Oxygen transport—1. Basic principles

In their ABC of oxygen: transport pubished in the British Medical
Journal Treacher and Leach observe that "a large study of postoperative
patients reported that increasing global oxygen delivery above normal
levels increased oxygen consumption and improved survival. This
demonstration of "supply dependence" led to the hypothesis that critically
ill patients had covert oxygen debt that could be eliminated by increasing
oxygen supply and spawned the era of "goal directed therapy. Cardiac
output was increased to achieve oxygen supply rates above 600 ml/min/m2 by
aggressive volume loading and the use of vasodilating inotropes"(1).

They add that "although increasing the oxygen supply by volume
replacement in relatively volume depleted postoperative patients is
appropriate, recent European studies have shown that it may be detrimental
in adequately resuscitated patients presenting with incipient or
established multiorgan failure. Aggressive fluid loading done with goal-
directed therapy may impair pulmonary gas exchange and reduce oxygen
diffusion in tissues due to increased endothelial permeability and
myocardial dysfunction in inflammatory and septic conditions in critically
ill patients. The increase in mortality associated with the use of
pulmonary artery catheters may reflect the adverse effects of their use in
attempting to achieve supranormal levels of oxygen delivery".

I shared Treacher's and Leach 's views at the time they wrote their
paper but have had to modify them as my understanding of metabolism has
improved especially in regards to the unappreciated importance of ATP
resynthesis by increased glycolytic turnover independently of ATP
resynthesis by oxidative phosphorylation, that is anaerobic metabolism.

Twenty years ago we had found in anaesthetised dogs that the
inflection point in the plot of oxygen consumption (VO2) against oxygen
delivery (DO2) , performed to define the DO2 at which supply-dependency
occurred, corresponded with that point at which the intestinal
intramucosal pH fell below baseline to abnormally low levels (2). The fall
in intramucosal pH was subsequently interpreted as evidence of dysoxia,
that is a state in which ATP resynthesis is abnormally dependent upon
anaerobic metabolism and a greatly increased rate of glycolytic turnover
(3,4). This is a state characterised by a tissue acidosis putatively
induced by the persistence of unrevered ATP hydrolysis, that occurring by
oxidative phosphorylation but not that occurring by glycolysis removing
accumulated protons.

It transpires that ATP resynthesis by anaerobic means is the
preferred means for ATP resynthesis in healing wounds, neoplasms and stem
cells, circumstances in which there is an especially high demand for
energy from ATP hydrolysis. Anaerobic metabolism is an inefficient means
of ATP resynthesis for nineteen times as much nutrient is required to
generate one mole of ATP as compared with that generated by glycolysis and
oxidative phosphorylation. It is, nevertheless a very effective means of
generating ATP in these dynamic cellular circumstances.

The shortfall in ATP resynthesis by oxidative phosphorylation is
matched and even exceeded by a capacity to increase glycolytic turnover by
as much as a thousand times. The efficiency with which the energy derived
from ATP hydrolysis is used in these circumstances is improved by the
inhibition of those biochemical reactions that normally use ATP for
higher functions, such as the secretion of gastric acid, in accordance
with the Daniel Atkinson nomogram for energy charge. An increased rate of
glycolytic turnover is, however, only an effective means of ATP
resynthesis if there are adequately oxygenated distant organs, notably
the liver, capable of metabolising the lactate and alanine produced by the
anaerobic tissues and replenishing the NADH needed for the conversion of
pyruvate being produced by glycolysis into the lactate and its
accompanying resynthesise of ATP.

If tissue can survive and thrive in nthe absence of oxygen why are
the effects of oxygen deprivation so bad? Because some functions, notably
myocardial and hepatic function, remain at least partly dependent upon ATP
resynthesis by opxidative phospiorylation. There is, furthermore, ample
evidence to suggest that the continued oxygenation in severely hyoxic
tissues is far more harmful that the absence of any perfusion certainly
for a limited period. Increasing oxygen delivery in these circumstances
can only make matters worse by incrasing free radical release.

ATP resynthesis by anaerobic means is the first call for energy in
exercising muscle after the PCr and ATP pools have been depleted, there
being far fewer metabolic steps involved in generating ATP in glycolysis
relative to those needed in oxidative phosphorylation. Anaerobic
performance or the he capacity to replenish ATP stores by anaerobic means
is limited by the availability of glycogen, presumably because fatty
acids "burn in the flames" of carbohydrate metabolism and ceases when
muscle glycogen levels fall below critical levels.

