CHEST Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Monitoring Tissue Perfusion, Oxygenation,

and Metabolism in Critically Ill Patients
Nasirul J. Ekbal, MBBS; Alex Dyson, PhD; Claire Black, MSc; and Mervyn Singer, MD

Alterations in oxygen transport and use are integral to the development of multiple organ failure;
therefore, the ultimate goal of resuscitation is to restore effective tissue oxygenation and cellular
metabolism. Hemodynamic monitoring is the cornerstone of management to promptly identify
and appropriately manage (impending) organ dysfunction. Prospective randomized trials have
confirmed outcome benefit when preemptive or early treatment is directed toward maintaining
or restoring adequate tissue perfusion. However, treatment end points remain controversial, in
large part because of current difficulties in determining what constitutes “optimal.” Information
gained from global whole-body monitoring may not detect regional organ perfusion abnormal-
ities until they are well advanced. Conversely, the ideal “canary” organ that is readily accessible
for monitoring, yet offers an early and sensitive indicator of tissue “unwellness,” remains to be
firmly identified. This review describes techniques available for real-time monitoring of tissue
perfusion and metabolism and highlights novel developments that may complement or even
supersede current tools. CHEST 2013; 143(6):1799–1808

Abbreviations: ATP 5 adenosine triphosphate; COX 5 cytochrome oxidase; LDF 5 laser Doppler flowmetry; MRS 5
magnetic resonance spectroscopy; NADH 5 reduced form of nicotinamide adenine dinucleotide; NIRS 5 near-infrared
resonance spectroscopy; PCr 5 phosphocreatine; Pi 5 inorganic phosphate; SDF 5 sidestream dark field; Sto2 5 tissue
oxygen saturation; tPo2 5 tissue oxygen tension

Theoxygen
role of the circulation is to deliver adequate
and nutrients to meet tissue metabolic
demands.1 Circulatory shock represents inadequate
cellular oxygen supply (hypoxia), and/or impaired
oxygen use (dysoxia). This can, if not corrected promptly,
progress to organ dysfunction and failure. Early resus-
citation regimens targeted toward prespecified hemo-
dynamic values improve outcomes in patients with
severe sepsis or undergoing high-risk surgery.2,3 This
strategy does not, however, benefit patients in estab-
lished organ failure.4,5 Thus, a relatively narrow window
of opportunity exists to provide tissues with sufficient
oxygen to restore cellular metabolism and prevent/ame-
liorate further organ dysfunction.
Assessment of the adequacy of oxygen delivery and
use is therefore key to early identification and inter-
vention. Traditional markers such as urine output and
BP remain in common use to evaluate tissue hypop-
erfusion yet are nonspecific and often change belatedly.6
Newer techniques, although superior, still have limi-
tations. For example, mixed or central venous oxygen
saturation reflects the global oxygen supply-demand
balance yet may not recognize any local mismatch,
particularly in “canary organs” whose perfusion may
be compromised before others. Organs vary in their
metabolic activity and the blood flow they receive. As
exemplars, 70% to 75% of hepatic blood flow arises
from the portal vein that carries blood already deoxy-
genated after passage through the gut. Renal blood
flow accounts for 20% to 25% of cardiac output yet
only consumes 7% to 8% of total oxygen consump-
tion. The kidney regions also vary markedly in terms of
oxygen delivery and metabolic rate, resulting in marked
intrarenal differences in oxygen tension.7 Oxygen
extraction by the resting heart exceeds 55%, so sub-
stantial increases in myocardial oxygen supply require
significant (up to fivefold) increases in coronary blood
flow.8 Hyperlactatemia, the product of an imbalance
between lactate production and metabolism, is also
frequently used as a marker of tissue hypoperfusion.
Although sensitive, it too is a somewhat nonspecific
marker of global tissue hypoxia.9
Recognition of the limitations of global “whole body”
monitoring techniques has stimulated efforts to develop
devices that evaluate regional tissue perfusion and
oxygenation. Characteristics of the ideal monitoring

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 system are summarized in Table 1. For any monitor
of a regional bed, an important consideration is whether
it reflects changes occurring in other organs during a
systemic insult. Preferably, this should occur concur-
rently or, ideally, beforehand to provide an early warn-
ing system enabling prompt intervention and correction
of the problem. This is particularly pertinent when
using an accessible site such as mouth (sublingual),
bladder, muscle, or subcutaneous tissue as a surro-
gate for deeper “vital” organs such as liver, brain, and
kidney. This is complicated by physiologic differences
specific to certain organs, as described previously, and
to pathophysiologic or compensatory mechanisms.
