V
Chapter
74
Cellular Respiration
Jerry J. Zimmerman, Amélie von Saint André-von Arnim, and Jerry McLaughlin
In every one of us there is a living process of combustion going
on very similar to that of a candle, and I must try to make that
plain to you. For it is not merely true in a poetical sense.
Michael Faraday, A Course of Six Lectures
on the Chemical History of a Candle (1861)
PEARLS
• M itochondria are responsible for the generation of more
than 95% of adenosine triphosphate synthesized to support
aerobic respiration. Mitochondria are also involved in
intracellular signaling, intracellular calcium regulation, cellular
differentiation and growth, and cellular death pathways. An
independent mitochondrial genome is located within the
mitochondrial matrix.
• T here are three paramount regulatory steps along the
respiration metabolic pathways:
1. Oxygen availability to serve as the ultimate electron acceptor.
2. Availability of nutrient metabolism to generate reducing
equivalents in the form of reduced nicotinamide adenine
dinucleotide (NADH) and the reduced form of flavine
dinucleotide (FADH2).
3. Overall cellular energy state defined by the ratio of
adenosine triphosphate/adenosine diphosphate.
• L actate metabolism in critical illness is complex and often
does not necessarily indicate ischemic tissues. A common
clinical scenario occurs during volume and vasoactive-
inotropic resuscitation of patients with normal saline
and epinephrine, in which a chloride load (iatrogenic
hyperchloremia) and type B lactic acidosis may be interpreted
as recalcitrant shock requiring further escalation of fluid and
vasoactive-inotropic support. This scenario may initiate a
vicious cycle and potential overresuscitation.
• If any of the five sources of hypoxemia—hypoventilation,
diffusion impairment, low inspired oxygen, shunt, ventilation/
perfusion mismatch—impairs adequate oxygenation of
hemoglobin and limits cellular respiration, hypoxemic dysoxia
results.
• C ytopathic dysoxia occurs when oxygen delivery is normal but
cellular pathophysiology prevents utilization of oxygen as the
terminal electron transport acceptor.
In 1920, Haldane was credited with the observation that hypox-
emia not only stops the [respiration] machine, but wrecks
the [respiration] machinery as well. Indeed, the priorities of
pediatric advanced life support are to avoid shock and respira-
tory failure, and the focus of cardiopulmonary ­resuscitation is
1058
restoration of airway, breathing, and circulation, all targeted
to maintain or reestablish oxygen delivery to tissues and cells.
During critical illness, marginal oxygen delivery and/or oxy-
gen consumption frequently manifest as the rate-limiting step
for efficient energy production in the form of adenosine tri-
phosphate (ATP). Inadequate ATP impairs the translation of
cellular structure to cellular function, a defining characteristic
of life.1 A working knowledge of cellular respiration basically
summarizes the key tenets of critical care medicine. This chap-
ter reviews the metabolism of respiration, summarizes various
modalities for monitoring respiration, and provides clinical
correlation of alterations in respiration that are addressed by
intensive care.
Metabolism of Respiration
Oxygen Chemistry
It is appropriate to initiate a discussion of respiration by describ-
ing the relevant characteristics of the rate-limiting substrate,
namely molecular oxygen, that serves as the terminal electron
acceptor in cellular respiration.1 Because of the paramount role
of oxygen in facilitating efficient production of ATP, oxygen has
played a central role in terms of evolution of complex multicellu-
lar life.2 In the biosphere, the concentration of oxygen is carefully
regulated by the processes of photosynthesis and respiration, the
former producing—and the latter consuming—atmospheric
dioxygen. Premolecular oxygen appeared on Earth’s surface
approximately 2 billion years ago and now represents the most
abundant element on Earth’s crust. At its baseline triplet state,
oxygen is a diradical with two unpaired electrons with paral-
lel spin occupying the outer orbital. In its role as the ultimate
electron accepter in cellular respiration, molecular oxygen
undergoes a four-electron reduction to water. With the bene­
fit of multiple redox electron exchanges, this process permits
controlled release of energy from carbohydrate, fat, and protein
energy substrates. Successive one-electron additions to molecu-
lar oxygen result in the production of superoxide anion, hydro-
gen peroxide, hydroxyl radical, and water, respectively (Figure
74-1). These partially reduced oxygen compounds are referred
to as reactive oxygen species and identify the so-called antagonistic
pleiotropy characteristic of oxygen.3
Derivation of the parent toxic reactive oxygen species,
superoxide anion, occurs by multiple mechanisms, but the
following four are prominent:
1. Mitochondrial electron transport bleed (approximately
1% to 2% of all electrons shuttled across mitochondrial
complexes I, II, and III produce partially reduced oxygen
­species)4

