Monitoring oxygenation

THE ROLES OF OXYGEN IN AEROBIC ORGANISMS

Oxygen has several physiological roles:
1. Bioenergetics: aerobic mitochondrial respiration accounts for 90% of oxygen
consumption, generating adenosine triphosphate (ATP) by oxidative
phosphorylation. Mitochondrial electron transfer oxidase systems provide the
fundamental machinery, in particular the cytochrome oxidase of complex IV.
Oxygen acts as a terminal electron acceptor, combining with two protons to
produce water.
2. Biosynthetics: oxygen transferase systems incorporate oxygen into
substrates, such as prostanoids, catecholamines and some neurotransmitters.
3. Biodegradation and detoxification reactions:these mixed function oxidase
reactions require oxygen and a co-substrate (e.g. NADPH). The cytochrome
P-450 hydroxylases are examples.
4. Generation of reactive oxygen species:these are essential anti-microbial
defences deployed by neutrophils and macrophages.

HYPOXIA AND DYSOXIA

The term hypoxia connotes tissue oxygen deficiency, and has largely
superseded the older term anoxia. In 1977 dysoxia was introduced as a broader
term signifying any form of oxygen-limited cytochrome turnover causing
progressive ATP depletion. By this definition dysoxia can occur as a result of
hypoxia, but can also be present in states of normal or supranormal oxygen tissue
availability
THE SPECTRUM OF DYSOXIA
1. Stagnant hypoxia, where the primary abnormality is reduced tissue blood
flow
2. Oxygen transport block at capillary, interstitial or intracellular levels
3. Hypoxaemic hypoxia, where the primary abnormality is a low arterial
oxygen tension
4. Anaemic hypoxia, where the primary abnormality is a low haemoglobin
concentration
5. Cytopathic dysoxia, a phenomenon often attributed to sepsis and defined
as abnormal cellular oxygen utilisation despite adequate oxygen delivery
6. Oxygen toxicity, defined as abnormal cell function due to high oxygen
tensions.

CONSEQUENCES OF TISSUE HYPOXIA

As tissue PO2 falls, biosynthetic and biodegradation systems fail first.
Aerobic ATP production initially adjusts to match ATP consumption by several
adaptive metabolic mechanisms including increased glycolysis. Cell signalling by
reactive oxygen species, released at mitochondrial complex III, activates hypoxia-
inducible factor-1, a transcription factor up-regulating genes
important in hypoxic cell survival. Oxidative phosphorylation itself begins to
fail when intracellular PO2< 0.11 mmHg (0.0130.13 kPa), equivalent to an
extracellular PO2< 35 mmHg (0.390.65 kPa). Stopgap ATP production
continues by anaerobic glycolysis, but without correction of dysoxia there is
progressive lactic acidosis and eventual cell death by apoptosis and necrosis. On
reoxygenation, a further release of reactive oxygen species causes oxidant
stress, often overshadowing the hypoxic insult.

THE OXYGEN CASCADE

In unicellular organisms, oxygen reaches the mitochondria across a short
diffusion path with a steep partial pressure gradient. In multicellular animals
the much longer diffusion path traverses a series of stepped partial pressure
reductions known as the oxygen cascade. As a result, oxygen tensions in
intracellular organelles remain above the anaerobic threshold. Important steps in
the oxygen cascade include:
1. Inspired gas
2. Alveolar gas
3. Arterial blood
4. Microcirculation
5. Interstitium
6. Mitochondria and other intracellular organelles.
The cascade can be jeopardised at any step. If more than one step is
involved there is oxygen deprivation amplified downstream in mitochondria
and other intracellular organelles. In this chapter we will consider how
oxygenation can be monitored at strategic points along the cascade.

INSPIRED GAS
Monitoring the fraction of inspired oxygen (FiO2) is necessary to prevent the
adverse effects of both hypoxaemia and excess oxygen. The inspired oxygen
tension (PiO2) of humidified gas is determined by the FiO2, the barometric
pressure (BP) and the saturated vapour pressure of water (47 mmHg (6.11 kPa)
):
Pio2 = Fi02 x (BP 47)

Gas supply pressures are monitored continuously. Ventilators incorporate

input pressure alarms and oxygen analysers within the inspiratory module to
identify oxygen source failure. Direct measurement of circuit oxygen
concentration can be added.
TRANSFER OF INSPIRED GAS TO ALVEOLI
Communication is open between oxygen delivery system and pulmonary
alveoli if:
1. There are no signs of upper airway obstruction
2. Expired tidal and minute volumes and airway pressures for the ventilated
patient are within correctly set alarm limits.
3. There is an appropriate end-tidal CO2 waveform

ALVEOLAR GAS
In a patient receiving 100% oxygen, alveolar PO2 in individual lung units
can range from <40 mmHg to >600 mmHg (<5.2 >78 kPa). Consequently,
end-tidal PO2 monitoring is of little value.

