Page 574 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

562 FLUID THERAPY

Cellular Hypoxia When inadequate cellular energy metabolism occurs,
When tissue oxygen supply is inadequate, either due to cell function is compromised. Maintenance of ionic
gradients across the cell membrane requires active trans­
global decreases in blood flow or maldistribution of
blood flow, oxidative metabolism is compromised and port systems that consume 20% to 80% of all cellular
98
energy produced. Some organs are more susceptible
cellular function becomes dependent on anaerobic
energy production. Glycolysis, the only source of cellular to hypoxic injury than others. The brain and the heart
are obligate, aerobic, energy-dependent organs. Neurons
energy in an anaerobic environment, is extremely ineffi­
use the majority of cellular energy in the preservation of
cient with only 2 mol of adenosine triphosphate (ATP)
ionic gradients and membrane potentials while
being produced from each mole of glucose. This
myocardial cells have a high-energy requirement to fuel
represents approximately 3% of the potential energy in
contractile processes. In the face of inadequate cellular
the glucose molecules. For a short period of time this lim­
energy production, the active transport systems
ited anaerobic energy production may prevent cell injury
controlling cell volume, such as the Na-K-ATPase pump,
and death. When 1 mol of glucose is metabolized by
fail. As a consequence the entry of ions such as sodium
glycolysis it produces 2 mol of pyruvate, in anaerobic
and calcium into the cell is favored. In response to the
conditions most of the pyruvate is then converted to lac­
tate. 54 This conversion allows glycolysis to continue as it increasing intracellular osmolarity, water shifts into
þ
regenerates essential NAD and prevents the accumula­ cells leading to cell swelling and can ultimately result in
cell death. 17
tion of pyruvate. Lactate production during anaerobic
metabolism occurs in conjunction with an equimolar pro­ Increases in intracellular calcium trigger activation of
calcium-dependent phospholipases and proteases that
duction of hydrogen ions as a consequence of concurrent
hydrolysis of ATP (Figure 23-2). 120 The result is the for­ can cause cellular injury. This includes calpainlike
proteases that convert xanthine dehydrogenase to xan­
mation of lactic acid. Given its inefficiency, anaerobic
thine oxidase. 134 Without sufficient levels of xanthine
metabolism is limited in its ability to maintain normal
dehydrogenase, intracellular hypoxanthine accumulates.
function. In situations of acute, absolute cellular hypoxia,
such as asphyxiation, anaerobic metabolism can only These changes have important repercussions during the
support life for approximately 1 minute. reperfusion period.
Free Radical Damage
Glucose
Reperfusion of organs following a period of ischemia,
G although essential for survival, can also be a mechanism
NAD + L
Y of tissue damage. When oxygen is reintroduced to cells,
C
O it is used by xanthine oxidase (which accumulates during
L the ischemic period) to convert hypoxanthine (also
Y
S
NADH accumulated during the ischemic period) to reactive oxy­
I
S NADH NAD + gen species, such as the superoxide anion and hydrogen
peroxide. These products will cause direct cell injury by
damaging proteins and DNA and causing lipid peroxida­
Pyruvate
Lactate
Lactate tion. Both rises in intracellular calcium concentration and
dehydrogenase plasma membrane damage can trigger activation of
phospholipase A 2 , leading to arachidonic acid formation
ATP and eicosanoid synthesis including thromboxane A 2
and leukotrienes. 148 These arachidonic acid products
have many functions including pro-inflammatory,
Mitochondria H + ADP procoagulant, and vasoactive effects.
Reactive oxygen species in turn have been shown to
activate the nuclear transcription factor kB (NF-kB),
which causes transcription of proinflammatory
mediators, including more reactive oxygen species, leu­
O 2 kocyte adhesion molecules, and tumor necrosis factor­
Figure 23-2 Anaerobic metabolism. Glycolysis occurs in the a. 94 These processes have also been shown to damage
cytoplasm and results in the production of pyruvate, which under mitochondria such that cellular energy production may
normal circumstances enters the mitochondria for further remain impaired, despite adequate oxygen delivery. 16,47
metabolism. In the absence of oxygen, pyruvate is converted to This abnormality has been coined “cytopathic hypoxia”
lactate. During anaerobic metabolism there is a concurrent and is currently considered to be a contributor to the
accumulation of hydrogen ions from the hydrolysis of ATP; development of multiple organ dysfunction syndrome
these combine with lactate to produce lactic acid. 83
(MODS) in various disease states.