Techniques that monitor regional perfusion target
different compartments (Fig 1). This review highlights
key principles underlying these techniques and their
current usefulness. Some are available as clinical tools,
whereas others are still at the animal or early human
testing stage. No commercial device has yet been
enshrined as “standard of care” within (inter)national
management protocols. This is often because of their
relative lack of user friendliness as a bedside tool,
and/or an inability to deliver quantitative data, and/or
a paucity of multicenter trial outcomes data to make
an overwhelming case for their incorporation as a
routinely used bedside device.
Microcirculation Measurements
The microcirculation is defined as vessels with diam-
eters , 100 mm (ie, arterioles, capillaries, and venules).10
Several techniques can monitor or visualize the micro-
circulation in situ and are available for patient use.
Microcirculatory Hemoglobin Oxygenation
Near-infrared resonance spectroscopy (NIRS) is a
noninvasive optical technique based on passage of
infrared light (680-800 nm) through biologic tissues.
By the Beer-Lambert law, the NIRS signal is limited to
Manuscript received July 23, 2012; revision accepted November 27,
2012.
Affiliations: From the Bloomsbury Institute of Intensive Care Med-
icine, Division of Medicine, University College London, London,
England.
Funding/Support: The authors work at University College London
Hospitals/University College London, which receives a propor-
tion of its funding from the UK Department of Health’s National
Institute for Health Research Biomedical Research Centre’s fund-
ing scheme. Dr Ekbal is funded by the Medical Research Council
and Claire Black by the UK National Institute for Health Research.
Correspondence to: Prof Mervyn Singer, MD, Bloomsbury
Institute of Intensive Care Medicine, University College London,
Cruciform Bldg, Gower St, London, WC1E 6BT, England; e-mail:
m.singer@ucl.ac.uk
© 2013 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-1849
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Table 1—Key Properties of an Ideal Monitor for Organ
Hypoperfusion
Provides accurate and reproducible results
High sensitivity and specificity delivered at an early point
Easy to use
Noninvasive or minimally invasive and causes no harm
Provides continuous and interpretable data
Not only reflects regional data but also useful as an early indicator of
systemic hypoperfusion
Provides information to guide therapeutic interventions
interrogating small vessels (, 1 mm diameter) only. The
amount of light recovered after illumination depends
on the degree of scattering within the tissue and by the
three molecules known to affect near-infrared light
absorption, namely hemoglobin, myoglobin, and mito-
chondrial cytochrome oxidase (COX). Differential
absorption patterns depend on whether these chromo-
phobes are oxygen bound (Fig 2). Predefined algo-
rithms generate concentrations; as the contributions of
myoglobin and COX to light attenuation is relatively
minor, NIRS predominantly assesses microvascular
oxyhemoglobin and deoxyhemoglobin. Some special-
ized machines can generate a COX signal (see later).
Tissue oxygen saturation (Sto2) is calculated from
the fractions of oxyhemoglobin and deoxyhemoglo-
bin. As 75% of blood within skeletal muscle is venous,
the NIRS Sto2 value mostly represents local venous
oxyhemoglobin saturation rather than that of tissue.
It thus reflects both local supply-demand balance and
any arteriovenous shunting present.
The thenar eminence, a superficial muscle with
little interference from overlying fat and subcutaneous
tissue, is the main site used for Sto2 monitoring. Edema
may result in artifact and be problematic, with venous
congestion, hypoalbuminemia, and/or increased endo-
thelial leak. Brain Sto2 monitoring has been success-
fully applied in neonates11 and animal models12 but is
more challenging in adults because of interference
from scalp blood flow.13 An issue with thenar muscle
NIRS monitoring is the wide range (52%-98%) found
in healthy subjects.14 NIRS values are also affected by
age, BMI, sex, race, and smoking.