DISTRIBUTION OF ALVEOLAR VENTILATION

Clinicians routinely track chest movement, auscultate air entry, and
examine plain chest radiographs. Intermittent CT scanning can reveal occult
overdistension but has logistic disadvantages and is a significant radiation hazard.
Electrical impedance tomography shows promise as a real-time non-invasive
monitor of recruitment, overdistension and regional lung mechanics. With contrast
injections of hypertonic saline it has additional potential for assessment of
regional lung perfusion.

MATCHING OF VENTILATION AND PERFUSION

For efficient gas exchange, the majority of lung units must receive
well-matched alveolar ventilation and perfusion with most V/Qratios close to
unity, but even in health there is some spread to lower and higher ratios.
When lungs are diseased, the proportion of lung units with high and low
V/Qratios increases. The adult lung contains at least 100 000 individual gas-
exchanging unit whose V/Qratios potentially range from zero to infinity. Such
complexity resists simple bedside quantification. The gold standard is the
multiple inert gas technique (MIGET), which describes a 50-compartment lung
model. By measuring the retention and elimination of six inert gases of
varying solubility infused in pre-equilibrated saline, MIGET quantifies the
distribution of ventilation and perfusion to 50 lung units spanning a range of
V/Q ratios from zero to infinity. However, lung models with fewer
compartments may suffice for clinical quantification of lung pathophysiology,
with the advantage that they can be more easily applied at the bedside.
Instead of inert gas infusions, stepped FiO2 changes can serve as a forcing
function while blood gas values and end-tidal gas concentrations are tracked
(or pulse oximetry in the least invasive versions).

THE IDEAL ALVEOLUS AND THE THREE-COMPARTMENT

LUNG MODEL
Meanwhile a three-compartment model devised in the mid twentieth century14
is still in use, with no need for FiO2 switching or inert gas infusions. The
trade-off is that because the model is overly simplistic it has poor predictive
capacity in many respiratory disorders. The three compartments are:
1. The ideal compartment, consisting of alveoli with perfectly matched
perfusion and ventilation (V/Q = 1)
2. The venous admixture or shunt compartment, containing perfused non-
ventilated alveoli (V/Q = 0)
3. The alveolar dead space compartment, consisting of ventilated non-perfused
alveoli (V/Q = ). The alveolar PO2 in the ideal compartment (PAO2) is
calculated from the alveolar gas equation:
PAO2 = -(1 - FiO2 x (1 - R) x Paco2/R
where Ris the respiratory exchange ratio, either measured by indirect
calorimetry or assumed to be. PiO2 is calculated as in Equation. PaCO2 is arterial
PCO2. Most clinicians use the following approximation:
PAo2 = Pio2 Paco2/0.8
It is important to remember that PAO2 is derived from a non-
physiological three-compartment lung model. Parameters such as the Aa
gradient and venous admixture that are also based on the model (see below) must
be regarded in the same light.

TRANSFER FROM ALVEOLI TO ARTERIAL BLOOD

(PULMONARY OXYGEN TRANSFER)
The MIGET technique has identified V/Q mismatch and intrapulmonary
right-to-left shunt as the two main causes of reduced pulmonary oxygen transfer
in critical Intrapulmonary shunt predominates in the acute respiratory distress
syndrome (ARDS), lobar pneumonia and after cardiopulmonary bypass, whereas
V/Q mismatch without shunt is more prominent in chronic lung disease
illness. causes of reduced pulmonary oxygen transfer in critical illness.15
Intrapulmonary shunt predominates in the acute respiratory distress syndrome
(ARDS), lobar pneumonia and after cardiopulmonary bypass, whereas V/Q
mismatch without shunt is more prominent in chronic lung disease.

BEDSIDE INDICES OF PULMONARY OXYGEN TRANSFER

These are either tension based or content based.

