Vol. 21, No.
4 April 1999 V 20TH ANNIVERSARY
CE Refereed Peer Review
FOCAL POINT
★Although prolonged exposure
to high alveolar oxygen (O2 )
concentrations can lead to
pulmonary injury, O2 therapy
should not be withheld from
hypoxemic patients.
KEY FACTS
■ Under normal conditions, O2
supplementation has little benefit
in increasing arterial O2 content if
the measured partial pressure is
higher than 70 mm Hg or the
fraction of saturated hemoglobin
is greater than 93%.
■ Prolonged use of high fractional
inspired O2 concentrations (FiO2)
can lead to tracheobronchial
irritation, atelectasis, and
decreased ability to transport
O2 from the environment to the
alveoli and from the alveoli to
the blood.
■ Positive end-expiratory pressure
and continuous positive airway
pressure are two ventilatory
modalities that can lessen the
need for high FiO2.
■ Once changes begin in the lungs,
higher O2 concentrations may be
required to achieve desired
levels in the blood, creating a
vicious cycle of O2-induced lung
injury.
Oxygen Toxicity
Dove Lewis Emergency Animal Hospital
Tufts University Portland, Oregon
Steven Mensack, VMD Robert Murtaugh, DVM, MS
ABSTRACT: Molecular oxygen (O2) manifests its toxic effects through the production of free
radicals. If an animal breathes a high fractional inspired O2 concentration (FiO2), the increased
production of free radicals can overwhelm the endogenous antioxidant systems. Depending
on the atmospheric pressure by which O2 is delivered, clinical signs of toxicity may be exhibit-
ed in the lungs or central nervous system. Under conditions of normal atmospheric pressure,
the lungs are the primary target for manifestations of toxicity. Clinically, increased work of
breathing, decreased tidal volume, and increased arteriovenous shunting are manifestations of
O2 toxicity. Although there is no therapy, several methods are being investigated to ameliorate
the pathologic changes associated with prolonged exposure to toxic O2 concentrations. Until
treatment methods are available, judiciously limiting exposure to high Fio2 is the key to pre-
vention.
S
ince the discovery of oxygen (O2) in the late 18th century, scientists have
postulated that although it is necessary for life, too much exposure can be
detrimental. As human and veterinary critical care medicine have ad-
vanced, the use of supplemental O2 therapy has become more common. With
increased O2 use comes the need to recognize possible complications. This article
addresses the biochemical and pathophysiologic effects of prolonged use of high
O2 concentrations. The primary focus is on the pulmonary effects of O2 deliv-
ered at normal atmospheric pressure (normobaric toxicity), although the toxic
neurologic effects of hyperbaric (high-pressure) oxygen (HBO) therapy is also
addressed. Finally, prevention and therapy for O2 toxicity and tolerance to high
O2 concentrations are discussed.
RATIONAL USE OF OXYGEN
The use of supplemental O2 therapy has gained widespread acceptance in vet-
erinary medicine. Indications for supplemental O2 include providing supportive
care for anesthetized patients; increasing the O2 content in blood during periods
of hypoxemia; and aiding in the healing of chronic complicated wounds, acute
traumatic soft tissue injuries, and serious skin wound infections (HBO therapy).
Oxygen Transport
To understand when supplemental therapy is necessary, it is important to un-
derstand normal O2 transport. One of the primary purposes of both the respira-
tory and circulatory systems is the transport of O2 from the outside environment
to tissues. In the lungs, O2 diffuses down its concentration gradient from the
alveolus into the blood. Once in the blood, O2 is transported to the tissues,
where it again diffuses down its concentration gradient to be used for normal
cellular metabolism. The amount of O2 delivered to a particular tissue depends
Small Animal/Exotics
100
90
Oxygen Saturation of Hemoglobin (%)
80
70
60
50
40
30
20
10
0
0 10 20 30 40 50 60
Partial Pressure of Oxygen (Po2) (mm Hg)
SaO2 (normal)
SaO2 (left shift)
SaO2 (right shift)
Figure 1—The oxyhemoglobin dissociation curve. A left shift
from normal is caused by decreased body temperature, in-
creased blood pH (alkalosis), decreased partial pressure of
carbon dioxide (PCO2) in blood, or decreased red blood cell
(RBC) concentration of 2,3-diphosphoglycerate (2,3-DPG).