2. Reduced nicotinamide adenine dinucleotide phosphate
(NADPH) oxidoreductases and the related cytochrome
P-450 oxidation reactions5
3. Xanthine oxidase during reperfusion following ischemia
events6
4. Cyclooxygenase and lipoxygenase pathways in the metabo-
lism of arachidonic acid7
Oxygen toxicity was first predicted by both Priestly and
Lavoisier in 1729. It has been estimated that approximately
2 billion molecules of superoxide anion and hydrogen perox-
ide are produced per cell per day. An antioxidant repertoire
that includes superoxide dismutase, catalase, glutathione
peroxidase, uric acid, vitamin C, and vitamin E counteracts
this oxidant stress to minimize a tendency toward “rust and
rancidity.” However, oxidant stress plays an important role in
generalized aging as well as inflammation and ischemia-reper-
fusion pathophysiology. As Fridovich8 has noted, “the aerobic
lifestyle offers great advantages but is fraught with danger.”
Nitrogen chemistry is also involved in the generation of
reactive molecular species. Nitric oxide (NO) is known to be
generated from at least four NO synthase isoenzymes, includ-
ing constitutive, inducible, neuronal, and mitochondrial
forms. Figure 74-2 depicts the reaction catalyzed by nitric
oxide synthase.9
Production of NO is particularly prominent during peri-
ods of inflammation. At least in septic patients, intensity of
inducible NO production as measured by blood or urine
end catabolic products nitrate and nitrite, is directly associ-
ated with various measures of illness severity reflecting mul-
tiple organ dysfunction syndrome and death. Particularly in
the setting of tissue hypoxia, NO is believed to play a role
in regulation of mitochondrial respiration through nitrosyl
complexes with various iron-sulfur center enzymes as well as
Dioxygen O2
e–
·
Superoxide anion O2–
e–
Hydrogen peroxide H2O2
e–
Hydroxyl radical HO•
e–
Water H2O
Figure 74–1.  Successive one-electron reductions of molecular dioxygen
to water.
Arginine
H3N CH (CH2)3 NH C NH2
NADPH
COOH NH O2
BH4
Figure 74–2.  Synthesis of NO by NO synthase. BH4, Tetrahydrobiopterin.
Chapter 74 — Cellular Respiration 1059
direct competition with oxygen for binding at the heme active
site of cytochrome oxidase.10,11 Competitive inhibition of NO
with oxygen at cytochrome oxidase results in decreased oxy-
gen consumption, decreased binding affinity for oxygen, and
reduced ATP production.
Under specific conditions superoxide anion and NO can
condense to form the powerful oxidant peroxynitrite with
­diffusion-limited kinetics: 7 × 109 M−1 × sec−1.12 Behavior of
NO, superoxide anion, and peroxynitrite in clinical biochem-
istry has been characterized as “the good, the bad, and the
ugly.”13 For example, nitrotyrosine and dityrosine represent
tissue markers of peroxynitrite histopathology.14 Peroxynitrite
has been demonstrated to be involved in lipid peroxidation of
cell and organelle membranes, damage to various elements of
the mitochondrial electron transport chain and ATP synthase,
inhibition of glyceraldehyde 3-phosphate dehydrogenase,
injury of the sodium-potassium ATPase pump, disruption of
plasmalemma sodium channels, production of DNA strand
breaks, and activation of the poly-adenosine ribosyl phos-
phate system.15 Again in reference to cellular respiration,
peroxynitrite can mediate irreversible inhibition of the Krebs
cycle enzyme aconitase; mitochondrial complexes 1, 2 and
3; cytochrome oxidase; ATP synthase; and creatine kinase as
well as increase wasteful proton leakage. Reduced suflhydryls
represent another important target of peroxynitrite oxidation,
resulting in alteration of protein structure and function.16
Peroxynitrite is known to directly alter pulmonary surfactant
and injure human myocardial protein.14,17
Reactive oxygen and nitrogen species are also known to
affect intracellular signaling through a number of redox-sen-
sitive transcription factors, notably nuclear factor-κB (NFκB)
and activator protein-1 (AP-1).18 For example, as an aspect
of the pathophysiology of gram-negative sepsis, interaction of
endotoxin, toll-like receptor-4, and NADPH oxidase result in
an increased flux of reactive oxygen species and subsequent
activation of NFκB associated with transcription activation of
a host of proinflammatory mediators.19 In addition, peroxyni-
trite is known to modulate cell signaling by both phosphoryla-
tion as well as oxidation of critical protein tyrosine residues
along the mitogen-activated protein kinase pathways.20
Mitochondria
It has been estimated that more than 1 billion years ago some
aerobic bacteria invaded and subsequently colonized some
form of primordial eukaryotic cells that themselves lacked the
ability to use oxygen. At some point a symbiotic relationship
developed between the cell and the aerobic bacteria, and this
relationship has remained steadfast through evolution.21,22 Evi-
dence for the persistence of this endosymbiotic relationship sug-
gesting that mitochondria have retained many aspects of their
bacterial origins includes the observations that mitochondria
only arise from other mitochondria; that mitochondria main-
tain their own genome; that the mitochondrial chromosome
Citrulline
H3N CH (CH2)3 NH C NH2 + NO•
COOH O
1060 Section V — Renal, Endocrine, and Gastrointestinal Systems
is bacteria-like, circular in structure, and without associate
histones; that mitochondria synthesize their own proteins;
and that these mitochondrial proteins, like bacterial proteins,
exhibit N-formyl methionine; and that antibiotics that inhibit
protein synthesis in bacteria are also toxic to mitochondria.23
Mitochondria are responsible for the generation of more
than 95% of ATP synthesized to support aerobic respiration
(Figure 74-3). Enormous oxygen consumption by “power
plant” mitochondria represents a double-edged sword, on the
one hand permitting efficient production of ATP, but on the
other hand a potential source of high quantities of reactive
oxygen species. Assuming 388 L of oxygen consumed per day
by a normal adult, this would require 2 × 1019 molecules of
cytochrome oxidase. Considering this requirement as well as
that of other members of the mitochondrial electron transport
chain outlined below, the surface area of mitochondrial cristae
inner membrane to scaffold this quantity of respiration ele-
ments24 is approximately 14,000 m2.
In addition to their role in facilitating aerobic respira-
tion, mitochondria are also involved in intracellular signal-
ing, intracellular calcium regulation,25 cellular differentiation
and growth, and cellular death pathways.26,27 With respect to
the latter function, the mitochondria provide close monitor-
ing for a number of cellular “danger signals.” These include
loss of transmembrane potential, decreased ATP production,
increased influx of reactive oxygen and reactive nitrogen spe-
cies, leakage of mitochondrial proteins into the cytoplasm via
mitochondrial permeability transition pores, activation of
hypoxia-responsive genes, and recognition by the cell of mito-
chondrial proteins with signature N-formyl methionine.23
Mitochondria in cells may undergo cycles of both fusion and
fission.28 If the mitochondria “senses” overwhelming cell dam-
age as manifested by excessive reactive oxygen species, DNA
damage, denatured protein, ongoing inflammation, hypoxia,
or even deprivation of growth factors, the mitochondrial
pathway of cellular apoptosis may be initiated.29,30 If apoptosis
is initiated by excessive reactive oxygen species, activation of
the sphingomyelin/ceramide cycle precedes apoptosis.
Critical mitochondrial damage results in increased mito-
chondrial permeability, the mitochondrial permeability
transition that results in release of proapoptotic proteins,
including cytochrome c from the mitochondria into the cyto-
plasm. This results in activation of various caspase cascades
Figure 74–3.  Electron micrograph of a mitochondria at the site of cellu-
lar respiration. An invaginated cristae membrane provides the scaffolding
for components of the electron transport chain.
and resultant DNAase activation and DNA dissolution.31 Acti-
vation of the apoptotic pathway orchestrating cell death is also
governed by the relative concentrations of proteins BCL-2
and BCL-X. Integrity of the mitochondrial transport chain
complexes defines a fine line between maintaining mitochon-
drial homeostasis and efficient respiration versus excessive
oxygen free radical production, mitochondrial dysfunction,
and mitoptosis. This balance is maintained through multiple
feedback signals related to mitochondrial proton and calcium
concentrations, reactive oxygen species, overall mitochondrial
redox state, mitochondrial membrane potential, and mito-
chondrial matrix pH, all of which affect the cascade of electron
transfer along the mitochondrial transport chain.23 It has been
demonstrated that pathologic metabolic downregulation of
cytochrome oxidase, such as in the setting of excessive mito-
chondrial production of reactive nitrogen and oxygen species,
manifests as multiple organ dysfunction syndrome.32
Alterations in mitochondrial function in the setting of
shock have been extensively scrutinized.33-35 In addition to
decreased activity of specific mitochondrial enzymes previ-
ously indicated, altered translocase activity and mitochondrial
calcium transport are also coincident with actual changes in
mitochondrial morphology. In sepsis, increased NO produc-
tion has been associated with activation of the poly-adenosine
ribosyl phosphorylase (PARP) pathway, the former associated
with impaired binding of oxygen to cytochrome oxidase and
the latter associated with cellular depletion of NADH.36 In
various models of multiple organ dysfunction syndrome and
sepsis, mitochondrial permeability transition has been shown
to result in collapse of the mitochondrial electrochemical
gradient and impairment of ATP synthesis coincident with
calcium influx into the mitochondria. Sepsis inflammation
can induce a vicious cycle of oxidative mitochondrial dam-
age leading to an increased flux of reactive oxygen species
that further damage mitochondrial respiration components,
resulting in mitochondrial glutathione depletion, enhanced
mitochondrial membrane lipid peroxidation and decreased
copy number, increased deletions, and decreased messenger
RNA transcripts from mitochondrial DNA (Figure 74-4).37
Reactive*
oxygen
species
Endotoxin *O2•, H2O2, HO•
• Mitochondrial DNA
1. Decreased copy number
2. Increased deletions
3. Decreased mRNA transcripts
• GSH depletion
• Enhanced lipid peroxidation
Figure 74–4.  Vicious cycle mitochondrial injury in the setting of exces-
sive reactive nitrogen/oxygen species.
 Chapter 74 — Cellular Respiration 1061

The independent mitochondrial genome; located within the
mitochondrial matrix, is comprised of double-stranded, circu-
lar DNA of 16.6 kb and codes for 37 genes, including proteins
involved in various redox reactions, oxidative phosphoryla-
tion, ATP synthesis, and enzymes comprising the Krebs cycle,
fatty acid beta-oxidation, and pyruvate oxidation.38 Mito-
chondrial DNA mutations associated with the gene coding
for cytochrome oxidase have been clinically linked to Leigh
syndrome; mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke (MELAS); encephalomyopathy; lactic aci-
dosis; and mitochondrial proliferation in muscle biopsies, the
so-called characteristic histopathology of ragged red fibers.21
Adenosine Triphosphate
ATP is considered the molecular unit of intracellular energy
currency. ATP derives its inherent energy secondary to anhy-
dride bonds connecting adjacent phosphate functional groups.
Hydrolysis of ATP energy generates energy for all cellular
processes. In addition ATP also serves as a cofactor for sig-
nal transduction reactions using a variety of kinases as well as
adenyl cyclase. Normally cellular ATP concentration is main-
tained in the range of 1 to 10 mmol/L, with a normal ratio of
ATP/ADP of approximately 1000. Totally quantity of ATP in
an adult is approximately 0.10 mol/L. Approximately 100 to
150 mol/L of ATP are required daily, which means that each
ATP molecule is recycled some 1000 to 1500 times per day.
Basically, the human body turns over its weight in ATP daily.39
Transmembrane proton flux through the mitochondrial
ATPase synthase complex occurs at an estimated rate of 3 ×
1021 protons per second. This corresponds to ATP reformed at
a rate of 9 × 1020 molecules/sec, or approximately 65 kg ATP
recycled per day in a normal resting adult (Figure 74-5).24
Respiration, Metabolic Pathways
Glycolysis
As previously indicated, cellular respiration allows controlled
release of free energy from carbohydrate, fat, and protein
energy substrate. Cellular respiration consists of three related
series of biochemical reactions:
1. Degradative reactions resulting in the formation of acetyl
coenzyme A and reducing equivalents
2. Metabolism of acetate to carbon dioxide in the Krebs cycle
with generation of additional reducing equivalents
3. Shuttling of electrons generated from reducing equivalents
along the mitochondrial electron transport chain
Acetate coupled to coenzyme A (AcCoA) is derived from
carbohydrates, lipids, and proteins. Glucose is transported
into cells via glucose transporter (GLUT) receptors and
osmotic gradients (see Chapter 77). Ten enzymatic reac-
tions within the cell cytoplasm define the metabolic pathway,
termed glycolysis. These initial series of reactions ultimately
generate two net molecules of ATP, two molecules of NADH,
and two molecules of pyruvate.

Adenine

High energy NH2

anhydride Ester
linkages linkage N
N

O O O N
N
–O P O P O P O
O
–O –O –O

H
OH OH

Ribose

Adenosine

ATP

NH2 NH2

N N
N N

N N
O O N O N
–O P O P O –O P O
O O
–O –O –O

H H H H
OH OH OH OH
ADP AMP
Figure 74–5.  Structure of ATP. (Modified from Baynes JW, Dominiczak MH: Medical biochemistry, New York, 2009, Mosby Elsevier.)
1062 Section V — Renal, Endocrine, and Gastrointestinal Systems