TENSION-BASED INDICES
Aa gradient
The Aa gradient is calculated as PAO2PaO2, where
PAO2 is the ideal compartment alveolar PO2 determined from the alveolar gas
equation (Equation18.2). Hypoxaemia can then be classified under two
headings:
Normal Aa gradient
1. Alveolar hypoventilation (elevated PACO2)
2. Low PiO2 (FiO2<0.21, or barometric pressure <760mmHg
(99kPa)).

Raised Aa gradient
1. Diffusion defect (rare)
2. V/Q mismatch
3. Right-to-left shunt (intrapulmonary or cardiac)
4. Increased oxygen extraction (CaO2CvO2). Although the Aa gradient is
a component of the
APACHE II, III and IV scoring systems,17,18 several drawbacks limit its
clinical usefulness. They include:
1. Normal values that vary with FiO2 and age. The normal Aa gradient breathing
air is 7mmHg (0.91kPa) in young adults and 14mmHg (1.82kPa) in
the elderly. On 100% oxygen, these values become 31mmHg (4kPa) and
56mmHg (7.3kPa) respectively.
2. An exaggerated FiO2 dependence in intrapulmonary shunt (Fig. 18.1) and even
more so in V/Q mismatch.

PaO2/F iO2 ratio

The PaO2/FiO2 ratio is used to define acute lung injury and ARDS,21 and
is an input variable in SAPS II and III, SOFA, APACHE IV and lung injury
scoring systems. At sea level its normal value is 500mmHg (65kPa). In
acute lung injury, PaO2/FiO2<300mmHg (39kPa), whilst in ARDS
the ratio is <200mmHg (26kPa). Its main advantage is simplicity. There are
several disadvantages:
1. Barometric pressure alters the normal PaO2/FiO2 ratio. For a young adult
breathing air, a ratio of380mmHg (49.4kPa) is unremarkable at 1600 metres
elevation, but not at sea level.
2. Unlike the Aa gradient, the PaO2/FiO2 ratio cannot distinguish hypoxaemia
due to alveolar hypoventilation from other causes.
3. The ratio is markedly FiO2 dependent, both in rightto- left shunt (the
predominant ARDS abnormality) and in lungs with a wide V/Q scatter (COPD).
4. The ratio is also highly dependent on CaO2CvO2, which tends to
fluctuate markedly in sepsis.

CONTENT-BASED INDICES
Venous admixture (Qs/Qt)
Venous admixture is another construct based on the three-compartment
lung model (see above). It represents the proportion of mixed venous blood
flowing through the shunt (V/Q=0) compartment. It is determined according
to the formula:

where CcO2, CaO2 and CvO2 are the oxygen contents of pulmonary end-
capillary, arterial and mixed venous blood respectively. CaO2 and CvO2 are
calculated using data from arterial and mixed venous blood gas analysis and CO-
oximetry. CcO2 must be derived differently, since pulmonary end-capillary blood
cannot be sampled. PcO2 is assumed to equal PAO2 as derived from the alveolar
gas equation. ScO2 (normally close to 1) can then be computed from an algorithm
for the HbO2 dissociation curve.

Advantages of venous admixture:

1. Unaffected by barometric pressure
2. Unaffected by alveolar hypoventilation
3. Provided intrapulmonary right-to-left shunt is the dominant pathology (e.g.
ARDS), venous admixture is stable across the entire FiO2 range, despite
variations in CaO2CvO2 .

Disadvantages of venous admixture:

1. Sampling mixed venous blood requires a PA catheter.
2. In V/Q mismatch without right-to-left shunt, venous admixture varies markedly
with FiO2 and virtually disappears at FiO2>0.5 . Venous admixture is thus
of little use in conditions where the dominant gas exchange abnormality is not
intrapulmonary right-to-left shunt, such as COPD.
When determined at FiO2=1, venous admixture is an accurate
measure of right-to-left shunt. However, exposure to 100% oxygen causes
absorption atelectasis of unstable low V/Q units, which increases intrapulmonary
shunt.

Estimated shunt fraction

If a fixed CaO2CvO2 is assigned, no PA catheter is necessary.
However, in critical illness CaO2CvO2 can range from 1.3mL/dL to
7.4mL/dL. Hence the inaccuracy from assigning a fixed value is such that even
the direction of change of estimated shunt can be wrong.