A right shift from normal is caused by increased body tem-
perature; decreased blood pH (acidosis), increased PCO2, and
increased RBC concentration of 2,3-DPG (O2 = oxygen;
SaO2 = fraction of saturated hemoglobin).
on the amount entering the lungs, efficiency of pul-
monary gas exchange, blood flow to the tissue, and
ability of blood to carry O2.
Under standard conditions (barometric pressure
[Patm], 760 mm Hg; fractional inspired oxygen concen-
tration [FiO2] in room air, 21%), each 100 ml of arteri-
al blood carries approximately 19.5 ml of O2,1,2 which
can be calculated by the following equation:
O2 content = (1.34 × [Hb] × SaO2) + 0.003 PaO2
where 1.34 = the amount (in ml) of O2 carried by 1 g
of hemoglobin (Hb), Hb = the concentration of he-
moglobin in blood (normal, 15 mg/dl), SaO2 = the frac-
tion of saturated Hb (normal, 93% to 97%), and PaO2
= the partial pressure of O2 dissolved in arterial plasma
(normal, 85 to 105 mm Hg).1–6 As calculated by this
equation, the majority of O2 carried by blood is bound
to Hb (19.2 ml) and very little is dissolved in plasma
(0.3 ml).1–4 The SaO2 can be measured by cooximetry
or estimated by pulse oximetry, the Hb concentration
attributable to red blood cells (RBCs) can be measured
by a hemoglobinometer or estimated by multiplying
the measured hematocrit by one third, and the PaO2
OXYHEMOGLOBIN DISSOCIATION CURVE ■ NONANESTHETIC OXYGEN SUPPLEMENTATION
20TH ANNIVERSARY Compendium April 1999
can be measured by arterial blood gas analysis.
The ability of blood to carry O2 is profoundly affect-
ed by the ability of Hb to bind O2. The oxyhemoglo-
bin dissociation curve (Figure 1) is sigmoid shaped and
represents the relationship between SaO2 and the partial
pressure of O2 (PO2).1,3,4,7 Under normal conditions, the
plateau of the curve occurs at a PO2 of approximately
70 mm Hg. An increase in the PO2 above this level
causes a minimal increase in the O2 saturation of Hb.
However, decreases in PO2 below 60 mm Hg have in-
creasingly negative effects on O2 saturation of Hb.5
The ability of Hb to bind O2 can be altered by sever-
al pathophysiologic variables: blood pH; body tempera-
70 80 90 100 ture; the partial pressure of carbon dioxide (P CO 2 )
dissolved in plasma; and in dogs, changes in the con-
centration of the RBC carbohydrate 2,3-diphospho-
glycerate (2,3-DPG).5 A right shift of the curve indi-
cates that an increased PO2 is needed for Hb to bind a
specific amount of O2. Increased body temperature, de-
creased blood pH, and increased P CO 2 all shift the
curve to the right.1,3,4,7,8 An increased 2,3-DPG also
shifts the curve to the right.1,3,4,7,8 Conditions that in-
crease the RBC concentration of 2,3-DPG include hy-
perthyroidism, anemia, chronic exercise, and chronic
hypoxia.1 The PO2 at tissue level is lower than it is in ar-
terial blood.5 Thus, a right shift favors the off-loading
of O2 from the Hb molecule.5
A left shift of the curve represents increased affinity
of the Hb molecule for O2 and decreased O2 delivery to
tissues. Decreased body temperature, increased blood
pH, decreased PCO2, and decreased RBC concentration
of 2,3-DPG shift the curve to the left.1,3,4,7,8 Stored
RBCs contain decreased amounts of 2,3-DPG.3 This
decreased level is not a problem in stored feline blood
because the release of O2 is independent of 2,3-DPG.9
Indications for Supplemental Oxygen Therapy
The most common nonanesthetic use of supplemen-
tal O2 is for treating or preventing hypoxemia. Hypox-
emia is a relative deficiency of O2 tension in arterial
blood (decreased PaO2 ) and becomes significant when
the PaO2 is lower than 70 mm Hg.2,6 Hypoxia, another
common but not interchangeable condition, is a rela-
tive deficiency of O2 in tissues and can be caused by
multiple factors, one of which is hypoxemia.1,10 Multi-
ple known causes of hypoxemia include low FiO2, hypo-
ventilation, diffusion
• •
impairment, pulmonary ventila-
tion/perfusion (V/Q) inequity, intrapulmonary shunting
of blood, and certain toxins that may inhibit O2 uptake
in the lungs (see Causes of Hypoxemia). These causes are
not mutually exclusive.