The fates of pyruvate is multiple. Under anaerobic con-
ditions, pyruvate may be reduced by NADH to lactate to
regenerate NAD+. Alternatively, pyruvate is shuttled to the
mitochondria, where it is further metabolized to carbon
dioxide (CO2) and AcCoA. Pyruvate transamination yields
alanine, whereas pyruvate carboxylase generates oxylacetate
(Figure 74-6).
Catabolism of fatty acids by β-oxidation generates one
molecule of AcCoA and one molecule each of FADH2 and
NADH for each two-carbon fatty acid fragment cycle. These
reactions occur in the mitochondria after fatty acid transport
by a carnitine transport system. It should be appreciated that
generation of AcCoA by fatty acid β-oxidation occurs inde-
pendent of pyruvate dehydrogenase that can be rate limiting
for complete glucose metabolism. Particularly as an aspect
of the metabolic stress response mediated by cortisol, cat-
echolamines, and interleukins 6 and 2, protein degradation
can occur with release of amino acids. All amino acids may
be catabolized to either AcCoA or some Krebs cycle interme-
diate. Accordingly, amino acids can be mobilized for energy
production as well as de novo protein synthesis. Alternatively,
amino acids can undergo gluconeogenesis, a costly process
Alanine
NADH
NAD+
Alanine Lactate
transaminase O dehydrogenase
CH3 C COOH
Pyruvate
CoA
ATP
NAD+
Pyr
that basically requires four ATP molecules plus two GTP mol-
ecules and two NADH molecules to regenerate one molecule
of glucose from two molecules of pyruvate (see Chapter 77).
ATP and GTP for these series of reactions are provided by
β-oxidation of fatty acids.
Pyruvate is metabolized in the mitochondria to AcCoA and
CO2 via pyruvate dehydrogenase, a large polyhedral protein
complex with molecular weight of 10 × 106 Da. Thiamin, lipoic
acid, magnesium, and coenzyme A serve as cofactors for this
reaction, which represents the first irreversible step in terms
of mitochondrial oxidation of pyruvate. This key reaction is
regulated by a family of pyruvate dehydrogenase kinases. As
noted above, AcCoA is also generated within the mitochondria
by β-oxidation of fatty acids. Two molecules of AcCoA may
condense to form acetyl acetate, which can subsequently be
metabolized to β-hydroxy butyrate and acetone, all of which
may be used as energy substrate by the heart, brain, and skel-
etal muscle during fasting after a depletion of glycogen stores.
Krebs Cycle
The Krebs cycle summarizes a circular series of reactions in
the mitochondria to metabolize AcCoA to two molecules of
CO2 with resultant generation of one molecule of GTP, three
molecules of NADH, and one molecule of FADH2. GTP is
Lactate
equivalent to ATP in terms of energy charge. Although oxygen
itself is not part of the Krebs cycle, its presence at the end of
the mitochondrial electron transport chains ensures recycling
of NAD+ and FAD required in the Krebs cycle (Figure 74-7).
AcCoA, derived from glucose, fatty acids, or protein catab-
olism, condenses with oxaloacetate in step 1. One rotation of
reactions in the mitochondria metabolizes the AcCoA to two
molecules of CO2, generates one ATP equivalent in the form
of GTP, and generates reducing equivalents in the form of
NADH and FADH2.
Electron Transport Chain
Electrons derived from reducing equivalents NADH and

FADH2 are shuttled along the mitochondrial electron trans-

uva

port chain, ultimately reducing molecular oxygen to water.

te d

Basically, for each pair of electrons involved in one hydride

se

ehy
la

ADP NADH equivalent, three molecules of ATP are produced. Five com-
oxy

dro

plexes of proteins and cytochromes comprise the mitochon-

arb

gen

CO2
drial electron transport chain and facilitate a step-down flow
te c

ase

of FADH2 and NADH reduction potential along the inner

uva

membrane of the mitochondria. These redox reaction com-

Pyr

O plexes include NADH dehydrogenase–ubiquinone oxidore-

CO2 ductase (complex 1), succinate dehydrogenase–ubiquinone
CH3 C SCoA
oxidoreductase (complex 2), ubiquinone–cytochrome C oxi-
Acetyl-CoA doreductase (complex 3), cytochrome c oxidase (complex 4),
and ATP synthase (complex 5). Electrons in the form of
Citrate synthase
hydride ions from NADH and FADH2 cascade along these
protein/cytochrome complexes toward molecular oxygen.
COOH Protons generated during these reactions are pumped across
CH2 COOH the inner mitochondrial membrane matrix into the inter-
C O membrane space, generating a proton motive force. The
HO C COOH
CH2 proton electrochemical gradient across the inner mitochon-
CH2 COOH drial membrane drives ATP synthesis by a reaction that has
COOH been termed chemiosmosis.41 Energy for ATP synthesis arises
Oxaloacetate Citrate from an influx of these protons back into the matrix, literally
Figure 74–6.  Metabolic fates of pyruvate, end product of glycolysis. through the rotary motor of ATP synthase.42
(Modified from Baynes JW, Dominiczak MH: Medical biochemistry, New The proton pore involves the c-ring and the a-protein. The
York, 2009, Mosby Elsevier.) rotary component is the coiled-coil γ-subunit, which is bound
 Chapter 74 — Cellular Respiration 1063

CH2 COO–

C COO–

HC COO–
CoA-SH
O Cis-aconitate
CH2 COO–
CH3 C SCoA HO C COO–
Acetyl-CoA CH2 COO–
CH2 COO–
O C COO– 1 2
Citrate HO C COO–
CH2 COO– HO C COO–
NADH + H+
Oxaloacetate NAD+
H
Isocitrate
3
8 CO2
NAD+
NADH + H+
H
CH2 COO– Enzymes:
HO C COO– 1. Citrate synthase
CH2
2. Aconitase
CH2 COO–
O C COO– 3. Isocitrate dehydrogenase
Malate 4. α-ketoglutarate dehydrogenase
α-ketoglutarate
5. Succinyl CoA synthase
7 CoA-SH 6. Succinate dehydrogenase
NAD+ 7. Fumarase
H2O 8. Malate dehydrogenase
4
H C COO–
–OOC C H CH2 COO– CO2
Fumarate CH2 C SCoA NADH + H+
CoA
6 O
FADH2 5 Succinyl-CoA
CH2 COO–
CH2 COO– GDP
FAD Succinate

GTP

Figure 74–7.  Circular series of reactions involved in the Krebs cycle. (Modified from Baynes JW, Dominiczak MH: Medical biochemistry, New York,
2009, Mosby Elsevier.)

to the ε-subunit and to the c-ring. The stationary component
is the hexameric α3β3 unit and is fixed by the δ, b, and a pro-
teins (Figure 74-8).
Although multiple regulatory steps exist along the res-
piration metabolic pathways, the following three are
prominent:
1. Oxygen availability to serve as the ultimate electron accep-
tor. This will depend on oxygen delivery to the tissue as
well as regulation of oxygen binding to the heme moiety of
cytochrome oxidase by NO, as previously discussed.
2. Availability of nutrient metabolism to generate reducing
equivalents in the form of NADH and FADH2, as previ-
ously noted. Depletion of NADH can occur in instances of
severe cellular stress after activation of the PARP.
3. Overall cellular energy state defined by the ratio of ATP/
ADP.
Specific adenine nucleotide translocase on the inner mito-
chondrial membrane as well as a voltage-dependent ion channel
representing the most abundant protein of the outer mitochon-
drial membrane facilitate ATP transport out of the mitochon-
dria for use as energy currency for all cellular functions.
Monitoring of Tissue
Oxygenation
Blood Lactate Monitoring in Critically Ill
Patients
In general, lactic acidosis occurs when there is an imbalance
between production and clearance of lactate. Measurement of
lactate in human blood was first described in 1843 in a lethal
case of fulminant septic shock due to puerperal fever in a
young woman.43 Blood lactate monitoring is frequently per-
formed in critically ill patients, usually with the aim of detect-
ing tissue hypoxia44 with resultant anaerobic hyperlactatemia,
traditionally termed type A lactic acidosis. However, other pro-
cesses not related to tissue hypoxia can also result in increased
blood lactate levels,45 such as aerobic hyperlactatemia or type
B lactic acidosis that complicates clinical interpretation and
therapy in cases of elevated lactate concentration. Although
lactic acidosis is often associated with a high anion gap and is
generally defined as a lactate level greater than 5 mmol/L and
a serum pH less than 7.35, the presence of hypoalbuminemia
may mask the anion gap and concomitant alkalosis may raise
1064 Section V — Renal, Endocrine, and Gastrointestinal Systems
Intermembrane
H+
space H+
H+
H+ H+
C-ring
Inner a c F0
mitochondrial protein pore
membrane and motor
H+ b (7) several drugs and intoxications such as epinephrine (by
b F1
Matrix ATP synthase
(ATPase)
ADP + Pi ATP
Figure 74–8.  ATP synthase complex consists of a motor (proton gradient
pore, F0) and generator (ATP synthase, F1). (Modified from Baynes JW,
Dominiczak MH: Medical biochemistry, New York, 2009, Mosby Elsevier.)
the pH. As originally reported by Huckabee,45a normal arte-
rial blood lactate is approximately 0.620 mmol/L and venous
lactate is slightly higher at 0.997 mmol/L.
Anaerobic Hyperlactatemia
During anaerobic conditions, pyruvate derived from the con-
version of glucose cannot enter the Krebs cycle via AcCoA to
produce energy. Instead, pyruvate is converted into lactate,
known as the Pasteur effect. The normal lactate/pyruvate ratio
is approximately 20:1, and it rises under hypoxic conditions.
The causal relationship between anaerobic hyperlactatemia
and tissue hypoxemia has been confirmed by experimen-
tal46,47 and clinical44 studies; decreasing systemic oxygen deliv-
ery (DO2) until oxygen demand can no longer be met and
limiting oxygen consumption by DO2 coincides with a sharp
increase in lactate levels. Accordingly, in the early phase of sep-
tic shock hyperlactatemia is accompanied by oxygen supply
dependency.48 In severe sepsis or septic shock prior to resus-
citation, hyperlactatemia coincides with a low central venous
oxygen saturation49 and increased lactate/pyruvate ratios,50
whereas increases in DO2 are associated with reductions in
lactate.49 No critical level of DO2 or SvO2 could be associated
with hyperlactatemia. This could represent regional differ-
ences in DO2 and demand.51 However, improving capillary
perfusion was shown to correlate with a reduction in lactate
levels in patients with septic shock, independent of changes
in systemic hemodynamic variables.52 The latter observation
illustrates the hypothesis that, in the absence of low systemic
DO2 relative to systemic metabolic demand, microcirculatory
processes hampering oxygen use at the tissue level may raise
lactate levels.
Aerobic Hyperlactatemia
Various studies demonstrate that mechanisms other than
tissue hypoxia can account for hyperlactatemia, including
(1) mitochondrial dysfunction35,53,54; (2) decreased lactate
clearance in liver dysfunction,55,56 status post liver surgery57
and cardiac surgery,58 as well as in sepsis,59,60 where it was
shown to predict poor outcome61; (3) increased aerobic glycol-
ysis resulting in amounts of pyruvate exceeding the pyruvate
dehydrogenase capacity that can be triggered by cytokine-
mediated uptake of glucose62,63 or catecholamine-stimulated
increased Na-K pump activity45,64-67; (4) impaired activity of
pyruvate dehydrogenase, essential for the conversion of pyru-
vate into AcCoA, that can be inhibited in sepsis,68,69 as well as
in thiamin deficiency (beriberi)70; (5) alkalosis71 by increasing
cellular lactate efflux due to an H+-linked lactate carrier mech-
anism across the cell membrane; (6) acute lung disease55,72;
increased glycogenolysis, glycolysis, and stimulation of the
Na-K pump),73,74 metformin (particularly in the presence
of renal insufficiency), and nucleosidic reverse transcriptase
inhibitors for the treatment of HIV (by inducing mitochon-
drial cytopathy)75-77; and (8) intoxications with methanol,
cyanide (by inhibition of oxidative phosphorylation),78 or
ethylene glycol (by artifactual reaction of lactate electrodes).79
In summary, during critical illness, the source of lactate
is often assumed to be ischemic tissues that use anaerobic
metabolism. This is superficially supported by lactate as an
adverse prognostic marker.80,81 However, lactate metabolism
in critical illness is complex and often does not indicate isch-
emic tissues.82,83 A common clinical scenario occurs during
volume resuscitation of patients (iatrogenic hyperchloremia)
or epinephrine infusions, in which a chloride load and type B
lactic acidosis are interpreted by the body as “shock,” requir-
ing more fluid and more vasoactive-inotropic support. This
scenario may initiate a vicious cycle and potential over-resus-
citation.84 It is essential to diagnose this syndrome correctly
and adjust management accordingly.
Given the available evidence, patients presenting with
hypotension and an elevated lactate level (>5 mmol/L) have
a grave prognosis with a high mortality rate (>80%). Like-
wise, patients who are critically ill and do not clear lactate by
48 hours have a similarly high mortality rate.85 There are no
data currently available, however, to suggest that monitoring
lactate levels beyond this time frame is prognostically use-
ful. Early goal-directed therapy in severe sepsis is an example
of outcome benefit that arguably targets the patient’s pri-
mary pathophysiology rather than lactic acidosis per se.49,86
Hence, there are no current data demonstrating that thera-
peutic maneuvers specifically targeted at decreasing lactate
levels are beneficial. The treatment of the patient with lactic
acidosis should therefore be aimed at the underlying disease
and the maintenance of organ perfusion and not the lactate
concentration itself. Accordingly, the routine daily measure-
ment of serum lactate levels in critically ill patients remains
controversial.
Continuous Central Venous
Oxygen Saturation Monitoring
Monitoring of the mixed venous oxygen saturation (SvO2) is
used as a surrogate for quantifying the balance between sys-
temic oxygen delivery and consumption during the treatment
of critically ill patients.87 Measurement of SvO2 requires place-
ment of a pulmonary artery catheter with a risk/benefit ratio
that is still a matter of controversy in adult patients88-90 and
rarely performed in pediatric patients. However, measuring