Non-invasive estimates of V/Q mismatch and shunt

Simpler lung models using varying FiO2 as a forcing function are
discussed above.

Arteriol blood
Indices of arterial oxygenation are PaO2 and SaO2. They are linked by the
HbO2 dissociation curve. Hypoxaemia is defined as PaO2<60mmHg
(7.8kPa) or SaO2<0.9. These values lie near the descending por
tion of the HbO2 dissociation curve, so that a further drop in PaO2 leads to a
marked fall in SaO2 and thus CaO2.

BLOOD GAS ANALYSIS AND CO-OXIMETRY

Arterial blood is collected in a purpose-designed syringe containing lyophilised
heparin to a final concentration of 2050U/mL. PaO2 measurements are made
by a Clark electrode, and SaO2 by CO-oximetry. The Clark electrode works on
polarographic principles, and a CO-oximeter computes the concentrations of each
of the four main haemoglobin species (HbO2, Hb, COHb, MetHb) from light
absorbances of haemolysed blood at several wavelengths. SaO2 is functional
saturation, determined from concentrations of HbO2 and Hb. Interference to CO-
oximetry arises from substances with competing absorbance spectra, such as
bilirubin, HbF, lipid emulsions and intravenous dyes. Increasing the number of
wavelengths, for example to 128, can reduce or eliminate interference.
ERRORS
Pre-analytic and analytic errors in PO2 measurement are set out in.

TEMPERATURE CORRECTION
All measurements are at 37C. Temperature-corrected values can be
calculated if the core temperature of thepatient is entered into the device software.
Most clinicians interpret blood gas data at 37C, except when evaluating the Aa
gradient (Acidbase balance and disorders).

CONTINUOUS INTRA-ARTERIAL BLOOD GAS MONITORING

Multiparameter fibreoptic sensors can be placed in the arterial stream.
Fibreoptic sensors are called optodes, and those measuring PO2 normally
operate by fluo rescence quenching. They require calibration with precision
gases or solutions before use. Typical sensors are 0.5mm in diameter, and can
be inserted through 20G arterial cannulae. The 90% in vitro response time to a
change in PO2 is 78 seconds. PO2 drift in vivo is 0.03mmHg/h
(0.0039kPa/h). Recalibration in vivo can be performed against conventional
blood gas analysis. Accuracy on in vitro and animal testing is good.
Clinical trials evaluating the accuracy of these monitoring systems have
revealed varying degrees of bias and imprecision. Evidence demonstrating an
improved outcome when therapeutic decisions are based on data from these
devices is lacking. These factors combined with the costs of these devices have
limited their bedside application.
Problems encountered with intra-arterial sensors, particularly artefactual
due to flow and position, have prompted the development of extracorporeal
monitors that can be placed in line but ex vivo. These devices do not provide
continuous real-time data. When a measurement is desired, a sample is drawn into
the externally located cassette then returned. Results are available in two minutes.
In preterm neonates this method can reduce red cell transfusion requirements.28
TRANSCUTANEOUS PO2 AND PCO2 MONITORING
Continuous non-invasive assessment of blood gas tensions is possible with
transcutaneous PO2 and PCO2 monitoring. Available systems incorporate O2 and
CO2 electrodes with integral thermistors and servocontrolled heaters. PO2
measurement utilises the principle of the Clark electrode, while the PCO2 device
is a pH-sensitive glass electrode. The skin is warmed to 4244C to achieve good
correlation with arterial values. Transcutaneous monitors generate reliable PCO2
values provided perfusion is unimpaired, but PO2 measurements are more for
trend analysis. Skin warming necessitates frequent site changes to prevent burns,
and there is a need for regular recalibration. Monitoring is not recommended in
haemodynamically unstable patients.
Transcutaneous monitors have a role in the prevention of neonatal
hyperoxia, which is not reliably detected by pulse oximetry.29 They may also
have a role in the detection of sleep apnoea and hypoventilation syndromes, and
for monitoring during nocturnal noninvasive ventilation.

