sleeve holding a
Teflon or silicone rubber membrane, typically 12 mm thick,
over the glass surface, in some cases with a spacer of very
thin lens-cleaning paper between membrane and glass to
112 CO2 ELECTRODES
Figure 5. Cuvette with blood inlet and outlet connections in a
thermostated water jacket made for the Stow–Severinghaus pCO2
electrode (National Welding Co, San Francisco, 1959).
insure a uniform distribution of the electrolyte that is NaCl
or KCl with  5–20 mequiv/L of NaHCO3. For use in blood,
the electrode is mounted in a 37 8C cuvette into which a small
sample of blood can be injected (typically 50 mL) (Fig. 5).
The electrode output voltage is a logarithmic function of
pCO2,  60 mV for a 10-fold change of pCO2, which induces
a pH change of  1 pH unit. Sensitivity is defined as D pH/
D log pCO2, where S reaches nearly the ideal maximum
value of 1.0 with HCO 3 concentrations of 5–25 mM (Fig. 6).
At higher bicarbonate levels, carbonate acts as a buffer,
and reduces both sensitivity and speed of response.
Response is faster at lower bicarbonate concentration,
but carbonic acid pK’ is 6.1, resulting in some change of
bicarbonate as pCO2 changes, reducing sensitivity. As
bicarbonate concentration is lowered, sensitivity falls to
30 mV/decade pCO2 change, or S ¼ 0.5, at zero bicarbonate.
The log response is almost linear from 5 to 700 mmHg
pCO2. The response time to a step change of pCO2 is
exponential with a 95% response time of  30 s, depending
on the membrane thickness and material, bicarbonate ion
concentration and the thickness of the electrolyte layer
over the glass electrode surface. It can be made to respond
Figure 6. The first blood gas apparatus, with the Clark pO2
electrode (below) in a stirred cuvette, and the Stow–
Severinghaus pCO2 electrode above, tilted to keep the internal
air bubble of the pH electrode away from the tip (1957).
in < 1 s by using thin silastic (silicone rubber) membrane,
low bicarbonate concentration (i.e., 1 mequiv/L), and add-
ing carbonic anhydrase to the electrolyte, but the downside
is loss of stability and signal amplitude.
The CO2 electrode is usually calibrated to read in milli-
meters of mercury. It reads the same value for gas and
liquid equilibrated with that gas at the electrode tempera-
ture, usually 37 8C.
A useful test of a leaking membrane is to equilibrate a
dilute solution (e.g., 1 mequiv/L) of HCl, or lactic acid with a
known calibration gas, and test its reading. Any leak will
permit acid entry and an erroneously high pCO2.
Maintenance requires replacement of the membrane
and electrolyte when errors are detected or when drift
has driven the electrode beyond the ability of the apparatus
to compensate its potential. The pH glass may become so
impermeable to hydrogen ions that it shows low sensitivity
or slow response after years of use.
The amplifier circuit must be electrically isolated from
the ground because any ground path leakage will draw
current through the silver chloride reference and changes
its potential causing drift. The input impedance of all
modern pH and pCO2 meter amplifiers is >1011 V.
The Combined Blood Gas Analysis Apparatus
In 1956, Leland Clark disclosed his invention of the oxygen
electrode at a meeting in Atlantic City to which Severin-
ghaus had invited physiologists interested in measuring
pO2. That invention made a huge difference in blood gas
analysis.
While Severinghaus completed his anesthesia residency
at the University of Iowa, with help from the physiology
workshop, he constructed a thermostat into which he
mounted both the Stow–Severinghaus CO2 electrode and
the Clark O2 electrode in a stirred cuvette with a small
blood tonometer. That apparatus was exhibited at the
meeting of the American Society of Anesthesiologists in
October 1957 and at the meeting of the Federation of
American Societies of Experimental Biology in Atlantic City
in the spring of 1958 and published in 1958 (15) (Fig. 7).
Figure 7. The first three-function blood gas analyzer, using a
McInnes Belcher pH electrode (1930) with the pCO2 and pO2
electrodes in a 37 8C bath.