central venous oxygen saturation (ScvO2) only requires a cen-
tral venous catheter, routinely inserted in critically ill patients,
and a fiber optic catheter with a spectrophotometer for con-
tinuous ScvO2 assessment. ScvO2 largely reflects the degree of
oxygen extraction from the brain and the upper part of the
body since the catheter tip usually is located in the superior
vena cava. At baseline, ScvO2 is about 2% to 3% less than SvO2
because, overall, the lower body extracts less oxygen than the
upper body, resulting in a higher inferior vena cava oxygen
saturation. Readings may be taken intermittently by blood
sampling and co-oximetry or continuously with a fiberoptic
catheter. However, beneficial effects on patient outcome to
date49 have only been demonstrated with continuous mea-
surement of ScvO2.
Low values of SvO2 or ScvO2 indicate a mismatch between
oxygen delivery and tissue oxygen need.91 Monitoring ScvO2
has been successfully used as a hemodynamic goal in the
management of early sepsis. Rivers et al.49 demonstrated in
a prospective randomized study in adult patients with severe
sepsis and septic shock that, in addition to maintaining central
venous pressure in the range of 8 to 12 mm Hg, mean arterial
pressure above 65 mm Hg, and urine output higher than 0.5
mL/kg/hr, maintenance of an ScvO2 above 70% resulted in an
absolute reduction of mortality by 15%. Thus the guidelines
of the Surviving Sepsis Campaign92 stated that the use of SvO2
and ScvO2 is equivalent in the management of adult patients
with severe sepsis and septic shock. In pediatric patients with
septic shock, directing treatment to the end point of ScvO2 at
70% or greater was also associated with a significant decrease
in the 28-day mortality rate from 39.2% to 11.8%.93 ScvO2
goal-directed therapy resulted in more crystalloid, blood
product, and inotropic support during the first 6 hours com-
pared with the control group receiving standard resuscitation.
Continuous monitoring of SvO2 is interesting, but clear
indications for this technique in children as well as ScvO2
target values remain to be determined. It has been shown
that exact numeric values of SvO2 and ScvO2 saturations are
not equivalent in various hemodynamic conditions.94 Some
authors have therefore argued that ScvO2 cannot be used as
surrogate for SvO2 under conditions of circulatory shock.95
However, for clinical purposes, the trends between these val-
ues were found to be reliable and clinically valuable.96 Based
on the evidence available, the primary indication for the use
of central venous oximetry is as part of the early resuscitation
in severe septic and septic shock patients. Further research is
needed to elucidate the efficacy of venous oximetry in other
patient groups as well as to assess whether an intermittent
measurement using central venous blood gas analysis is as
effective as continuous measurement of ScvO2 using fiberop-
tic catheters.
Functional Magnetic Resonance
Imaging
Functional magnetic resonance imaging (fMRI) is a non-
invasive technique for measuring brain activity. It works by
detecting the changes in blood oxygenation and flow that
occur in response to neural activity. When a brain area is
more active, it consumes more oxygen; to meet this increased
demand, blood flow increases to the active area.97,98 Hemo-
globin is diamagnetic when oxygenated but paramagnetic
when deoxygenated. This difference in magnetic properties
Chapter 74 — Cellular Respiration 1065
leads to small differences in the MR signal of blood depend-
ing on the degree of oxygenation. Since blood oxygenation
varies according to the levels of neural activity, these differ-
ences can be used to detect brain activity. This form of MRI
is known as blood oxygenation level–dependent (BOLD) imag-
ing, which is the most widely used method of fMRI with T2*-
weighted imaging revealing changes in vascular oxygenation.
A limitation is that the technique is also sensitive to changes
in hemoglobin concentration that may result from alterations
in vascular volume and flow as well as interconversion of oxy-
hemoglobin and deoxyhemoglobin. Therefore this technique
provides qualitative assessment of changes in oxygenation
rather than quantitative measurements. Thought to primarily
reflect changes in blood flow, BOLD is widely used for func-
tional brain mapping.99-101 BOLD is starting to be applied to
tumor studies.102-104 BOLD is particularly responsive to oxy-
gen manipulation accompanying hyperoxic gas breathing
as a simple way to ameliorate hypoxia.105,106 This technique
may also allow direct estimates of PO2, such as in the superior
mesenteric vein or heart of children. A recent study in pedi-
atric patients with complex congenital heart disease showed
a strong correlation between oxygen saturations measured in
the cardiac catheterization lab and saturations obtained non-
invasively by BOLD MRI.107 However, fMRI remains difficult
to perform in critically ill unstable patients; consequently, few
teams have acquired the equipment and experience necessary
to apply this technique.108
Magnetic Resonance Spectroscopy
MRI provides anatomic images and morphometric character-
ization of disease, whereas magnetic resonance spectroscopy
(MRS) provides noninvasive metabolite/biochemical infor-
mation about tissues in vivo. MRS has been used clinically for
more than 2 decades. The major applications of this advanced
tool include investigation of neurologic and neurosurgical dis-
orders, including blood vessel distribution and architecture,
blood flow velocity, regional perfusion and blood volume,
blood and tissue oxygenation, lactate production and intra-
cellular pH, Krebs cycle activity, and mitochondrial oxidative
phosphorylation.109 Phosphorus-31 MRS detects compounds
involved in energy metabolism such as creatine phosphate,
ATP and inorganic phosphate, and certain compounds related
to membrane synthesis and degradation. Proton MRS is most
commonly used. Four main markers related to O2 metabolism
are studied: the peak of N-acetyl-aspartate (NAA), an amino
acid present in neurons that reflects the status of neuronal tis-
sue; creatine, found in glia and neurons, that serves as a point
of reference because its level is believed to be stable; choline,
a constitutive component of cell membranes that reflects
glial proliferation or membrane breakdown110; and lactate, a
marker of anaerobic metabolism and therefore of ischemia.111
Elevated lactate and decreased NAA are associated with worse
neurologic outcome in neonates with asphyxial injury.112,113
Increased lactate may persist up to 1 week after asphyxial
injury.114 Compared with positron emission tomography
(PET), which is frequently used to evaluate tumor hypoxia but
requires injections of radioactive isotopes, multiple acquisi-
tions, and, therefore, extended imaging times, fMRI and MRS
have a number of advantages. Both MRI and MRS are cur-
rently used primarily for outcome prediction and not minute-
to-minute patient management.
1066 Section V — Renal, Endocrine, and Gastrointestinal Systems
Near-Infrared Spectroscopy
Near-infrared spectroscopy (NIRS) enables continuous, non-
invasive bed-side monitoring of oxygenation. As with pulse
oximetry, it is based on the principle that the oxygen-carrying
pigments hemoglobin and cytochrome aa3 have well-defined
absorption spectra that are influenced by oxygen binding.
NIRS technology thus uses a modification of the Beer-Lam-
bert law, which describes the relationship between absorption
of light and the concentration of intravascular (deoxygenated
hemoglobin [Hb] and oxygenated hemoglobin [HbO2]) and
intracellular (cytochrome aa3) chromophores. Key factors in
the Beer-Lambert calculation are the absorption coefficient,
tissue concentration of chromophore, distance between sen-
sors, differential path length factor (described below), and
scattering losses.115 The distance that the light travels, known
as the optical path length, must be determined to obtain quan-
titative concentration changes from the light absorption data.
Path length differs due to variable tissue scattering that is
reflected by the differential path length factor (DPF). The DPF
is a correction factor that is multiplied by the inter-sensor dis-
tance to obtain the true path length. NIRS uses light between
the 700 nm and 1000 nm wavelength. Measurement of scaled
hemoglobin concentrations, reported as the tissue oxygen-
ation index, is also available.
Clinically, NIRS is mainly accomplished by a continu-
ous-wave spectrometer with the two sensors placed on the
patient’s forehead at a fixed distance that emit and detect the
near-infrared light. NIRS has a greater tissue penetration than
pulse oximetry and provides a global assessment of oxygen-
ation in all vascular compartments (arterial, venous, and cap-
illary).116 Range of baseline cerebral oxygen saturation values
is very wide. In healthy children, cerebral oxygen saturations
are reported to be 68% ± 10%, whereas in children with cya-
notic heart disease, baseline values range from 38% to 57%.117
NIRS technology differs from pulse oximetry in that it does
not require a pulse; therefore cerebral NIRS monitoring can
be used during cardiopulmonary bypass. Perhaps the most
common application of NIRS is in intraoperative neurophysi-
ologic monitoring in children who have undergone repair of
a congenital cardiac condition.118 Therapeutic changes as a
result of NIRS have lead to decreased rates of neurologic com-
plications.118 Also, NIRS monitoring applied in the first 48
hours after neonatal asphyxia has been shown to be useful in
predicting outcome at 3 months.119
In addition to blood flow, evaluation of HbO2 and Hb,
NIRS can assess the cytochrome aa3 (cyt-aa3) redox state.
cyt-aa3 is the terminal component along the oxygen transport
chain that reduces oxygen to water and remains in a reduced
state during hypoxemia. The absorption spectrum of cyt-aa3
in its reduced state shows a weak peak at 700 nm, whereas the
oxygenated form does not. Therefore monitoring changes in
the cyt-aa3 redox state can provide a measure of the adequacy
of oxidative metabolism. The use of NIRS in deltoid muscle
during resuscitation of severe trauma patients has recently
been reported.120,121 A strong association was found between
elevated serum lactate levels and an elevated cyt-aa3 redox
state during 12 hours of shock resuscitation and the develop-
ment of multiorgan failure.120 A good relationship was also
shown among tissue O2, systemic oxygen delivery, and lactate
during and after resuscitation in severely injured patients dur-
ing the first 24 hours.121
Limitations of NIRS technology include its inability to
account for patients’ varying ratios of brain and extracranial
tissues and the fact that DPF values vary with age and patho-
logic state.122,123 Icteric patients exhibit depressed regional
cerebral oxygen saturation values, presumably due to absorp-
tion of light by bilirubin.124 Ongoing blood loss also is asso-
ciated with a decrease in regional cerebral oxygen saturation
that may indicate that a changing hemoglobin concentration
confounds cerebral oximetry measurement.125 Furthermore,
in infants the reproducibility of cerebral oxygenation mea-
surements is poor.126 The major limitation is that no target
or critical values exist with which to compare NIRS-derived
regional oxygen saturations. Poor-to-moderate correlation
is seen in comparing regional cerebral oxygen saturations to
global cerebral oxygenation measures, such as jugular venous
saturation,127 central venous saturation,128,129 and invasively
monitored cortical brain tissue PO2.130 However, NIRS mea-
surement of continuous oxygen saturation on the brain sur-
face could theoretically provide relative real-time alterations
in brain oxygenation, which can be useful in terms of titration
of therapies. A pediatric pilot study reported good agreement
between NIRS and jugular venous saturations in the normal
pediatric brain.131
Optical Spectroscopy
An extension of NIRS has been developed to allow interro-
gation of specific anatomic and physiologic compartments of
the body. Optical spectroscopy also uses absorption of light by
tissues to assess concentration of various analytes of interest.
By using an entire spectral region in the visible and/or near-
infrared spectral region that includes many (up to hundreds)
of wavelengths of light, improved distinction between similar
molecules is possible. In particular, oxygenation of myoglobin
can be measured distinctly from hemoglobin, even in blood-
perfused tissues. Myoglobin is an intracellular protein found
in skeletal and cardiac muscle cells and is involved in the
transport of oxygen from the cytoplasm to the mitochondria
where oxygen is used. Because myoglobin and hemoglobin
have very similar absorption spectra, it has generally been held
that distinction using optical methods is not possible. Quanti-
fication of myoglobin saturation (percentage of total myoglo-
bin bound with oxygen) directly yields intracellular PO2 per
the myoglobin oxygen dissociation curve that defines oxygen
binding to myoglobin modified by temperature and pH.132
Advances in optical spectroscopy have made it possible to
distinguish myoglobin saturation from hemoglobin satura-
tion by using multi-wavelength spectral analysis, despite their
very similar absorbance spectra. Measurements of myoglobin
saturation in the presence of hemoglobin,133-138 hemoglo-
bin saturation in the presence of myoglobin,139,140 and cyto-
chrome oxidation states,141,142 have been made from optical
reflectance spectra acquired from muscle. These advances
remove the ambiguity present in conventional near-infrared
spectroscopic methods in which hemoglobin and myoglo-
bin absorbances are combined.143,144 Optical spectroscopy
thus allows identification of oxygenation in anatomically and
physiologically distinct tissue regions: in the vascular space
(hemoglobin), at the cellular level (myoglobin), and at the
mitochondrial level (cytochromes).
Direct measurement of oxygenation at the cellular level in
skeletal muscle, based on distinct myoglobin saturation, has