PULSE OXIMETRY
Pulse oximetry determines SpO2 from the absorbance of light at
wavelengths 660nm (red) and 940nm (infrared) by tissue capillary beds
such as fingers, forehead, earlobes and the nasal septum. Two light-emitting
diodes cycle on and off at multiples of the mains frequency. A single photodiode
detects the transmitted light, and applies a correction for background ambient
light. The emergent signal is pulsatile due to arterial volume fluctuations.
Subtraction of the background signal (tissue, capillary blood and venous blood)
isolates the arterial component.
For both wavelengths, absorbance (A) is determined as follows:
A = log 10 (I0 /I)
where I0=incident light intensity and I=emergent light
intensity. For a given chromophore, A is proportional to its concentration (Beers
law) and to the path length( Lamberts law). From the pulsatile (AC) and
background (DC) absorbance signals at both wavelengths, a ratio (R) is derived:
 R = (AC660 /DC660 )/(AC940 /DC940 )
SpO2 is then computed from R, using software look-up tables of
empirically derived relationships between R values and either SaO2 or FHbO2
measured in the arterial blood of volunteers breathing hypoxic gas mixtures.
SpO2 is usually displayed as a percentage. Since the signal is derived from
two wavelengths there is an inherent incorrect assumption that HbO2 and Hb are
the only haemoglobin species in the light path. However, with normal
dyshaemoglobin concentrations the error is trivial. Some manufacturers calibrate
R against FHbO2 (fractional saturation) rather than SaO2 (functional saturation).
Provided volunteers generating the data have normal dyshaemoglobin
concentrations, differences between the two calibrations are small.

SPEED OF RESPONSE
SpO2 is averaged over 36 seconds, and updated every 0.51 second. With
forehead probes a sudden reduction in FiO2 produces a response within 1015
seconds, whereas with finger probes and peripheral vasoconstriction the delay can
exceed 1 minute.

ACCURACY
In the 9097% saturation range, SpO2 has a mean absolute bias of <1%,
and a precision (SD of bias) of <3%. At SaO2<0.8 there is significant
imprecision and a tendency towards negative bias. This is because very low SaO2
values are unsafe in volunteers, necessitating extrapolation from SpO2/R
relationships at higher saturations.

ERROR
Causes of error are set out in. A falsely high SpO2 is of greatest concern.
Unlike CO-oximetry, pulse oximetry is not subject to interference from bilirubin,
lipid emulsions and HbF.
Dyshaemoglobins and pulse oximetry
Pulse oximeters cannot distinguish COHb from HbO2. When [COHb] is
elevated, SpO2 tends to overestimate SaO2. SpO2 can thus provide false
reassurance when hypoxaemia is combined with a high [COHb], for example after
an inhalational burn injury. MetHb has more complex effects, since it absorbs
both wavelengths. At normal saturations, increased [MetHb] causes
underestimation of SaO2, but at very low oxygen tensions overestimation is
possible. At [MetHb]35%, the R value becomes unity, which translates
to SpO2=85%.

IMPORTANCE OF PULSE OXIMETRY

Pulse oximeters generate accurate real-time information without
calibration, within moments of sensor placement. They are mandatory in patient
transport, and in high-acuity areas such as operating rooms, recovery rooms and
intensive care units. They are also useful screening tools. On the down side, pulse
oximeters are insensitive to changes in arterial oxygenation at higher PaO2 values
(>70100mmHg (9.113kPa)). They are also the most common source
of false alarms in intensive care.

PULSE CO-OXIMETRY
Additional continuous real-time non-invasive monitoring of absolute total
haemoglobin concentrations and trends becomes possible with these
multiwavelength devices. Accuracy remains acceptable in low perfusion states
and in patients requiring vasopressor support.

MONITORING HAEMOGLOBINOXYGEN AFFINITY

Haemoglobinoxygen affinity is the relationship between the oxygen
tension of blood and its oxygen content, described by the sigmoid-shaped HbO2
dissociation curve. The P50 is the oxygen tension at SO2=0.5. The normal
value in humans is 26.7mmHg (3.47kPa). Factors that decrease
haemoglobinoxygen affinity increase the P50. They include acidaemia (the Bohr
effect), hypercarbia, increased erythrocytic 2,3-DPG and fever, whereas P50 is
decreased (increased affinity) by alkalaemia, hypo carbia, low 2,3-DPG
concentrations, hypothermia, COHb, MetHb and FHb. In the intensive care unit, it
is possible to calculate accurate P50 values from a single measurement of blood
gases and SaO2 up to SaO2=0.97. However, the impact of haemoglobin
oxygen affinity on tissue oxygenation in critical illness appears to be small,
making routine monitoring unnecessary.