As changes in Sto2 reflect changes in flow and/or
metabolism, a proportional change may leave Sto2
unaltered. This may explain why absolute values fell
outside the normal range in severely shocked trauma
patients14 and in septic shock only when oxygen delivery
fell markedly.15,16
More utility can be derived from a dynamic vascu-
lar occlusion test to evaluate the Sto2 response to a
sudden loss of oxygen supply.17,18 The rate of fall of
Sto2 following arterial and/or venous occlusion is
decreased in shocked compared with nonshocked
septic patients or healthy volunteers The Sto2 recov-
ery slope seen on reperfusion evaluates both the limb’s
Postgraduate Education Corner
 Figure 1. Techniques for monitoring regional perfusion. LDF 5 laser Doppler flowmetry; MRS 5
magnetic resonance spectroscopy; NIRS 5 near-infrared resonance spectroscopy; O2 5 oxygen; SDF 5
sidestream dark field; tPO2 5 tissue oxygen tension.
oxygen content and the capacity to recruit arterioles
and venules (microvascular reserve). The slope may
be altered by different pathologies or therapeutic inter-
ventions (Fig 3). In sepsis, the alterations seen sug-
gest both microcirculatory dysfunction and impaired
use of oxygen (mitochondrial dysfunction ⫾ reduced
metabolism).17,18
Figure 2. NIRS absorption spectra for HbO2 and Hb, MbO2, and
Mb. The spectrum for COx represents the oxidized minus the
reduced form. Line A and line B correspond to peak Hb and
HbO2 absorption wavelength, respectively. Line C corresponds
to the isobestic point. COx 5 cytochrome oxidase; Hb 5 deoxy-
hemoglogin; HbO2 5 oxyhemoglobin; Mb 5 deoxymyoglobin;
MbO2 5 oxymyoglobin. See Figure 1 legend for expansion of other
abbreviation.
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Laser Doppler Flowmetry
Laser Doppler flowmetry (LDF) uses wavelengths
of visible and infrared light to measure tissue perfu-
sion by exploiting changes in wavelength frequency
(Doppler shifts) that moving erythrocytes impart to
light. The chosen wavelength is usually 780 nm, as this
is near the isobestic point (800 nm) where the absorp-
tion spectra of oxyhemoglobin and deoxyhemoglobin
intersect (Fig 2); changes in blood oxygenation have
little effect on measurement. Laser light is delivered
fiberoptically and diffusely scattered by stationary tissue,
with some being reflected back with no change in wave-
length. However, photons that encounter moving RBCs
experience a Doppler shift, which is also detected.
This signal is proportional to perfusion (or flux) and
represents microvascular blood cell transport.19
In porcine hemorrhagic shock, changes in skin LDF
flux occurred earlier than heart rate, BP, arterial lac-
tate, or base deficit.20 After abdominal surgery or endo-
toxin administration, no effect was seen in intestinal
microcirculation despite fluid resuscitation and nor-
epinephrine to restore BP and regional blood flow to
baseline levels or above.21,22 By contrast, titrating nor-
epinephrine to obtain a mean arterial pressure of
90 mm Hg in patients with established septic shock
significantly increased red cell flux to deltoid muscle.23
LDF monitoring has several drawbacks. Outputs
are obtained as arbitrary perfusion units and not
CHEST / 143 / 6 / JUNE 2013 1801
 Figure 3. NIRS derived changes in thenar StO2 following arterial
and venous occlusion in septic patients. a 5 baseline measurements;
b 5 SI; c 5 reperfusion; d 5 reactive hyperemia; e 5 return to base-
line. SI 5 stagnant ischemia; StO2 5 tissue oxygen saturation. See
Figure 1 legend for expansion of other abbreviation.
absolute blood flow; thus, only trends can be assessed.
The result is a net vector flow in line with the direc-
tion of the incoming Doppler-shifted signal. As this
signal may contain components from blood flowing
through multiple vessels at varying angles to the
probe, results may vary considerably. This may also be
seen in tissues with a heterogeneous microcirculation.
It is thus important to fix the probe in position or to
use a multifiber array to increase the surface area
being captured.
Microvideoscopic Techniques
Historically, intravital microscopy was considered
the gold standard for microcirculation imaging. How-
ever, this is restricted to transilluminable tissues, such
as the nailfold bed, or requires specific dyes not licensed
for human use. Videomicroscopic imaging devices such
as sidestream dark field (SDF) imaging have sup-
planted intravital microscopy as a clinical tool to visu-
alize the microcirculation.24,25 Light is reflected by
superficial tissue layers but absorbed by hemoglobin
contained within erythrocytes. A 530-nm wavelength
is usually chosen, as this corresponds to the other
isobestic point in the absorption spectra of deoxyhemo-
globin and oxyhemoglobin. Absorbed light is reflected
back, allowing erythrocytes to be viewed as gray/black
bodies moving against a white background (Fig 4).