The glycerol released by lipolysis supplements the supply of pyruvate
from carbohydrates and hence the capacity for ATP resynthesis by
glycolysis with or without the addition of oxidative phosphorylation.
Indeed it is the fatty acids released by the lipolysis of the fat in
adipose tissues rather than the carbohydrates that provide most of the
nutrients used to resynthesise ATP during sustained exercise. In those
muscles in which oxidative phosphorylation becomes compromised the acetyl
coenzyme A derived from the betaoxidation of the fatty acids is converted
into ketone bodies which, like lactate, will not accumulate regionally and
inhibit ATP resynthesis provided it can be transported to and used as
substrate for oxidative phosphorylation in adequately oxygenated organs
notably the liver and brain. Betaoxidation of fatty acids per se does not
generate ATP unless the acetylcoenzyme A is used as substrate for
oxidative phopshorylation (5,6,7). It is just the glycerol that has the
capacity to replenish ATP in anaerobic tissues.

In healing wounds and probably all tissues dependent upon ATP
resynthesis by increased glycolytic turnover alone increasing the tissue
pO2 to normal or even to supranormal levels does not appear to have an
incremental effect upon the rate of ATP resynthesis, seemingly unless the
pH and accompanying energy charge has been returned to normality (8). In
circumstances, therefore, ATP resynthesis is dependent upon nutrient
transport, delivery and utilisation and not upon oxygen transport,
delivery, and uptake. This is teleologically appropriate for at some point
in anaerobic metabolism xanthine dehydrogenase will be converted into
xanthine oxidase and free radicals which may harm healthy cells, will be
generated.

In enterocytes, and probably all cells, free radicals trigger the
release of poly(ADP-ribose) polymerase (PARP) which depletes NAD(+)/NADH
pools and thereby decreases oxygen consumption. In limiting the likelihood
of free radical induced injury this may be regarded as a cytoprotective
response and therefore as a negative feedback control. However when
systemic the depletion of NASD(+)/NADH and decrease in oxygen consumption
may be cytopathic (9). Muscle contraction ceases when the tissue pH and
accompanying energy charge falls to extremely low levels. This is the
ultimate negative feedback control to enable depleted ATP stores to be
replenished for the need for increased energy from ATP hydrolysis is
eliminated.

In ICU patients, many of whom have the systemic inflammatory response
syndrome (SIRS), the cytokines being released may convert xanthine
dehydrogenase into xanthine oxidase and set the stage for free radical
release and hence the release of PARP, depletion of the NAD(+)/NADH
pools and a regional or even systemic decrease oxygen consumption. To meet
the continued need for energy from ATP resynthesis by glycolysis alone the
rate of glycolytic turnover and hence the demand for an increase in
nutrient transport, delivery and uptake must be greatly increased. [the
accompanying increase in temperature improves the efficiency of ATP
utilisation by increasing membrane fluidity and decreasing the amount of
enrgy required to drive reactions]. In other words the increase in cardiac
output and oxygen delivery seen in survivors may be more a reflection of a
need for increased transport, delivery and uptake of nutrient than of
oxygen.

Any incremental increase in VO2 in SIRS is, therefore, likely to be
due either to the need for additional ATP resynthesis by oxidative
phosphorylation or to an increased demand for oxygen by leukocytes which
require an "oxidative burst" to generate the free radicals they need to
kill the organisms they have phagocytosed (10). One would presume that, in
the absence of infection, the likelihood of the former might decrease as
the energy charge and tissue pH fell. In which case the need for nutrient
for ATP resynthesis by glycolysis alone should also increase as the energy
charge and tissue pH fall.

If the need for increased nutrition rather than oxygen is partly or
even wholly responsible for the hyperdynamic state seen in SIRS and overt
sepsis then one would presume that increasing the nutrient density,
calories per unit volume of blood, in intravenous solutions might decrease
cardiac output and accompanying workload on the myocardium. The nutrient
density might, for example, be increased by substituting fats for glucose.
The assumption in so doing is that the delivery of nutrients by parenteral
means will not increase the demand for energy beyond the capacity for ATP
resynthesis and thereby compound the severity of any energy defict
present.