Oxygen dinamicsOXYGEN DYNAMICS

Common indices of oxygen dynamics are set out in

DO2/VO2 RELATIONSHIPS
Nearly 40 years ago an association was reported between hyperdynamic
oxygen flow patterns and survival after high-risk non-cardiac surgery. This led to
the concept that maintaining an induced perioperative hyperdynamic state to
prevent an acquired oxygen debt might be protective. Although supported at a
singlecentre level, this hypothesis was not validated by large multicentre studies.
In fact, aggressive pursuit of hyperdynamic goals seemed counterproductive for
the broad ICU population.
Common therapeutic goals were CI>4.5L/min/m2, DO2
I>600mL/min/m2, VO2 I>170mL/min/m2. How ever the VO2 I
target was especially difficult to achieve. The focus subsequently narrowed to the
DO2 I target alone, which removed the need for PA catheterisation. On this basis
there is better emerging evidence of benefit in high-risk surgery,4143 although
definitive multicentre confirmation is awaited.

MEASURING DO2I
Although DO2 I determinations require accurate measurements of CI and
CaO2 , a PA catheter is not essential. Normal ranges can be quoted, but oxygen
demand in critical illness is so variable that isolated DO2 I measurements are
difficult to interpret.
MEASURING VO2I
The two methods of measuring VO2 I are the reverse Fick method and
indirect calorimetry.

Reverse Fick method

The reverse Fick method requires a PA catheter, and has large random
errors ranging from 17% overestimation to 13% underestimation. Changes cannot
be detected reliably unless they exceed 20%. The error is increased by lung
inflammation, when up to 20% of VO2 I can arise from the lungs alone.

Indirect calorimetry
Indirect calorimetry has better accuracy. VO2 I is determined from the
volumes and oxygen concentrations of inspired and expired gas. However, high
FiO2 settings introduce error. Newer devices retain accuracy up to
FiO2=0.8, with relative errors of <5%.

MIXED VENOUS BLOOD

Mixed venous sampling is by gentle aspiration of blood from the distal
port of an unwedged PA catheter to ensure complete admixture of blood from
superior and inferior venae cavae and coronary sinus. Mixed venous O2 and CO2
tensions and content are flow-weighted averages of the venous effluents of
multiple tissues. As such they can fail to detect pockets of hypoxia and
hypercarbia.

MIXED VENOUS PO2 (PvO2)

Venous gas tensions reflect post-capillary and tissue gas tensions. A PvO2
below 26mmHg (3.38kPa) is suggestive of cellular hypoxia. Paradoxically,
a normal or high PvO2 does not exclude regional tissue hypoxia, whether
cytopathic45 or as a result of tissue shunting.
MIXED VENOUS OXYGEN SATURATION (SvO2)
SvO2 is measured either intermittently by CO-oximetry on mixed venous
samples or continuously by fibreoptic reflectance oximetry using a modified PA
catheter. SvO2 measurements have a number of potential uses:
1. To calculate CvO2. CvO2 can then be used to determine Qs/Qt, VO2 I by the
reverse Fick method, the oxygen extraction ratio, and cardiac output by the Fick
method.
2. As an indirect index of tissue hypoxia. A SvO2 value of 0.5 corresponds to the
theoretical critical PvO2 of 26mmHg (3.38kPa). Values between 0.7 and
0.8 represent a desirable balance between global oxygen supply and demand, with
lactic acidosis appearing between 0.3 and 0.5.
Values exceeding 0.8 can be seen in high-flow states such as sepsis,
hyperthyroidism and severe liver disease. SvO2 as a therapeutic target (0.7)
failed to improve survival in a multicentre trial. Only two-thirds of the treatment
group achieved the target. Like PvO2, SvO2 is insensitive to cytopathic hypoxia
and tissue shunting. In chronic heart failure, low values are surprisingly
well tolerated.