Tissue perfusion can be characterized in individual
vessels or averaged over an area within the device’s
field of vision. Studies have mainly focused upon the
sublingual circulation, although brain, eye, and diges-
tive tract have also been assessed in patient studies.26,27
The microcirculation cannot be monitored contin-
uously with SDF, although repeated images are gen-
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Figure 4. SDF imaging. A, Side view. B, Probe tip view. C, Still
SDF image of rat intestine microcirculation. LED 5 light emit-
ting diode. See Figure 1 legend for expansion of other abbreviation.
erally obtainable and reproducible. Recorded video
clips are measured offline using software that provides
a semiquantitative analysis. SDF is operator depen-
dent, so adequate training is needed to ensure that
image acquisition is satisfactory and video clips objec-
tively analyzed. A recent study found one-third of
recordings by a trained investigator were technically
excellent, whereas a further one-third showed pressure
artifact from the probe on the tissue surface.28 Recent
design improvements may overcome such issues.29
Notwithstanding these caveats, interesting data have
been generated during surgery in shocked patients
and animal models. The sickest septic patients pre-
senting to an ED had the greatest sublingual micro-
circulatory abnormalities, and this prognosticated for
eventual outcome.30 In a follow-up study investigating
early goal-directed therapy resuscitation, an associa-
tion was seen between microcirculatory improvement
and better outcomes.31 This may have been confounded
by greater norepinephrine use in patients with poor
outcome. In other human septic shock studies, no
change in preexisting sublingual microvascular flow
abnormalities was seen with norepinephrine, although
considerable interindividual variation was reported.23,32
Postgraduate Education Corner
 Hypoperfusion and increased flow heterogeneity
(rather than the expected hyperdynamic flow pattern)
are the main characteristics of the sublingual micro-
circulation in patients with established septic shock.33
Similar changes were seen in a cardiogenic shock
model, although the cerebral microcirculation remained
unaffected.34 Differences were also seen between
sublingual and intestinal microcirculations in septic
patients.35 Nitroglycerin in septic patients36 and fluid
loading plus dopexamine in high-risk surgical patients37
improved microcirculatory flow, yet no outcome ben-
efit was forthcoming. The precise role of microcircula-
tory manipulations in affecting mortality and morbidity
thus remains to be elucidated.
Monitoring the Extracellular
(Interstitial) Compartment
Tissue Oxygen Tension
Tissue oxygen tension (tPo2) measures the partial
pressure of oxygen within the interstitial (extravascular)
space. It represents the balance between local oxygen
delivery (from both macrocirculation and microcir-
culation) and consumption. Thus, matched increases
or decreases in local oxygen delivery and consumption
will not impact on tPo2. Depending upon an indi-
vidual organ’s metabolic activity and blood flow, the
tPo2 level varies markedly between organs.38
Traditional probes used Clark electrodes, which
generally contain a platinum cathode and silver anode
linked by a salt bridge. Oxygen diffusing through the
electrode membrane is reduced at the cathode sur-
face, completing an electrical circuit that generates a
current proportional to the oxygen content. Such
electrodes consume oxygen, which may be disadvan-
tageous when tPo2 is low. Newer techniques use dy-
namic luminescence quenching, involving transfer of
absorbed energy to oxygen from a light-excited lumi-
nophore (eg, ruthenium, platinum) encased within a
silicone matrix at the tip of a fiberoptic cable.38 No
oxygen is consumed by this process, and the decay
half-life (“quenching”) is inversely proportional to local
Po2. These optodes thus reliably determine low tPo2
values. Sensors can be precalibrated before insertion,
facilitating their use. We use a platinum-complex flu-
orophore sensor with an active surface area of 8 mm2
to broaden spatial tPo2 averaging. This sensor is now
being developed for patient use.
tPo2 monitoring has been studied widely in animal
models in multiple organs, including brain, gut, kidney,
liver, muscle, and bladder.39-41 In small-scale patient
studies, brain, conjunctiva, subcutaneous tissue, muscle,
and liver have been monitored during resuscitation
from hemorrhagic shock and trauma, during sepsis and
cardiogenic shock, and perioperatively.42-48 Outcome
improvements have been reported following the use of
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brain tPo2 monitoring after traumatic brain injury43,44;
however, this requires confirmation in larger studies.