The Three-Function Blood Gas Analyzer
In 1958, after moving from the National Institutes of
Health to the University of California, San Francisco,
Severinghaus and Bradley added a pH electrode to the
blood gas electrode waterbath, making the first three-
function blood gas apparatus (Fig. 8). Forrest Bird,
Ph.D., M.D. (President, Bird Corporation, Palm Springs,
California) had designed popular positive-pressure venti-
lators, manufacturing them at the National Welding Co.
in San Francisco. He proposed to manufacture the CO2
electrode and to make it commercially available. From
1959–1961 the National Welding Co. sold the only avail-
able pCO2 electrode. The design concept was soon copied
and marketed by Beckman, Radiometer, Instrumentation
Labs and later by several other firms.
Impact of Blood Gas Analysis
During the 1960s, blood gas analysis became widely avail-
able in anesthesia, intensive and critical care facilities,
and cardiorespiratory research laboratories. For several
years, the Severinghaus paper (15) was among the most
quoted articles in biologic literature, and blood gases were
called the most important laboratory test for critically ill
patients. Blood gas apparatus now uses automatic self-
calibration and automatic transport of sample and wash-
ing of cuvettes, printing of results, and often sending the
values to remote terminals. In the United States, regula-
tions have been used by pathologists to require that these
automated instruments can only be used by licensed
technicians, usually meaning that the income flows to
pathologists. Gone are the days when students, nurses,
residents, and faculty all took part in doing blood gas
analysis.
A more complete history of the CO2 electrode and
related blood gas technology is available in References
(9,16).
Figure 8. Relationship of pCO2 electrode sensitivity to its
internal electrolyte bicarbonate ion concentration. Maximum
sensitivity occurs at  20 mM HCO 3 , but for faster response,
most electrodes operate at 5–10 mM.
CO2 ELECTRODES 113
HISTORY AND THEORY OF TRANSCUTANEOUS BLOOD
OXYGEN MONITORING
From 1951 to 1952, the discovery of oxygen related blind-
ness in premature infants created an urgent need for
continuous noninvasive monitoring of blood oxygen. A
new solution to the problem came from physiologists study-
ing skin respiration. Human skin breathes, taking up
oxygen and giving off CO2 to the air. If skin is covered
(as by a flat unheated pCO2 electrode) the surface tcpO2
falls to zero in a few minutes. However, in 1951 Baumber-
ger and Goodfriend showed that if skin blood flow is greatly
increased by the highest tolerable heat (45 8C), the surface
pO2 rises to about paO2 (arterial blood) (17).
Within a year after Clark’s invention of the membrane
covered platinum polarographic electrode (18,19), Rooth
used polarography to confirm the Baumberger report (20).
Researchers tried unsuccessfully to use chemical vasodi-
lators to make skin pO2 a monitor of paO2. Kwan and Fatt
(21) noted that pO2 of the palpebral conjunctiva measured
with an unheated tiny Clark electrode mounted facing
outward on a contact lens over the cornea simulated
paO2. This device was briefly marketed a decade later,
but discontinued due to the danger of infection.
In Marburg, Germany, Professor of Physiology Dietrich
Lübbers and students, especially Renate Huch, pursued
the concept of heating the skin under an oxygen electrode
by heating the electrode itself to as high as 45 8C. They
were joined by Patrick Eberhard, and the group soon found
ways of making electrically heated, thermostated oxygen
surface electrodes. By 1972, they had shown a good rela-
tionship between heated skin and arterial blood pO2 in
infants (22). Several firms began to design electrodes for
this purpose.
DEVELOPMENT OF METHODS AND UNDERSTANDING OF
THEORY
By 1977, the Marburg group had published at least 11
papers documenting the validity of transcutaneous oxygen
measurement. At least three commercial tcpO2 electrode
systems were available (Helige, Roche, Radiometer). In
November 1977, some 18 research teams joined for a work-
shop on transcutaneous blood gas methods in San Fran-
cisco, assessing the theory, problems, possibilities, and
progress (23–30). The following summer (1978) many of
these workers joined the Marburg team and others for the
first international congress on transcutaneous blood gas
monitoring, establishing the technology as an essential tool
in neonatology and as useful in many other fields (31,32).
The agreement of tcpO2 with paO2 proved to be a
cancellation of two opposing effects illustrated in Fig. 9
(27,33).