CENTRAL VENOUS SATURATION (ScvO2)47

As with SvO2, ScvO2 can be measured either continuously using a central
venous catheter modified for reflectance oximetry, or by intermittent sampling
and CO-oximetry. ScvO2 is normally 23% lower than SvO2. However, in shock
this difference can be reversed. Trends in SvO2 and ScvO2 in response to
management usually run in parallel. In the Rivers single-centre study of early
intervention in the hypodynamic phase of severe sepsis and septic shock,
resuscitation was directed at a ScvO2 target of >0.7, along with specific central
venous pressure and mean arterial pressure goals and an aggressive transfusion
policy.
There were reductions in 28- and 60-day mortality and in the duration of
hospitalisation compared with standard treatment. A target of ScvO20.7
now has equal billing with SvO20.65 in the management guidelines of the
Surviving Sepsis Campaign.It is unclear whether intermittent sampling can be
substituted with equivalent benefit. In a subsequent multicentre study with a
protocol similar to that of the Rivers study, 10% venous lactate clearance was at
least equivalent (non-inferior) to ScvO2 as a therapeutic target in severe sepsis
and septic shock. Furthermore, judging by the low take-up in Australia and New
Zealand clinicians still question whether the Rivers findings can be generalised to
the wider emergency and critical care septic population. This is the subject of a
multicentre trial (Australasian Resuscitation in Sepsis Evaluation Randomised
Controlled Trial.

MIXED VENOUSARTERIAL PCO2 GRADIENT (_PCO2)

_PCO2 (normally about 6mmHg (0.78kPa)) is markedly
increased during cardiac arrest and in experimental low-output states, but lacks
sensitivity and specificity as a global index of tissue hypoxia. A sudden increase
in the respiratory quotient (VCO2/VO2), or in the venoarterial CO2 tension
difference/arteriovenous O2 content difference to >1.454 may be more reliable
markers of the onset of anaerobic metabolism. The central venous arterial PCO2
gradient appears to behave similarly to _PCO2 as an index of reduced tissue
perfusion.

Regional oxygenation indices

REGIONAL PCO2
Regional PCO2 reflects the balance between arterial blood CO2 content,
tissue blood flow and tissue CO2 production. The CO2 gap, which is regional
PCO2PaCO2, was devised to correct regional PCO2 for varying arterial
CO2 content. As tissue blood flow falls, reduced CO2 clearance causes the CO2
gap to increase. With the onset of anaerobic metabolism, tissue CO2 production
steadily decreases, although regional metabolic acidosis generates some CO2
by proton titration of tissue and capillary HCO3 . A rising CO2 gap signals
falling tissue blood flow. It cannot identify the onset of anaerobic metabolism.57
GASTRIC TONOMETRY
Gastric tonometry was developed in the knowledge that splanchnic
hypoperfusion occurs early in circulatory shock, tends to persist as covert shock,
and is manifested by intramucosal hypercarbia and acidosis. A gastric tonometer
was developed as a modified nasogastric tube with a silicone balloon 11.4cm
from the tip. Gastric mucosal CO2 equilibrates with luminal CO2, which
equilibrates with (and is measured in) fluid filling the balloon. Early on, this fluid
was saline. Subsequently air was found to have more rapid equilibration
characteristics. The original method involved calculation of intramucosal pH
(pHi) by substituting gastric luminal PCO2 and arterial [HCO3] in the
HendersonHasselbalch equation. Intramucosal acidosis was defined as
pHi<7.3 and taken to indicate inadequate splanchnic perfusion.
However, although pHi can reflect shock severity, it has been difficult to
demonstrate its value as a therapeutic target. Changing the monitoring end-point
from pHi to the mucosalarterial CO2 gap (normally 810mmHg (1.04
1.3kPa)) has removed the most fundamental flaw: the use of arterial
[HCO3] as a surrogate for mucosal [HCO3]. The gastric CO2 gap derived from
air tonometry is an independent prognostic factor in critical illness. Simultaneous
end-tidal CO2 measurement allows the regular calculation of a gastric to end-tidal
CO2 gap, a parameter linked to outcome in high-risk surgery.
Despite these improvements, the technique has not found widespread
application. There have been several barriers:
1. The need for a nasogastric tube
2. Signal degradation by luminal contents, including feeds and blood; feeds must
be stopped 2 hours prior to measurements, jeopardising nutritional support
3. Inability to identify a clear hypoxic threshold; empirical recommendations have
been to target a CO2 gap <25mmHg (3.25kPa)
4. A need to suppress gastric acidity to prevent luminal CO2 generation by HCl
titration of duodenal bicarbonate
5. A lack of convincing evidence that tonometryguided therapy improves
outcome.
SUBLINGUAL CAPNOMETRY56
Measurement of the sublingual interstitial CO2 tension has the advantage
of accessibility with minimal invasion. Optode sensors provide the most rapid
response. As with all tissues, sublingual PCO2 is best combined with PaCO2 to
generate the sublingual CO2 gap, which tracks sublingual microcirculatory blood
flow. The sublingual CO2 gap has predicted outcome better than lactate or SvO2
in a limited number of shocked patients. It remains to be seen whether the
technique can be used to guide therapy. More recently earlobe PCO2 has shown
similar potential.