Fructose/ 1,6 bisphosphate might be more appropriate nutritient than
glucose in these circumstances for it should aid in the conservation of
ATP stores by doubling the net yield of ATP from glycolysis (11). Enteral
feeding should be less efficient in that, unlike parenteral nutrients, it
requires energy from ATP hydrolysis for the secretion and synthesis of
digestive enzymes and gut hormones, and the absorption and hepatic
metabolism of nutrients. There is also a risk that enteral feeds will harm
gut mucosa in which the intramucosal pH has fallen to abnormally low
levels by increasing the magnitude of any energy defict and accompanying
intramucosal acidosis present (3). The benefit ascribed to enteral
relative to parenteral feeding might be largely if not solely due to the
absence of the sepsis and the other complications associated with the use
of the central line.

Neither oxygen supply-dependency nor nutrient supply-dependency is a
very helpful clinical state to define for each is dependent upon and
certainly intimately related to variations in the other. Energy supply-
dependency is little better because there are no clearly defined normal
limits, other than athletic performance in the healthy and tolerance to
exercise or some form of stress test in the ill. The energy charge is not
helpful either because it is based upon too many variables and at the end
of the day ATP degradation, upon which changes in energy charge depend,
is a relatively late event in the course of severe exercise or an acute
illness.

The tissue pH is much more meaningful because it is directly related
to the protonmotive force needed to drive ATP resynthesis by oxidative
phosphorylation in accordance with the Nobel Laureate Peter Mitchell's
hypothesis The tissue pH is also related to the function of enzymes,
which is pH and temperature-dependent. [Like the tissue pH the temperature
is intimately dependent upon mitochondrial function and changes are
indicative of pathologic perturbations of mitochondrial function].

It makes sense to aim to restore the tissue pH and temperature to
normality for, provided they stay normal, a normal pH in an afebrile
patient is accurately predictive of an excellent prognosis. It also makes
sense to make the elimination of a pCO2-gap in a steady state in an
afebrile patient an early if not the earliest goal in the resuscitation
and management of the critically ill. An abnormally elevated pCO2-gap in a
steady state is indicative of impaired tissue perfusion be that due to
regional impairment in blood flow or perfusion or to hypovolaemia. A
normal pCO2-gap does not, however, exclude the presence of a tissue
acidosis or indeed a fall in energy charge indicative of ATP degradation.

It is not surprising that goal-directed therapy has proved to be of
some, although questionable, benefit in preventing a fall in tissue pH in
elective surgery. It is certainly not surprising that goal-directed
therapy has proved ineffective or even harmful in ICU patients. The
goals in the resuscitation and management of the critically ill remain
seriously flawed and in urgent need of revision.

1. D F Treacher and R M Leach
ABC of oxygen: Oxygen transport1. Basic principles
BMJ, Nov 1998; 317: 1302 - 1306.

2. Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED, Dantzker
DR. Adequacy of tissue oxygenation in intact dog intestine. J Appl
Physiol. 1984 Apr;56(4):1065-9.

3. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.

4. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.

5. Biochemistry, 5th edition, Berg JM, Tymoczko JL, Stryer L Edds, WH
Freeman and Company, New York, 1995.

6. Salway JG. Metabolism at a glance. Blackwell Scientific, Oxford, 1999

7. Exercise physiology, 5th edition. Lippincott Williams and Wilkens,
Philadelphia, 2001

8. Wilmore DW, Stoner HB. The wound-organ. in Scientific Foundations of
Trauma. Cooper GJ, Dudley HAF, Gann DS, Little RA, Maynard RL, Eds.
Butterworth/Heinemann, Oxford. 1997, Chapter 38, pp524-529.

9. Khan AU, Delude RL, Han YY, Sappington PL, Han X, Carcillo JA, Fink
MP.Liposomal NAD(+) prevents diminished O(2) consumption by
immunostimulated Caco-2 cells. Am J Physiol Lung Cell Mol Physiol. 2002
May;282(5):L1082-91.

10. Hunt TK, Hopf HW, Mueller RV. Wound healing in Scientific Foundations
of Trauma. Cooper GJ, Dudley HAF, Gann DS, Little RA, Maynard RL, Eds.
Butterworth/Heinemann, Oxford. 1997, Chapter 39, pp530-550

11. Richard G Fiddian-Green
Fructose/ 1,6 bisphosphate loading for marathon runners?
http://bmj.com/cgi/eletters/327/7407/113#35349, 4 Aug 2003

Competing interests:
None declared