1. Heating of desaturated blood raises its pO2 by 7%/8C,
or 50% at 43 8C, but in saturated blood, as in water,
pO2 rises only 1.3%/8C (35);
2. Skin metabolism at the high temperature consumes
O2 as it diffuses outward from capillaries through
living cells, reducing the value to about paO2.
114 CO2 ELECTRODES

Figure 9. A schema of the effect of both heating of skin surface by

a transcutaneous electrode, and of local metabolism, on the tissue
internal oxygen tension from the arteries out past the capillaries
and the living and dead epidermis to the surface, and through the
Figure 10. The time course of skin pO2 and pCO2 on an arm after
electrode membrane into the cathode that keeps its surface pO2 ¼ 0
sudden circulatory occlusion with a blood pressure cuff. The rate of
by its electrical negative potential (39).
fall of pO2 from a high level is a measure of the skin metabolic rate.
The pCO2 rises at first from metabolic CO2 production, but later at
The outward oxygen diffusion is facilitated by heat that a steeper rate as skin generates lactic acid when skin pO2 reaches
zero. With release of occlusion, the electrode recovery time is
proved to ‘‘melt’’ some skin diffusion barriers (33,36). Skin
delayed by both the skin washin and washout, and by electrode
O2 conductivity C (adult volar forearm) was determined by
equilibration (34).
two groups by comparison of flux with two membranes
(teflon and mylar) of very high and low conductivity. With
Severinghaus (48). Figure 12 schematically shows the
a large gold cathode Clark electrode, C ¼ 15 nL  cm2  s1 
internal design of an early Radiometer combined electrode.
atm1(37) and with a mass spectrometer C ¼ 10 nL  cm2 
Figure 13 shows the electrode with a membrane mounted.
s1  atm1(38).
When a heated combined pO2–pCO2 electrode is first
Skin O2 consumption (VO2) was determined after ther-
attached to skin, the time needed to equilibrate is  5 min
mal vasodilation by the rate of fall of tcpO2 with circulatory
for both electrodes, although the pO2 electrode may show
occlusion (arm cuff) (Fig. 10) (27). Relative skin blood flow
later small changes as thermal vasodilation slowly develops
under the heated electrode was estimated by measuring
(Fig. 14). The response to step changes in alveolar and
the required heating power (39). Analysis of data collected
arterial pCO2 is slower as seen in Fig. 15. Here the response
at two levels of pO2 and two temperatures permitted
is delayed both by the washout or washin of CO2 into the
calculation of blood flow, capillary temperature under a
tissue by blood flow, and the electrode’s own delay. The
heated electrode, and diffusion gradient from capillary to
response is pseudoexponential, a combination of the two
surface (40). Mean adult volar forearm skin VO2 was
delays, resulting in a 95% response times of  10 min.
4.2 0.4 mL  g1min1 at 44 8C and 2.8 0.3 mL  g1  min1
Without correction, tcpCO2 is not similar to paCO2.
at 37 8C. At 44 8C, skin blood flow averaged 0.64 0.17 mL 
Heating of blood (and water) raises pCO2  4.6%/8C
g1  min1, capillary temperature was 43 8C and the diffusion
gradient was 32 7 mmHg.

TRANSCUTANEOUS CO2

In 1959, Severinghaus constructed a 37 8C thermostated

open tipped CO2 electrode to determine pCO2 of various
tissue surfaces in animals (Fig. 11) (41). Without heating
the skin well above body temperature, skin pCO2 at 37 8C
climbed steadily over one-half of an hour to > 80 mmHg.
Dog intestinal mucosa and liver surfaces were very high.
Fifteen years later, the success in transcutaneous mea-
surement of oxygen led to design and testing of electrodes
to measure tcpCO2 by Beran et al. (42,43), Huch et al. (44)
and Severinghaus et al. (45,46). Combined tcpO2–tcpCO2 Figure 11. The first tissue surface pCO2 electrode (41) with a
electrodes were initially described by Parker et al. (47) and circulating temperature controlled water jacket.