several advantages for metabolic monitoring: it is noninva-
sive, it facilitates early diagnosis of shock, and it may enhance
resuscitation strategies. During shock, blood and oxygen
delivery are diverted to the critical organs (brain, heart, and
kidneys), whereas blood flow to the physiologically “expend-
able” tissues (muscle and skin) is sacrificed.145,146 Low muscle
cellular oxygenation may be the “canary in the coal mine” for
the presence of shock—an early, sensitive indicator of inad-
equate systemic perfusion. Vital signs are not accurate in early
shock assessment because compensatory mechanisms often
mask changes in these variables.147 Metabolic indexes such as
arterial base deficit and lactate have been found to correlate
with the severity of shock.148-150 However, since lactate levels
and base deficits are metabolic responses to the presence of
shock, these serum values lag changes in cellular oxygenation.
During resuscitation, the optimal therapeutic end points
remain unclear.146,151,152 Restoration of blood pressure, heart
rate, and urine output alone may result in under-resuscita-
tion because patients may remain in compensated shock after
these traditional end points have been achieved.153 Patients
with occult hypoperfusion, in whom tissue acidosis persists
even after resuscitation appears to have been successful, are
at increased risk for multiple organ dysfunction syndrome
(MODS), respiratory complications, and death.154 Accurate
assessments of cellular oxygenation are needed to refine ther-
apy and decrease the incidence of MODS.
There is a varied and confused literature on the opti-
cal measurement of skeletal muscle oxygenation.155-158 The
problem with these attempts is that a combination of hemo-
globin and myoglobin oxygen saturation was determined,
with hemoglobin being the dominant signal.143,144,159 Any-
thing that increases the venous blood volume in the muscle
(e.g., venous congestion) may be erroneously recorded as
hypoxia. In addition, the intracellular oxygen tension remains
unknown. Direct cellular oxygenation measurement by opti-
cal spectroscopy distinguishes myoglobin oxygen saturation
from hemoglobin saturation and is thus capable of measuring
intracellular tissue oxygen tension, independent of changes in
blood volume.
Carbomyl Phosphate
Synthase—A Marker of
Mitochondrial Damage
Mitochondrial damage and dysfunction are thought to play
an important role in the pathogenesis of sepsis-induced organ
failure. Specific markers of mitochondrial damage in vital
organs do not currently exist. Recently, carbomyl phosphate
synthase (CPS)-1, a protein localized primarily in liver mito-
chondria, was found to be present in high concentrations in
the plasma of septic humans and could serve as a novel marker
of mitochondrial damage in sepsis.160
Clinical Correlations in Altered
Cellular Respiration
Biochemical pathways and cellular energetics may seem far
removed from the daily care of patients in the PICU, where
discussions about the respiratory and circulatory systems
seem to dominate. However, at its core, the goal of critical
care medicine is to maintain and support the basic physiologic
functions of the patient until their own homeostasis returns.
Chapter 74 — Cellular Respiration 1067
This means the real goal is the support of cellular function,
and that function requires energy derived from the metabo-
lism of oxygen. Therefore the foundation of critical care medi-
cine is the understanding and support of oxygen delivery and
utilization.
The role of inadequate oxygen delivery in the pathogen-
esis of disease has been recognized for more than 80 years. In
1920, Joseph Barcroft wrote in The Lancet about three types
of hypoxia: deficient delivery of oxygen to blood, or hypoxic
(hypoxemic) hypoxia; deficient oxygen carrying capacity, or
anemic hypoxia; and deficient circulatory delivery of oxygen,
or stagnant (ischemic) hypoxia.161 Later this century it became
recognized that under certain states, even in the presence of
normal or supranormal oxygen delivery, there was an appar-
ent inability of cells to appropriately extract or utilize oxygen.
This was most apparent in sepsis and certain poisonings. In
1997, Fink coined the term “cytopathic hypoxia” to describe
such states.162 In 1997, as the study of oxygen supply and uti-
lization evolved, Robin proposed the general term “dysoxia”
to describe abnormal tissue oxygen metabolism, and this is
the term used in this chapter.163 Now four classifications are
recognized: hypoxemic dysoxia, anemic dysoxia, ischemic
dysoxia, and cytopathic dysoxia.
Abnormal tissue oxygenation can be divided into three the-
oretic thresholds. In the first, cellular oxygen levels are below
normal but ATP production matches ATP utilization through
cellular adaptation. Cellular metabolism and mitochondrial
energy production shift but aerobic metabolism is maintained.
In the second level, cellular oxygen levels are so low that ATP
production and utilization can only be matched through
supplementary production of ATP via anaerobic metabolism.
An increased supply of glucose is required, and lactate will be
produced. The third level describes a state where ATP produc-
tion has become oxygen limited. Neither cellular adaptation
nor glycolysis is sufficient to provide adequate cellular energy.
Without additional oxygen, or an increase in the cell’s ability
to utilize oxygen, cellular structure and function will fail. Some
researchers have proposed that the third level be referred to as
“dysoxia.”164 However, levels one and two represent abnormal
cellular states that can generate intracellular and extracellular
signals that result in altered physiologic function. Therefore
“dysoxia” is used to describe any of the three states.
This section reviews examples of abnormal cellular respi-
ration using common clinical scenarios, including hypogly-
cemia (substrate deficiency), the four dysoxias, and specific
respiratory poisons such as cyanide, aspirin, and propofol. In
addition, sepsis is used throughout as a model to demonstrate
the complex interplay of oxygen delivery and altered cellular
metabolism.
Substrate Deficiency
(Hypoglycemia)
Hypoglycemia is probably more common in the neonatal
intensive care unit (NICU) than the PICU. However, it repre-
sents the most basic form of altered energy production—inad-
equate energy substrate—and certainly requires recognition
and therapy when it occurs (see Chapter 77). Although the
clinical manifestations of acute hypoglycemia are well known to
physicians, cellular hypoglycemia is a more complex problem.
As described earlier in this chapter, ATP can be produced
from the metabolism of fats, proteins, and carbohydrates.
1068 Section V — Renal, Endocrine, and Gastrointestinal Systems
However, carbohydrates represent the dominant energy
source in the regular diet of most humans, and the levels of
enzymes necessary for conversion of various macronutrients
into energy are skewed in favor of glucose metabolism.
There are two primary advantages of carbohydrate when
compared with fat as a metabolic fuel. First, carbohydrate
metabolism is the only mechanism by which cells can produce
ATP in the absence of oxygen, that is, the anaerobic state. The
metabolism of glucose to pyruvate yields a net of two molecules
of ATP per molecule of glucose. This is obviously important to
cells in crisis where oxygen delivery may be impaired. However,
it is also important in the normal physiologic state for cells that
have lost their mitochondria, such as red blood cells, and to
cells that have high energy demands and operate under condi-
tions of low O2 tension even in the healthy state, such as renal
tubular medullary cells. A second advantage of carbohydrate as
fuel is efficiency. The ratio of ATP production to oxygen con-
sumption is higher with glucose than with fats. Thus glucose is
a more efficient fuel for ATP production yielding a 10% to 15%
advantage.165 This advantage may seem small but may become
quite significant in states of high energy requirement or limited
oxygen delivery such as seen in exercise or critical illness.
Glucose is important to other aspects of cellular function
as well. Its participation in the pentose phosphate pathway
facilitates reduction of NADP+ to NADPH, a reaction product
linked to many important cellular metabolic functions. It is
also the source of the 5-carbon sugar ribose, which is neces-
sary for DNA and RNA synthesis and repair.
Besides red blood cells and renal tubular cells, glucose is the
preferred energy source for various other tissues in the body,
including the central nervous system and the testes. Although
the brain can adapt to using ketones as an energy source, this
enzymatic transition takes time. Lack of immediate availabil-
ity of these enzymes is readily seen in the severe central ner-
vous system effects manifested with acute hypoglycemia. In
the testes, the metabolism of glucose to lactate is necessary for
healthy spermatogenesis.166
The Four Dysoxias
Before reviewing the various dysoxias, a brief review of DO2
and oxygen consumption (VO2) is in order (see Chapter 20).
Oxygen delivery is defined as the product of the arterial oxy-
gen content of the blood (CaO2) and the cardiac output (CO)
and is often indexed to the body surface area in square meters
(BSA):
DO2 index = [(1.34 × Hb × SaO2 ) + (0.003 × PaO2 )] (1)
× CO × 1 / BSA
Given that the amount of dissolved O2 is so small, it is often
dropped from the calculation for simplicity. Derivation of car-
diac output is described elsewhere in this text (see Chapters 19
through 22).
Oxygen consumption is defined as the amount of oxy-
gen extracted by the body from the blood and, according to
the Fick principle, is calculated by the difference between
the CaO2 and the CvO2 (the oxygen contents of arterial and
mixed venous blood) multiplied by the cardiac output. It, too,
is often indexed to BSA:
VO2 index ≅ [1.34 × Hb × (SaO2 − SvO2 )]
× CO × 1 / BSA  (2)
In the normal, healthy state DO2 is in significant excess of
VO2. That is, the blood is carrying an excess of oxygen com-
pared with the amount of oxygen the body needs. The ratio of
consumption to delivery is called the oxygen extraction ratio
(ERO2) and is calculated as follows:
ERO2 = (CaO2 − CvO2 ) / CaO2 ≅ (SaO2 − SvO2 ) / SaO2 (3)
Given that typical SvO2 is approximately 65% to 75%, this
ratio is typically 0.25 to 0.35. This means that delivery exceeds
consumption by a factor of 2 to 3. Thus a buffer exists where
decreases in cardiac output are well tolerated across a certain
range. In this setting, VO2 remains unaffected by changes in
DO2; this is accomplished by an increase in ERO2.
There is a point, however, at which the oxygen extraction
capabilities of the tissues are exceeded. At that point, VO2
becomes dependent on DO2. This biphasic relationship of
DO2/VO2 is shown in Figure 74-9.
The importance of this concept cannot be overempha-
sized as it relates to cellular respiration. DO2 and VO2 can be
altered in many physiologic and pathologic states. Sleep, exer-
cise, pain, anxiety, and fever are just a few examples. Drugs,
too, can have simultaneous effects on VO2 and DO2, such as
with catecholamines and shock.167 With certain poisons and
with cytopathic dysoxia, oxygen consumption can be directly
affected by the tissues’ ability to extract oxygen from the blood
and use it as the terminal mitochondrial electron acceptor. In
these situations, tissue oxygen extraction, not DO2, represents
the limiting factor; DO2 may be normal or even elevated.
Accordingly, a complicated interplay exists among DO2,
VO2, and ERO2. Although described in text and graphs in
what appear to be straightforward ways—just as with preload,
afterload, contractility, and stroke volume—their practical
measurement remains exceedingly difficult. Bedside evalu-
ation of DO2 and VO2 would be of great value to the clini-
cian. Unfortunately, most of the methods of calculating VO2
rely on cardiac output (via the Fick principle), which results
in a situation where a single measured variable is included in
two parts of a regression analysis, so-called mathematical cou-
pling. This dependency leads to amplification of any error in
that measurement and may result in an apparent relationship
between variables that does not truly exist.168 As in many areas
Increasing No
lactic lactic
acidosis acidosis
Supply Supply
dependent independent
oxygenation oxygenation
C B A
O2 consumption
(mL/min)
O2 delivery (mL/min)
Figure 74–9.  Biphasic relationship between oxygen delivery and oxygen
consumption.