Microdialysis
Microdialysis enables monitoring of energy-related
metabolites within the interstitial space. A solution of
known solute concentration (eg, Hartmann solution)
is slowly pumped through a thin catheter with a semi-
permeable membrane sited in interstitial tissue. This
is designed to mimic a capillary. Soluble small molecules
up to 30,000 Da (eg, glucose, lactate, pyruvate [reflect-
ing carbohydrate metabolism] and glycerol [reflecting
lipid breakdown]) equilibrate across the membrane
between extracellular space and perfusion fluid that
can be collected and analyzed. Other small molecules
such as adenosine, urea, amino acids such as glutamate,
hormones, and cytokines can be measured to enable
evaluation of drug delivery, pharmacokinetics/dynam-
ics, bioavailability, and bioequivalence.
Animal studies of sepsis49 and hemorrhage50 show
an increased tissue lactate and, more usefully, lac-
tate:pyruvate ratios. This has been reproduced in
studies of patients in septic shock.51,52 Changes in glu-
cose, glycerol, glutamate levels, and lactate:pyruvate
ratios denote the severity of brain injury and ischemia
following trauma and can independently prognosti-
cate.53 Tissue cortisol and antibiotic concentrations
can also be measured in patients.54,55 Before introduc-
tion into routine clinical practice its use as a monitoring
tool needs to be validated.
CO2 Tonometry
Tissue CO2 represents the balance between local
production and removal. A rising value likely reflects
a decrease in local blood flow rather than increased
local production of CO2 related to buffering of lactic
acid by tissue bicarbonate.56
Tissue CO2 has been measured in various tissues,
including subcutaneous, sublingual, small and large
bowel and, most notably, the stomach. Gastric tonom-
etry was in vogue as a research tool 15 to 20 years ago,
prompted by the identification that an increasing
gastric-arterial or gastric-end-tidal Pco2 gap or a falling
gastric intramucosal pH (placing the values into a
Henderson-Hasselbalch equation) were predictive of
complications and mortality in patients admitted to
intensive care or undergoing major surgery.57,58 The
original technique involved inserting saline into a
semipermeable gastric luminal balloon, allowing Pco2
equilibration with the gastric mucosa over 30 min,
and then aspirating the saline and measuring the Pco2
level in a blood gas analyzer. Gastric feed had to be
interrupted premeasurement, and gastric acid sup-
pressants were required. This proved too cumbersome
CHEST / 143 / 6 / JUNE 2013 1803
 for regular use. An automated, semicontinuous air
tonometric technique using infrared spectropho-
tometry to measure gastric CO2 levels offered faster
equilibration times and ease of use. However, a mul-
ticenter study failed to confirm adequate prognostic
capability,59 so the product was commercially aban-
doned. Despite this checkered history, utility in early
identification of tissue hypoperfusion has been dem-
onstrated in animal shock models using alternative
locations, such as subcutaneous tissue and bladder.50,60
Potentially, with newer technology offering user friend-
liness and increased accuracy, this concept could be
gainfully revitalized.
Mitochondrial Monitoring
Most of the body’s oxygen consumption is used by
mitochondria towards production of adenosine tri-
phosphate (ATP) and heat. Cell death pathways are
triggered by a rapid fall in ATP levels or via specific
mitochondrial mechanisms. Mitochondrial dysfunc-
tion also appears to be integral to the development of
multiorgan failure in sepsis.61 Therefore, assessing
mitochondrial function represents the holy grail of
monitoring the adequacy of organ perfusion. Early
identification of mitochondrial stress during major
surgery or critical illness from reactive species and
oxygen lack would enable prompt treatment and,
potentially, improved outcomes.
Mitochondrial Redox State
The mitochondrial electron transport chain accepts
electrons donated from the Krebs cycle via nicotin-
amide adenine dinucleotide (NADH) (to complex I)
and flavin adenine dinucleotide H2 (to complex II).
These electrons are passed down the chain, which
Figure 5. The mitochondrial electron transport chain. I, II, III, IV, and V 5 mitochondrial respiratory
chain complexes I to V; CoQ 5 conenzme Q; cyt c 5 cytochrome c; FAD 5 flavin adenine dinucleotide;
FADH2 5 flavin-adenine dinucleotide (reduced form); NADH 5 reduced form of nicotinamide adenine
dinucleotide; Pi 5 inorganic phosphate.