Figure 12. Schema of the design of a combined tcpO2–tcpCO2
electrode. (a) pO2 cathode, the end of a 12 mm platinum wire
fused in glass. (b) A silver wire reference electrode. (c) pH glass
electrode surface. (d) solid silver internal pH electrode (used
to improve heat transfer to skin). (e) Internal pH electrolyte.
(f) Heater Zener diode. (g) Thermistor. (h) Silver body, and
reference electrode. J, K, L, M: O rings. N: Lexan jacket. Q:
epoxy. P: Cable (48).
Figure 13. Photograph of combined pO2–pCO2 electrode with
teflon membrane (48).
CO2 ELECTRODES 115
Figure 14. Initial responses of a combined pO2–pCO2 electrode
when first mounted on skin. Both electrodes need  5 min to
equilibrate, the pO2 showing a small late rise as skin
hyperemia develops from the heating (49).
(41), metabolism adds  3 mmHg pCO2, and the cooling by
skin and blood of the electrode surface further raises the
electrode reading. The effect of heating on blood pCO2 may
be computed as DpCO2 ¼ exp(0.046[T – 37]) (51). The net
effect at 43 8C was found to be tcpCO2 ¼ 1.33paCO2 þ
4 mmHg (48,52) or tcpCO2 ¼ 1.4paCO2 (53). This form of
temperature-dependent correction factor was later incor-
porated in most commercial transcutaneous blood gas
monitoring apparatus.
With this correction factor, the relationship of tcpCO2 to
paCO2 is excellent, as shown in Fig. 16. The previous
correction factors appear to have become incorrect for a
second generation of the Radiometer tcpCO2 electrodes, due
to a design change in the internal temperature coefficient
of the glass pH electrode. The additive factor of 4 mmHg
changed to  8 mmHg in the newer instruments (Kagawa
S, personal communication).
Although tcpCO2 appears to work at 42–43 8C, Tremper
et al. showed that 44 8C was a better temperature when
Figure 15. Transcutaneous pCO2 electrode response to a step
increase of ventilation adjusted by the subject to reduce end tidal
pCO2 suddenly from 40 to 20 mmHg and hold it at a constant level
for 18 min, followed by addition of enough CO2 to inspired gas to
raise end tidal pCO2 as quickly as possible to  50 mmHg. The
response time constants (63%) are  5 min (45).
116 CO2 ELECTRODES
Figure 16. Transcutaneous pCO2 correlates well with arterial
pCO2 in patients during anesthesia or intensive care (48).
blood pressure was or had been low (54). The tcpCO2 value
was better than the PETCO2 value (end-tidal or end-expired
air) in predicting paCO2 (bias and s.d.
1.6  4.3 mmHg) in
anesthetized adults (n ¼ 24) (55).
A special advantage of tcpCO2 is that it averages out
breath-by-breath variations, and has almost no inherent
‘‘noise’’ or variability, such that it often is found to be the
best trend monitor for detecting small changes in paCO2
such as those induced by experimental variations (anesthe-
sia, ventilatory settings, posture, FIO2, FICO2, blood pres-
sure, pharmacologic agents, etc).
APPLICATIONS
Transcutaneous technology is used in many ways, some of
which are discussed in accompanying papers:
1. Neonatology: Guidance of O2 therapy remains the
most common use of transcutaneous monitoring
(56–58). The suspected etiologic role of hyperoxia
(tcpO2 > 80 mmHg) in retinitis of premature infants
has been confirmed in a cohort study (59). The tcpO2
value can be measured above and below the ductus
to demonstrate closure (60). In low birth weight
infants, tcpCO2 (at 40 8C!) is the best available
monitor of ventilation (61).
2. Fetal Monitoring: Using specially designed electro-
des attached to the fetal scalp, intrapartum monitor-
ing revealed some important new pathophysiologic
understanding (62–65). As hoped, changes in tcpO2
rapidly reflected changing maternal and fetal condi-
tions (66). The tcpO2 value fell and tcpCO2 rose with
contractions during the second stages of labor (67).
The tcpCO2 value closely followed fetal paCO2(68).
When there were signs of fetal distress, fetal scalp
tcpO2 was < 15 mmHg (69). Surprisingly, O2 admin-
istration to mothers with fetal distress did not alter
fetal pCO2 or raise pO2(70). During maternal hypo-
capnia, fetal tcpO2 fell due to the Bohr effect, whereas
it rose during hypercapnia (71). Fetal tcpO2 was
considered influenced by local scalp blood flow (72).