of critical care medicine, when something cannot be measured
directly, a surrogate measure must be used.
Anemic Dysoxia
The majority of oxygen delivered to tissues is carried by hemo-
globin in the red blood cells. The dissolved component of oxy-
gen represents a very small, and usually insignificant, portion.
It is therefore reasonable to postulate that in severe anemia,
the decreased oxygen carrying capacity of blood may result in a
severe limitation in DO2, perhaps severe enough that VO2 may
be limited. Such limitation would represent anemic dysoxia.
How anemic must a child be to suffer from anemic dysoxia?
A clinical scenario is instructive:
Assuming that a normal child, approximately 1 m2, has a VO2
of 200 mL/min and a normal cardiac output of about 4 L/min,
the formula for VO2 (Equation 2) may be rearranged to obtain
the minimum hemoglobin concentration necessary to deliver
that amount of oxygen. An extreme oxygen extraction, 80%, is
also assumed (this would reflect an SvO2 of 20%!):
Hb = VO2 / (1.34 × (SaO2 − SvO2 ) × 10 × CO) = 5.2 g / dL
This equates to a hematocrit of just over 15%. Additional
manipulation of the numbers reveals that to maintain an SvO2
in the normal range of approximately 70%, CO would have to
increase by a factor of 2.7! (It should be appreciated that the
increased CO itself increases VO2.)
Oxygen content of such a patient’s blood is next considered.
Using the data from above and a normal PaO2 of 90 mm Hg:
CaO2 = (1.34  ×  5.2  ×  0.96) + (0.003  ×  90) = 7.0 mL / dL
Notice that the dissolved portion in this patient, 0.27mL/dL,
represents less than 4% of the total CaO2. If the same patient
were administered 100% FiO2, a PaO2 of approximately 600
mm Hg would be likely. In this case:
CaO2 = (1.34  ×  5.2  ×  1.00) + (0.003  ×  600) = 8.8 mL / dL
This represents an increase in CaO2 of 22%, with the dis-
solved portion now representing more than 20% of the total
CaO2.
This example illustrates the need for significant tachycardia
in children with severe anemia and the significant contribu-
tion of dissolved O2 in such patients. Anemic dysoxia alone
is not a common source of problems in the pediatric popu-
lation. However, anemic patients are frequently encountered
in the PICU, and the increased VO2 caused by acute illness
coupled with the decreased DO2 of anemia may indeed lead to
significant negative impact on cellular respiration.
Hypoxemic Dysoxia
With a normal cardiac output and a normal oxygen carrying
capacity, effective oxygenation of red cell hemoglobin ensures
adequate tissue delivery of oxygen. If any of the five sources
of hypoxemia—hypoventilation, diffusion impairment, low
inspired oxygen, shunt, ventilation/perfusion mismatch—
impairs adequate oxygenation of hemoglobin and limits cel-
lular metabolism, hypoxemic dysoxia results.
Respiratory diseases represent a significant portion of pedi-
atric illness, and hypoxemia is a common finding in the PICU.
In addition, such patients often have fever and increased work
of breathing. Thus they exhibit increased VO2 and diminished
Chapter 74 — Cellular Respiration 1069
DO2. This altered ratio of VO2/DO2 can lead to impaired cel-
lular respiration and a shift toward anaerobic metabolism.
Another example is outlined below:
An infant with bronchiolitis has a fever of 40° C, a pulse of
180 beats/min, and a respiratory rate of 80 breaths/min. Her
hemoglobin is 10 and her oxygen saturation on arrival is 75%.
Fever increases metabolism by approximately 14% per 1° C
temperature increase. Work of breathing accounts for about
15% of oxygen consumption in a resting infant and can double
or triple in severe states. Thus a conservative estimate of this
infant’s current VO2 is:
VO2 (current) = Baseline VO2 + 0.42 baseline (for fever) +
0.15 baseline (for work of breathing)
= 1.57 VO2 (baseline)
If the patient’s hemoglobin oxygen saturations were normal,
the 50% increase in her heart rate (assuming a normal of 120
beats/min) would just offset her increased VO2. However, her
hypoxemia causes a 25% reduction in CaO2. A quick calcula-
tion reveals:
DO2  (current) = 1.50 × CO (baseline) × 0.75 CaO2  (baseline)
                        = 1.12 DO2  (baseline)
It is immediately apparent in this example that the increase in
VO2 has not been offset by the increase in DO2. This gener-
ates a state in which the VO2/DO2 curve has shifted, and the
threshold at which VO2 becomes limited by DO2 is lowered.
The treatment in this case is obvious. Application of supple-
mental O2 will likely alleviate her hypoxemia, and with her
tachycardia, CaO2 will return to a normal or even increased
level.
As another example, children with right-to-left intracar-
diac shunting are frequently encountered in the PICU. These
patients live in a chronic state of hypoxemia, yet grow and
develop. Again, examining the equation for DO2:
DO2 index = [(1.34 × Hb × SaO2 ) + (0.003 × PaO2 )]
× CO × 1/BSA  (4)
To maintain adequate oxygen delivery in the face of persis-
tent hypoxemia, these patients must increase cardiac output,
hemoglobin, or both. It is worth remembering that because
CaO2 is a product of hemoglobin concentration, SaO2, and
CO, a reduction in one can be fully compensated for by an
appropriate increase in the other(s). Some quick math reveals
that for a patient whose arterial oxygen saturation is chroni-
cally 75%, a cumulative increase in hemoglobin and/or car-
diac output of 30% is necessary to equate an SaO2 of 100%. An
increase in hemoglobin of 3 to 4 g/dL is obviously less stress-
ful to a system than a chronic increase in CO of 1.0 to 1.5 L/
min/m2. This is especially true when one recalls that many of
these patients have some element of heart failure and are not
capable of long-term significant increases in cardiac output.
It should also be recalled that for such patients any increase
in CO results in an increase in VO2 assuming that cytopathic
dysoxia is not operative. It is obvious why these patients are
so fragile. They have a limited ability to increase DO2. Essen-
tially, they live close to point C on the VO2/DO2 curve shown
in Figure 74-9. Any illness or acute stressor that results in an
increase in VO2 can lead to a state at which VO2 becomes lim-
ited by DO2 and cellular respiration begins to suffer.
In summary, although hypoxemia is a common finding in
the PICU, patients typically compensate through an increase
1070 Section V — Renal, Endocrine, and Gastrointestinal Systems
in cardiac output. For chronically hypoxemic patients, part
of their compensation derives from elevated levels of hemo-
globin. It is in those patients whose ability to increase cardiac
output or whose level of VO2 is significantly elevated that the
physician must be most concerned that limited CaO2 will
cause an inability to meet VO2 and cellular respiration will fail.
Ischemic Dysoxia
It is obvious that in tissues for which blood supply is elimi-
nated, oxygen delivery will be eliminated and cellular energy
production will fail—not only from a lack of oxygen, but
also from a deficiency of substrate. This represents the most
extreme form of ischemic dysoxia. However, this is less fre-
quently encountered than are situations in which blood sup-
ply is merely compromised. At some point (point C on Figure
74-9), the decrease in DO2 may fall below the level of VO2 and
cellular respiration will falter.
Ischemic dysoxia can occur on a macroscopic level, and this
is how it is usually considered. A patient with severe brady-
cardia but normal SaO2 suffers from global ischemic dysoxia
purely as a result of inadequate cardiac output. DO2 is severely
limited and cannot meet VO2. Anaerobic metabolism begins,
and if the bradycardia is not reversed, cellular function will
begin to fail. In another example, a patient develops a subdu-
ral hematoma after a fall. The increased intracranial pressure
creates regional ischemia and inadequate DO2 to that area.
Draining the hematoma relieves the pressure and DO2 returns
to normal or even increased levels. There is, indeed, injury
associated with the restoration of DO2, a so-called reperfusion
injury (see Chapter 62).
In contrast to the macroscopic examples above, ischemic
dysoxia occurs much more frequently on a microscopic level.
In many ways, this concept is only on the threshold of under-
standing. Even in good health, many areas of the body demon-
strate “marginal” DO2, with limited oxygen supply relative to
metabolic needs. Classic examples include the renal medulla
and corticomedullary junction and the centrilobular regions
in the liver.169-171
In the kidney, the tubular cells of the medullary region con-
tain a high concentration of mitochondria to provide energy
for pumping ions against a strong gradient. However, the cells
exist near the end of the peritubular capillaries where DO2 is
at or nearly at the limits of VO2. In the liver the centrilobular
cells lie at the end of the sinusoids, just proximal to the venous
system. In addition, more than half of the liver’s blood sup-
ply is provided by the portal vein with its already low oxygen
tension. Once again, DO2 hovers close to VO2. In these exam-
ples any situation in which blood pressure or cardiac output
is compromised can lead to significant insult to these areas;
VO2 simply cannot be met, cellular energy production falters,
and cell functions fail. Clinically this is reflected as acute renal
insufficiency due to acute tubular necrosis or hepatic dysfunc-
tion due to ischemic hepatitis—so called “shock liver.”172
The structure of the microcirculation, a network of vessels
less than 100 to 150 μm in diameter, is important when con-
sidering dysoxia. It is composed of arterioles, capillaries, and
venules and represents the functional unit of the circulation,
supplying tissues with oxygen and substrates and removing
metabolites. It is also important to understand two aspects of
the microcirculation as they relate to dysoxia. First, in the clas-
sic Krogh model of microcirculation, oxygen exchange occurs
in the capillary bed. However, research reveals that a signifi-
cant amount of oxygen can be lost through the arterioles.173
This is important because it suggests that as blood enters the
capillary bed, it may have already released a significant amount
of oxygen to the periarteriolar tissues and may be relatively
desaturated. Oxygen diffusion from the arteriole toward the
capillary may or may not be able to compensate for this. This
means that any state of ischemic dysoxia may be complicated
by hypoxemic dysoxia at the capillary level.
The second aspect of the microcirculation to note is its
overall structure. Progressively smaller vessels supply progres-
sively larger areas of tissue. In addition, precapillary sphinc-
ters and thoroughfare channels are present. Accordingly, there
exist multiple opportunities for blood to partly or entirely
bypass regional capillary beds. Dysregulation of the arterioles
or precapillary sphincters shunts blood directly from arteriole
to venule. In sepsis, plugging of capillaries due to endothe-
lial swelling, microscopic clots, activated white blood cells,
or nondeformable red cells does the same. These scenarios
all give rise to microscopic regional ischemia and potentially
regional ischemic dysoxia. Much research has been devoted to
the microcirculation and its role in critical illness. It is believed
by many to be the pathophysiologic basis for MODS, and in
sepsis its role is believed by some to be so important as to be
deemed the “motor of sepsis.”174-178 Throughout the tissues
there seem to be areas in the microcirculation fundamentally
vulnerable to ischemic dysoxia; these areas have been termed
microvascularly weak units.179,180
Cytopathic Dysoxia
The term cytopathic hypoxia arose just over 10 years ago to
describe “diminished production of ATP despite normal (or
even supranormal) PO2 values in the vicinity of the mitochon-
dria.”162 This term arose because of increasing evidence that in
sepsis there was insufficient energy production in cells despite
adequate oxygen delivery. Indeed, this does occur in sepsis,
and increasing research points to it as a fundamental cause of
the multiple clinical manifestations of sepsis. There are also
chemicals and drugs that, despite adequate intracellular oxy-
gen, can lead to cellular energy failure via direct functional
inhibition of or damage to the mitochondria. These include
cyanide, 2,4-dinitrophenol (DNP), aspirin, and propofol.
Cytopathic dysoxia during sepsis is an active area of
research, and many proposed theories abound. No single
pathway to cellular energy failure has proved dominant, and
some proposed hypotheses have yielded conflicting results. It
is beyond the scope of this chapter to review all of these in
detail, but some theories bear discussion.
Inhibition of pyruvate dehydrogenase complex (PDC) has
been implicated in some of the altered cellular metabolism
and increased lactate production in sepsis.181,182 Glycolysis
is stimulated in many cells during sepsis. For glycolysis to be
linked to oxidative phosphorylation and cellular respiration
in the mitochondria, glucose must be converted first to pyru-
vate then irreversibly to AcCoA, which subsequently enters
the mitochondria. This conversion of pyruvate to AcCoA is
accomplished through the action of PDC. During sepsis, this
enzyme complex is inhibited by stimulation of a PDC-kinase.
The trigger for this is poorly understood. When pyruvate can-
not be converted to AcCoA, energy production in the mito-
chondria diminishes due to a lack of substrate entering the