Hypoventilation, which decreases O2 delivery from
the environment to the lungs, can be caused by drugs
Compendium April 1999 20TH ANNIVERSARY
(e.g., narcotics and barbiturates that depress the respira-
tory centers of the brain),3,6,11,12 thoracic wall trauma,3,7
pleural space disease (e.g., pneumothorax, hemothorax,
pleural effusion, diaphragmatic hernia with abdominal
content displaced into the pleural space),7,11 central ner-
vous system (CNS) trauma,12 upper airway obstruc-
tion,7,11 and neuromuscular disease (e.g., polyradicu-
loneuritis, myasthenia gravis).3,7
Diffusion impairment develops when equilibration
cannot occur between alveolar gas and pulmonary cap-
illary blood because of a thickened alveolar wall or
decreased contact time between blood and gas in the
alveolus.7 Conditions such as pulmonary fibrosis and
pulmonary edema • •
can cause diffusion impairment.11
Pulmonary V/Q inequity occurs when areas of the
lungs are receiving adequate fresh gas from the environ-
ment but• blood
•
flow is inadequate to effect gas ex-
change (V/Q higher than 1) or when areas of the lungs
are not receiving fresh gas from the environment but
are receiving
• •
a normal supply of fresh blood for gas ex-
change
• •
(V/Q lower than 1).1,3 Conditions that lead to
V/Q mismatching include atelectasis, alveolar pneumo-
nia, pulmonary edema of any cause, and pulmonary
thromboembolism.7,11,12
Causes of Hypoxemia
■ Hypoventilation (less oxygen delivered from the
environment to the lungs)
— Drugs (narcotics and barbiturates)
— Thoracic wall trauma (rib fractures)
— Pleural space disease (pneumothorax,
hemothorax, pleural effusion, diaphragmatic
hernia)
— Central nervous system trauma
— Upper airway obstruction (foreign body, laryngeal
paralysis, edema, neoplasia)
— Neuromuscular disease (polyradiculoneuritis,
myasthenia gravis)
— Diffusion impairment (thickened alveolar septa
or decreased transit time of blood through
pulmonary capillaries prevents equilibration
of oxygen between alveolus and blood)
— Pulmonary edema
— Pulmonary fibrosis
• •
■ Ventilation/perfusion (V/Q) mismatching (excessive
• •
blood flow to a region of underventilated lung [V/Q
HYPOVENTILATION ■ DIFFUSION IMPAIRMENT ■ INTRAPULMONARY SHUNTING
Small Animal/Exotics
• •
Intrapulmonary shunting, an extreme form of V/Q
mismatching, occurs if blood in the pulmonary circula-
tion totally bypasses ventilated lung • •
tissue before re-
turning to systemic circulation (V/Q = infinity).1,3,11,12
Conditions that cause intrapulmonary shunting of
blood include lung lobe consolidation, arteriovenous
fistulas, and right-to-left intracardiac shunts.11,12 O2
therapy can be beneficial to some extent in correcting
hypoxemia caused by any of these pathophysiologic
processes except intrapulmonary shunting.1,3
Supplemental O2 therapy may also have limited benefit
for severe anemia and acute hemorrhage.11 As indicated by
the equation presented earlier, approximately 97% of O2
in blood is in the form of oxyhemoglobin, whereas the re-
mainder is dissolved in plasma. With severe anemia or
acute hemorrhage, the amount of Hb is reduced and the
relative contribution of dissolved O2 to overall O2 content
in blood is greater. For each increase of 100 mm Hg in
PaO2, the overall increase of dissolved O2 in blood is very
small (approximately 0.3 ml O2 per 100 ml blood).1 Ulti-
mately, therapy for severe anemia involves replacing Hb in
the form of RBCs and/or an O2-carrying plasma-phase
Hb solution (Oxyglobin®; Biopure, Cambridge, MA). In