Repeated episodes of asphyxia were reported to
express catecholamines, which reduced blood flow
to the fetal skin, artifactually reducing tcpO2(73,74).
Fetal tcpCO2 may have failed to disclose severe
acidosis or circulatory impairment (75).
3. Sleep Studies: Combined pO2–pCO2 electrodes are
used in sleep studies in combination with pulse
oximetry, because nostril sampling of end-tidal
pCO2 is somewhat annoying and more apt to become
plugged or dislodged (76–83). The combined tcpO2–
tcpCO2 electrode made it possible to show that the
ventilatory response to induced mild hypoxia in
sleeping infants changes with age from acute depres-
sion at 1–5 days, to stimulation at 4–8 weeks, and mild
or no stimulation at 10–14 weeks (84). A method was
designed for estimating the ventilatory response to
CO2 during sleep using capnography and tcpCO2(79).
4. Peripheral Circulation: The tcpO2 electrodes are
extensively used in evaluating arterial disease in
the peripheral circulation (85–88). A test of ade-
quacy of peripheral circulation, ‘‘initial slope index’’
(ISI) was suggested by Lemke and Lübbers (89).
Blood flow is stopped by an arm cuff above the
electrode and restarted when tcpO2 ¼ 0. The initial
rate of rise should be a slope per min of at least 75%
of the preocclusion tcpO2.
5. Skin Circulation: Monitoring the viability of skin
after injury or transplant or flap movement (90,91).
6. Ventilatory Control: In intensive care, transcuta-
neous electrodes greatly increased the safety and
simplicity of PEEP optimization and respiratory
management of adults with respiratory distress
syndrome (92). They are widely used simply to
reduce arterial blood sampling.
7. Hyperbaric Oxygen: Monitoring and guiding hyper-
baric oxygen therapy, primarily for infections and
wound healing (93,94). The tcpO2 tracked paO2 up
to 4-atm hyperbaric pressure in normal subjects
(95). Surprisingly, no one has reported using tcpO2
in hyperbaric treatment of CO poisoning despite the
demonstration by Barker and Tremper in experi-
mental CO administration that transcutaneous pO2
falls linearly as COHb increases, and reaches about
one-fifth of its initial value at the highest COHb
levels despite the maintenance of constant arterial
pO2(96). It is thus unknown whether HBO can
normalize tissue pO2 in the presence of high levels
of COHb.
8. Clinical Physiology: Transcutaneous monitoring has
found use in exercise tolerance studies (97,98). End-
tidal CO2 is not exactly equal to paCO2 and the
difference between them varies with posture and
inspired oxygen concentration. When testing hypoxic
ventilatory responses by monitoring PETCO2, tcpCO2
helps to correct these small errors (99).

9. Pharmacologic Research: Transcutaneous monitor-
ing may be the simplest monitor of the depressant
effects of opiates, sedatives, and anesthetics espe-
cially in awake children (100).
10. Animal Studies: Intestinal or other tissue animal
experimental ischemia has been found to be better
detected by the rise of the organ or tissue surface
pCO2 using tcpCO2 electrodes at body temperature
than by gastric tonometry (101). Both tcpO2 and
tcpCO2 have been widely used in small and large
animal studies (102) and to assess the effect of
cardiopulmonary resusitation (CPR) (103).
ACCURACY
With the widespread use of tcpO2 and tcpCO2 came concern
about its accuracy and the possible sources and effects of
errors, especially with severe hypotension (28,104). Pea-
body et al.(25) identified two groups of infants in whom
tcpO2 was lower than paO2. These were infants receiving
an intravascular infusion of tolazoline and infants with
mean arterial blood pressures > 2.5 s.d. below the pre-
dicted average value. Vasoconstrictors also lower
tcpO2(105). Both of these situations represent extreme
alterations in peripheral blood flow. Mild hypotension,
hypothermia, anemia, radiant warmers, and bilirubin
lights did not adversely affect transcutaneous accuracy
(106). In a large multiinstitutional study of 327 patients
older than 1 month, when paO2 was between 80 and
220 mmHg, Palmisano found the mean bias
s.d. of tcpO2
was 43
40 mmHg, and the slope of the regression was
0.65 (107). It was determined that tcpCO2 correlated far
better with paCO2: R ¼ 0.929, slope 1.052, bias and
s.d. ¼ 1.3
4.0 mmHg (n ¼ 756).