CEREBROVENOUS OXYGEN SATURATION MONITORING DIRECT

TISSUE PO2 MEASUREMENT
Measurements have been recorded primarily in animal models in the brain,
subcutaneous tissue, muscle and renal beds under a variety of perfusion insults.
Tensions are commonly around 3045mmHg (3.95.85kPa), but can range
from <10mmHg (1.3kPa) in the renal medulla to >70mmHg (9.1kPa)
in subcutaneous tissue. In patients this is largely impractical, although in vivo
magnetic resonance imaging is one possible future approach.

OTHER REGIONAL TECHNIQUES DYNAMIC MICROCIRCULATORY

IMAGING
Orthogonal polarisation spectroscopy (OPS) and sidestream dark field
(SDF) imaging allow real-time quantification of microvascular flow via derived
indices such as the functional capillary density and mean flow index. The
tissue bed most commonly evaluated in intensive care has been the sublingual
circulation, but rectal, oral, ileal (via stoma) and other microcirculations can be
visualised. The rationale is an extension of the covert or compensated shock
concept as originally applied to gastric tonometry, in which multiple organ
dysfunction is driven by subtle microcirculatory compromise causing an ongoing
tissue oxygen deficit despite acceptable macrocirculatory parameters. Of some
concern, the relationship between sublingual and intestinal microcirculations may
not be reliably consistent, for example in early abdominal sepsis.

NEAR-INFRARED SPECTROSCOPY (NIRS) WITH FUNCTIONAL

OCCLUSION TEST
NIRS uses the differential absorbance properties of HbO2 and Hb in
muscle vessels with diameter <1mm (arterioles, venules and capillaries)
subjected to light of wavelengths 680800nm. Light at these wavelengths
penetrates >1cm below the skin, but 95% of the detected signal is from tissue
<2.4mm in depth. The thenar eminence is normally selected for its reliable low
subcutaneous thickness at any body mass index and its amenability to induced
proximal vascular occlusion via a blood pressure cuff. Device software calculates
three main parameters; tissue haemoglobin saturation (StO2), total tissue
haemoglobin (TTH) and absolute tissue haemoglobin index (THI). Preliminary
data from patients with septic shock suggest that the thenar eminence and knee
area tissue oxygen saturation may be predictive of mortality; however, these
variables were not superior to arterial lactate in their predictive ability. The
functional occlusion test is designed to detect subtle microcirculatory dysfunction,
which may be present in covert shock despite unremarkable resting StO2 values.
The sphygmomanometer cuff is inflated>30mmHg (3.9kPa) above systolic
pressure either for 3 minutes or until StO2 stabilises at 40%, then released.
The StO2 desaturation slope (RdecStO2) during occlusion is an indirect
index of muscle VO2 (reduced in sepsis and shock states). On cuff release the
resaturation slope (RincStO2) coupled with the degree of StO2 overshoot (_StO2 )
and the THI increment due to the associated reactive hyperaemia quantify
reperfusion dynamicsand vascular recruitment. These are also decreased in
sepsis and shock states. Other regional techniques showing some promise include
use of the pulse oximeter plethysmographic curve as a means of monitoring the
microcirculation (as well as macrocirculatory fluid responsiveness) and optical
spectroscopy.
THE PROBLEM OF TISSUE HETEROGENEITY
Despite the emerging human data concerning tissue oxygenation, several
areas of uncertainty remain due to the microcirculatory heterogeneity of different
tissue beds. There are important differences in both the magnitude and direction of
response to a hypoxic or a hypotensive insult. Consequently, identification of a
dysoxic threshold in individual tissues remains difficult. More precise knowledge
of these variables should eventually provide clinicians with practical resuscitation
end-points in hypoxia and shock and may facilitate the practice of permissive
hypoxia, but at present titration of therapy based on monitoring of tissue
oxygenation remains an elusive goal.
REGIONAL OXYGENATION