the interim, supplemental O2 therapy may help stabilize a
• •
lower than 1] or excessive capillary blood low [V/Q
higher than 1])
— Atelectasis
— Alveolar pneumonia
— Pulmonary edema
— Pulmonary thromboembolism
— Asthma
■ Arteriovenous shunting (blood in pulmonary
circulation bypasses ventilated lung tissue before
returning to systemic circulation)
— Atelectasis and lung lobe consolidation
— Arteriovenous fistula
— Right-to-left intracardiac shunt
■ Low fractional inspired oxygen concentration
— High altitude
— Administration of nitrous oxide
■ Toxins
— Carbon monoxide
— Methemoglobin
Small Animal/Exotics 20TH ANNIVERSARY Compendium April 1999

patient until additional Hb TABLE I aid in healing chronic com-

can be administered. In pa- Approximate Flow Rates of Oxygen plicated wounds, acute trau-
tients with low cardiac out- Administered by Nasal Cathetera matic soft tissue injuries, and
put, hypotension, hyperther- serious skin wound infec-
Oxygen Flow Rate (L/min)
mia, or problems with cellular tions.16,19 With these types of
O2 uptake, supplemental ther- Patient 30% to 50% 50% to 75% 75% to 90% injuries, sufficient O2 may
apy may have limited benefit. Weight (kg) FiO2 FiO2 FiO2 not reach areas of reduced
In these patients, therapeutic blood circulation. HBO ther-
considerations should be 0–10 0.5–1.0 1.0–2.0 3.0–5.0 apy allows increased O2 de-
aimed at correcting the un- 10–20 1.0–2.0 3.0–5.0 > 5.0 livery to tissues by increas-
derlying circulatory problem ing the amount dissolved in
20–40 3.0–5.0 > 5.0 Unknown
with the provision of intravas- plasma (up to 20 times nor-
a
cular volume expansion, posi- From Court MH: Respiratory support of the critically ill mal),16,17,19–21 which is benefi-
tive inotropes, or pressor agents. small animal patient, in Murtaugh RJ, Kaplan PM (eds): Vet- cial because O2 dissolved in
erinary Emergency and Critical Care Medicine. St. Louis, Mosby
Year Book, 1992, p 577 from data derived from Fitzpatrick RK,
plasma diffuses into tissues
Oxygen Delivery Crowe DT: Nasal oxygen administration in dogs and cats: Ex- more readily. Increased O2 sup-
Oxygen delivery should be perimental and clinical investigations. JAAHA 22:293–300, ply to damaged tissue leads
based on the FiO2 required, 1986. Reprinted with permission.) to increased antimicrobial ef-
the patient’s condition, and FiO2 = fractional inspired oxygen concentration. fects, induction and propaga-
available equipment. Endo- tion of angiogenesis, vaso-
tracheal intubation (or tra- constriction without O2 loss
cheostomy tube) connected to to tissues (which helps pre-
an O2 source with or with-
Cytochrome Oxidase vent edema), and fewer tissue
out concomitant use of any bubbles.16,17,19–21 HBO thera-
mechanical ventilation can e– e– 2H+ e– H+ –e H
– +
py may also prove to be use-
achieve 100% FiO2. O2 de-11 O 2 O 2
– H 2 O 2 OH H2O ful treatment of certain toxi-
livered via mask or Eliza- coses (e.g., cyanide or carbon
bethan collar fronted with
H2O monoxide poisoning).17,19–21
plastic wrap can attain 60%
FiO2,2,7 although nearly 100% Figure 2—Metabolism of oxygen (O2 ) to water. The sequen- OXYGEN METABOLISM
tial addition of single electrons to the O2 molecule yields tox-
can be achieved with a well- ic free radicals. Cytochrome oxidase within the mitochondria
AND PRODUCTION
fitted mask that contains a prevents these intermediates from escaping and causing dam- OF TOXIC OXYGEN
reservoir bag.2,6,11,13 age to cells (e – = electron; H + = hydrogen atom; H2O = water; METABOLITES