Defining a tcpO2 index as tcpO2/paO2, Tremper and
Shoemaker (108) studied the effect of shock. For 934 data
sets taken on 92 patients not in shock, there was a correla-
tion coefficient (r) of 0.89 and a tcpO2 index 0.79
0.12
(SD). In five patients with moderate shock, the r was 0.78
and the tcpO2 index was 0.48
0.07. In nine patients with
severe shock, there was no correlation between tcpO2 and
paO2 and the tcpO2 index was 0.12
0.12.
LIMITATIONS
Skin burns may occur after an electrode has been in one
place over several hours at 44–45 8C, and sometimes even
at 43 8C. Long-term monitoring requires site changes, or a
dual electrode alternating system (109). There may be
problems with drift of calibration, membrane failure, par-
tial loss of skin contact giving errors in both O2 and CO2
readings. Maintenance of these electrodes requires train-
ing and some technical proficiency.
IMPACT OF PULSE OXIMETRY
Pulse oximetry came into widespread use in 1985–1987,
and quickly replaced transcutaneous blood gas analysis in
many situations. However, after an initial switch to
CO2 ELECTRODES 117
oximetry, neonatologists found that oximetry failed to
detect hyperoxia adequately (110) and now mostly use both
technologies (111–115). In neonatology, a significant pro-
blem is that the inherent errors of pulse oximetry are  3%,
which could fail to warn of paO2 > 80 unless a set point of
 90% SpO2 is chosen (116). Some have arbitrarily dis-
missed transcutaneous monitoring as ‘‘. . .plagued by tech-
nical problems, . . .Its use in efforts to prevent retinopathy
of prematurity, an eye disease of preterm newborns often
leading to blindness, proved disappointing’’ (117). To them,
the transcutaneous field served as a model of problems
in medical innovation, new technology, and personnel
training. Not everyone agrees with this pessimism. Most
technical problems have been solved, and the occurrence of
blindness in very premature infants is now believed to be
multifactorial, not just due to hyperoxia. Therefore when it
occurs, it is not appropriate to attribute it to failed trans-
cutaneous methodology.
CONCLUSIONS
The enthusiasm for transcutaneous blood gas analysis of
the period 1976–1986 was followed by a decrease due to the
advent of pulse oximetry. The number of papers per year
listing medline keywords ‘‘transcutaneous blood gas’’
reached an early peak of 75 in 1979, when the first inter-
national symposium was devoted to this field, in Marburg
and 200 in 1987. However, after 1986 many papers used
the keywords ‘‘transcutaneous blood gas’’ when writers
meant to refer to pulse oximetry.
Transcutaneous technology is inherently somewhat
complicated. Users must change membranes and calibrate,
change skin sites periodically to avoid burns, beware of
drift or error due to poor circulation or poor skin attach-
ment, and take account of the slower response than given
by oximetry. Nonetheless, transcutaneous blood gas mea-
surement continues to be used because of its unique ability
to meet many special situations needing its characteristics
of noninvasively and continuously determining partial
pressures of O2 and CO2. Several professional organiza-
tions have published guidelines for use of these monitors
(118,119).
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1. Severinghaus JW. The current status of transcutaneous
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2. Severinghaus JW. The Invention and Development of Blood
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3. Severinghaus JW. Severinghaus electrode. In: JR Maltby,
editor. Notable Names in Anaesthesia. London: Royal Society
of Medicine Press Ltd.; 2002.
4. Severinghaus JW, Astrup P, Murray J. Blood gas analysis
and critical care medicine. Am J Respir Crit Care Med
1998;157:S114–S122.
5. Severinghaus JW, Stupfel MA, Bradley AFJ. Accuracy of
blood pH and pCO2 determinations. J Appl Physiol 1956;19:
189–196.
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nation of carbon dioxide tension in blood and plasma, total