Krebs cycle. In addition, when pyruvate cannot be converted
to AcCoA, its fate is to be converted to lactate via lactate
dehydrogenase.
NO and other reactive nitrogen species (RNS) have been
demonstrated in several studies to play active roles in the
pathogenesis of sepsis.183-185 As previously discussed, NO acts
as a reversible inhibitor of cytochrome c oxidase. At increased
concentrations, NO reacts to form OONO− (peroxynitrite),
NO2, and nitrosothiols. Increased concentrations of NO and
these compounds can cause irreversible inhibition of respira-
tory chain components, uncoupling of oxidative phosphoryla-
tion, enhanced permeability of the mitochondrial membrane,
and ultimately death of the cell.186 In some research, the degree
of mitochondrial dysfunction in sepsis was directly related to
extent of NO production.35
A final theory of sepsis-induced mitochondrial dysfunc-
tion involves PARP.187,188 This enzyme is involved in various
aspects of cellular function, but with respect to sepsis, its most
important function involves repair of single-strand breaks in
DNA. During sepsis there is an increase flux of reactive oxygen
and nitrogen species that mediate induce single-strand breaks
in DNA. PARP is activated to repair these breaks. Activation
of PARP leads to massive depletion of cellular NAD+/NADH.
Because NADH is the primary reducing equivalent transfer
molecule used in cellular respiration, its depletion results in
marked impairment of aerobic metabolism.
Drug Effects on Cellular Respiration
Cyanide
Cyanide ion is highly toxic via inhibition of cellular respi-
ration. It binds to the iron atom within the heme group of
cytochrome c oxidase, effectively shutting down aerobic
metabolism. Rhodanese is a mitochondrial enzyme that func-
tions to detoxify cyanide into relatively nontoxic thiocyanate.
In critical care medicine, sodium nitroprusside is used as
a vasodilator because of its ability to serve as an NO donor.
However, on exposure to light and degradation within the
body, a cyanide ion is released. Patients receiving high-dose,
long-duration sodium nitroprusside infusions should be
monitored for cyanide toxicity.
Aspirin
Salicylates have been used therapeutically since at least the
fifth century bce. Aspirin (acetylsalicylic acid) was synthesized
in the mid-nineteenth century and has been manufactured
and sold since. Toxicity to cellular respiration from aspirin
overdose has been recognized for decades, but the mechanism
has remained elusive. Some researchers have demonstrated an
uncoupling of oxidative phosphorylation.189 In this mecha-
nism aspirin induces mitochondrial permeability transition
(MPT). This transition allows the proton gradient estab-
lished across the inner mitochondrial membrane to depolar-
ize in a manner not linked to ATP production—hence the
“uncoupling.” This energy release manifests as heat. It may
be part of the pathophysiology of fever in salicylate toxicity,
though effects on hypothalamic function may also play a role.
Recently, another mechanism of salicylate toxicity has been
elucidated.190 This research demonstrated reversible and irre-
versible inhibition of α-ketoglutarate dehydrogenase (AKDH)
in the Krebs cycle by salicylate and acetylsalicylic acid,
Chapter 74 — Cellular Respiration 1071
respectively, resulting in diminished production of NADH
and failure of cellular respiration.
2,4-Dinitrophenol
DNP is a chemical compound used in the 1930s as a diet pill.
Today it is rarely used as such but frequently used in research
on membrane transport. Its popularity for both is due to its
ability to induce depolarization of the inner membrane of the
mitochondria. Just as with salicylates, this results in uncou-
pling of oxidative phosphorylation. Energy is released as heat
rather than used for production of ATP.
Propofol
Propofol is a frequently used anesthetic in the PICU and the
operating room. Although generally considered safe, there
have been increasing reports of patients developing meta-
bolic acidosis, rhabdomyolysis, refractory bradycardia and
cardiac failure, renal failure, and death from propofol infu-
sion syndrome.191 The pathophysiology of this syndrome
remains partially unexplained, but multiple studies show at
least some aspects related to propofol’s effects on the mito-
chondria.142,192-194 Some studies demonstrate leakage of pro-
tons across the inner mitochondrial membrane similar to
uncoupling of oxidative phosphorylation by DNP and aspirin.
Others show inhibition of enzymes along the electron trans-
port chain. Given that propofol infusion syndrome usually
occurs in the ICU in critically ill patients, some researchers
have looked at the possibility of an interaction between pro-
pofol and reactive oxygen and nitrogen species as a potential
mechanism.193 Other researchers have suggested that unrec-
ognized mitochondrial disease may predispose patients to
this syndrome, though no such association has yet been ascer-
tained.195 Whatever the ultimate pathway is for development
of this syndrome, it almost certainly involves the mitochon-
dria on some level. The mechanism of action of DNP, aspirin,
and propofol are suggested in Figure 74-10.40
Complex IV with cyt-aa3 uses four electrons from cyto-
chrome c and eight protons from the matrix. Four protons
and electrons reduce oxygen to water. Four additional protons
are pumped out of the matrix.
An electrochemical gradient consisting of protons and
other factors constitutes the mitochondrial membrane poten-
tial. Uncouplers transport protons into the mitochondrion,
dissipating the proton gradient. DNP, aspirin, and propofol
are examples of exogenous uncouplers. Endogenous uncou-
pling proteins in the inner mitochondrial membrane also exist
and are regulated by hormones.
Sepsis and Dysoxia
Historically, sepsis is typically regarded in macroscopic dimen-
sions. Intensivists support blood pressure, perfusion, and oxy-
genation because correction of these abnormalities has shown
improvement in outcome. However, the cellular microscopic
milieu constitutes the mechanistic focus for any macroscopic
abnormalities. The microcirculation and mitochondria are
at the core of organ failure and death in sepsis, although the
details remain sketchy. Currently, they also remain far from
therapeutic reach. Their increasingly recognized role in the
pathogenesis of sepsis has led to the term microcirculatory and
mitochondrial distress syndrome (MMDS), a term highlight-
ing the complex interplay between circulation and cellular
1072 Section V — Renal, Endocrine, and Gastrointestinal Systems