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consists of a series of redox reactions, with oxygen
being the terminal electron acceptor at complex IV
(COX). The passage of electrons allows proton move-
ment across the inner mitochondrial membrane; the
generated membrane potential drives ATP synthase
(complex V) to generate ATP from ADP and inor-
ganic phosphate (Pi) (Fig 5).
The redox reaction at complex I involves conver-
sion of the reduced form (NADH) to the oxidized
NAD1. At complex IV, oxidized COX is converted to
the reduced form. A lack of oxygen or a downstream
block in the chain (eg, carbon monoxide or cyanide
poisoning causing COX inhibition) will increase both
the NADH/NAD1 and the reduced/oxidized COX
ratios. Specific absorbance of light by reduced NADH
or oxidized COX enables ratiometric changes to be
followed, assuming total NAD and COX pools remain
unaltered. These properties can be used for clinical
monitoring to provide a reflection of oxygen avail-
ability within the mitochondrion.
NADH Fluorometry: Conveniently, NADH (but
not NAD1) autofluoresces in response to 340 nm
excitation light. The emitted light (450 nm) relates to
the concentration of the fluorescent compound and
represents changes in mitochondrial NADH, assuming
no change in the total NADH/NAD1 pool. Studies in
animals subjected to a range of physiologic and phar-
macologic insults have assessed NADH fluorescence
in various organ beds including brain, liver, kidney,
heart, spinal cord, and bladder.62-66 Clinical studies
are still limited. Mayevsky et al67 reported a case series
of responses of bladder wall NADH fluorescence in
patients in intensive care or undergoing surgery. Falls in
tissue oxygenation seen during aortic cross-clamping
or cessation of spontaneous breathing led to rises in
NADH. In a sequential hemorrhage rat model,68 there
were progressive rises in NADH fluorescence intensity
Postgraduate Education Corner
 to greater peaks, which then normalized through
hemodynamic/metabolic compensation. This contin-
ued until hemorrhage became so severe that compen-
sation was no longer possible and the NADH intensity
remained elevated (Fig 6).
Several challenges remain with this technique;
absolute values cannot be obtained, so changes in flu-
orescence are calculated as percentage values (or
arbitrary units) relative to calibrated signals made at
the beginning of measurement. Only surface probes
are used at present, and movement can result in
changes in fluorescence. This limits the technique at
present to short-term use. Data interpretation is also
complicated by distortion from tissue scattering and
absorption (eg, due to changes in blood volume),
requiring the need for correction techniques, which
also have limitations.69 More development is needed
to improve fixation to or within tissue before it can
become a commonplace clinical tool.
COX Redox State: COX contains two heme iron
(cytochrome a and a3) and two copper centers (CuA,
CuB) whose redox state changes during electron transfer
(Fig 7). The CuA center in the oxidized form strongly
absorbs in the near-infrared spectrum with a cha-
racteristic shape and broad peak at 830 nm. When
oxygen availability falls, the CuA center becomes
more reduced. This is detectable using near-infrared
spectroscopy70 and was shown in brain and skeletal
muscle to correlate well with oxygen use in animal
models of hypoxemia, hemorrhage, endotoxemia, and
ischemia-reperfusion.71-74 By contrast, oxygen delivery
and COX reduction were decoupled in trauma patients
with multiple organ failure compared with those
without multiple organ failure.75
Figure 6. Changes in skeletal tPO2, LDF, and surface NADH
fluorescence intensity following incremental hemorrhage. Due to
physiologic compensation, the NADH:NAD1 ratio recovers after
each 10% hemorrhage until 50% of blood volume has been removed.
See Figure 1 and 5 legends for expansion of other abbreviations.
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Figure 7. NIRS interrogation of cytochrome oxidase redox state.
c 5 cytochrome c; CuA and CuB 5 copper centers; Ha and Ha3 5
heme iron centers. See Figure 1 legend for expansion of other
abbreviation.
Advantages of this technique include the steady
state of the total COX concentration (unlike deoxyhe-
moglobin/oxyhemoglobin). However, the CuA con-
centration is , 10% that of hemoglobin, making optical
detection difficult. Since the absolute concentration
of CuA is unknown, as with oxyhemoglobin and NADH,
all measurements are expressed as absolute changes
from an arbitrary zero at the start of measurement.
Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy (MRS) may be
readily combined with MRI. MRI uses signals from
protons to form anatomic images, whereas MRS uses
radiolabeled molecules to determine metabolite con-
centrations and quantify tissue enzyme kinetics.
Although not a monitor as such, MRS offers useful
diagnostic capacity so will be briefly described.
In a magnetic field, nuclear magnetic resonance-
active nuclei absorb electromagnetic radiation at a
frequency specific to the isotope. Although various
nuclei may be used, only phosphorus and hydrogen
exist in concentrations high enough in vivo to be used
for routine clinical evaluation.76,77 For bioenergetic
studies, 31P-nuclear magnetic resonance is primarily
used, as it measures changes in phosphocreatine (PCr),
ATP, Pi, and intracellular pH during stress condi-
tions (eg, administration of dobutamine, transient
hypoxia).78,79 Values of ATP, PCr, and Pi are obtained
from characteristic peaks in the resonance spectrum.
Intracellular pH is calculated from the shift in dis-
tance between Pi and PCr peaks, as the Pi signal is
pH-sensitive (Fig 8).
PCr forms the primary ATP buffer in heart and
muscle cells, transferring its phosphate to ADP.79 Dur-
ing ischemia, PCr decreases while Pi increases to
maintain ATP homeostasis. Only when PCr is depleted
do ATP levels fall. A decrease in PCr/ATP ratio indi-
cates the level of stress to which myocardium or skeletal
CHEST / 143 / 6 / JUNE 2013 1805

Figure 8. Spectral peaks of ATP, PCr, and Pi obtained by nuclear
magnetic spectroscopy. ATP 5 adenine triphosphate; PCr 5 phos-
phocreatine; Pi 5 inorganic phosphate.
muscle is subject. This ratio remains constant under
mild to moderate stress but rapidly falls with tissue
ischemia. The rate of change in PCr/ATP ratio during
or on recovery from ischemia provides an index of flux.
Using saturation transfer techniques, ATP flux can be
measured. This flux is reduced in heart failure.79
Hydrogen MRS can measure molecules and metab-
olites involved in (patho)physiologic processes (eg,
N-acetyl-aspartate [decreased in brain injury], creatine
and phosphocreatine [involved in energy metabolism],
lactate [marker of anaerobic metabolism], alanine, glu-
cose, and choline compounds [markers of synthesis
and breakdown of cell membranes]). It is used clin-
ically for various conditions, particularly within the
brain, including oncology, demyelinating inflamma-
tory pathologies, infectious diseases, and metabolic
pathologies such as hepatic encephalopathy and dif-
fuse cerebral distress. In traumatic brain injury it
can delineate the degree of injury and prognosis, as the
detected metabolites are sensitive to hypoxia, energy
dysfunction, neuronal injury, membrane turnover, and
inflammation.80
Conclusions
The goals of resuscitation in critically ill patients
are to ensure adequate tissue perfusion and cellular
metabolism. Current clinical tools are, however, lack-
ing in the sensitivity and specificity needed to guide
optimal management. Advances in technology are
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providing promising noninvasive or minimally invasive
techniques. These, however, require initial validation
to ensure reliability and to gain the necessary confi-
dence that they can be used as surrogates reflecting
or, better still, preceding changes in deeper, more vital
organs. On satisfactory demonstration of the above,
randomized controlled trials can assess their impact
upon outcomes, and this must occur before potential
implementation into management guidelines.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Ekbal holds a UK
Medical Research Council Studentship to investigate NADH
fluoroscopy. Dr Dyson participated in a study funded as above to
develop tissue Po2 technology. University College London has
an Intellectual Property agreement with Oxford Optronix Ltd to
develop a clinical tissue Po2 monitor. Dr Black holds a fellow-
ship grant from UK National Institutes of Health Research assessing
means of individualizing rehabilitation of critically ill patients.
This partly involves study of metabolic monitoring, a device for
which was purchased under the grant. Dr Singer holds UK gov-
ernment/charitable grants to develop tissue Po2 and NADH fluo-
rometry technologies and to study metabolic monitoring.
Role of sponsors: The sponsors had no role in the design of the
study, the collection and analysis of the data, or in the preparation
of the manuscript.
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