4cyt c H+
(Fe3+) H+ H+
H+
4cyt c 2H20
(Fe2+) Intermembrane space

4e–

a a3 Complex IV Inner membrane

Matrix
O2 H+ H+
H+ H+ H+ H+
H+ H+

H+
H+ O– O–
H+
NO2 NO2

H+
NO2 NO2
H+ H+
DNP– DNP
Intermembrane space IMM H+
UCP

Matrix H+
H+ H+
H+ H+

OH O–
NO2 NO2

NO2 NO2
DNP DNP-
Figure 74–10.  Schematic depiction of proton coupling to drive oxidative phosphorylation and decoupling activity of drugs such as DNP, aspirin, and
propofol. (Modified from Baynes JW, Dominiczak MH: Medical biochemistry, New York, 2009, Mosby Elsevier.)

metabolism in sepsis.175 Studies examining cellular energy,
microcirculation, and mitochondria in sepsis have yielded
conflicting results regarding the exact mechanisms and contri-
butions each plays in sepsis pathogenesis. As with most areas
in medicine, it is likely that the answer overlaps with multiple
contributions, with no single element emerging as the defini-
tive problem.
Hibernation Physiology in Sepsis
One final aspect of cellular metabolism and energetics worth
mentioning is that of hibernation. Although sepsis often pro-
gresses to MODS and death, tissue examination frequently
reveals little histologic evidence of cell injury and death.196
Some research indicates a form of cellular hibernation is trig-
gered in sepsis. Energy metabolism is altered to preserve cell
life, but physiologic cell function nearly ceases. The exact
mechanism is not understood, and its role in sepsis has not
been extensively evaluated.32,197 However, it does provide an
explanation for extreme organ dysfunction in the absence of
cell death and a platform for future study.
References are available online at http://www.expertconsult.
com.