Oxygen can also be deliv- H2O2 = hydrogen peroxide; O2 – = superoxide radical; OH – Oxygen normally exists as
ered by nasal cannulation; = hydroxyl radical). (From Rochat MC: An introduction to a molecule of two O2 atoms
depending on the flow rate, reperfusion injury. Compend Contin Educ Pract Vet with two unpaired electrons
patient tolerance, and 13(6):925, 1991.) in the outer orbital. These
whether one or two cannulas electrons prevent the
are used, up to 90% Fi O 2 can be achieved (Table molecule from being highly reactive because of their
I).7,11,14,15 Intratracheal catheterization has been reported parallel spins, a concept called spin restriction.2,5,22 Nor-
to attain 80% to 90% FiO2 while using lower flow rates mal cellular O2 metabolism involves the stepwise addi-
than that used for nasal cannulation.15 Commercial tion of four single electrons (Figure 2), a process called
cages typically do not exceed 50% FiO2.7,10,11 reduction.2,5,22–24 During reduction, each addition of an
electron to O2 creates a reactive O2 species; these reac-
Hyperbaric Oxygen tions normally occur under controlled conditions with-
Hyperbaric oxygenation is just beginning to be used in the cell in the presence of catalysts, usually cy-
in veterinary medicine. This therapy involves placing tochrome oxidase.5,24 Under conditions of normal PaO2
patients in a chamber and supplying 100% O2 at pres- (100 mm Hg), 95% of the molecules are completely re-
sures greater than 1 atm at sea level (760 mm Hg).16–21 duced to water2,22,24 and the remaining molecules are
A common treatment protocol involves administering partially reduced, generating toxic metabolites.24 These
O2 at 2.0 to 2.4 atm (1520 to 1800 mm Hg) for 40 to reactive molecules have a high affinity for other elec-
60 minutes once or twice daily.16 trons within surrounding molecules, potentially result-
The most common indications for HBO therapy are to ing in oxidative damage to the molecules.

ACHIEVING OXYGEN REQUIREMENTS ■ HYPERBARIC OXYGEN THERAPY ■ OXYGEN METABOLISM

Compendium April 1999 20TH ANNIVERSARY
Cellular O2 metabolism involves the addition of single
electrons to molecular O2, yielding sequential reactive O2
intermediates.5,23,24 The addition of the first electron
yields the superoxide anion (O2–), a very reactive prod-
uct. The addition of a second electron (in the presence of
hydrogen atoms) yields hydrogen peroxide (H2O2 ), a less
reactive intermediate. The addition of a third electron
yields the very highly reactive hydroxyl radical (OH–)
and a molecule of water; through the addition of the
fourth electron, OH– is finally reduced to water. Within
the mitochondria, cytochrome oxidases that contain cop-
per or iron bind most of the molecules involved in the
reduction reactions, preventing the escape of reactive O2
species generated during the reactions.2,22,23
Under normal cellular conditions, approximately 5%
of the O2 metabolized within the mitochondria is only
partially reduced, generating toxic free radicals (FRs)2,22
that leak into the cytosol and out from the cell, possibly
through anion channels.2,22 O2-derived FRs in the cy-
tosol or outside the cell undergo further reactions. Two
superoxide anions can spontaneously react to form
H2O2. In the presence of iron or copper, O2– may react
with existing H2O2 to produce OH– and singlet oxygen
(1O2), a reaction known as the Fenton reaction.2,24,25
These FRs (O2–, OH–, 1O2) are believed to cause much
of the cellular damage observed with O 2 toxicity. 25
H2O2 is a less reactive toxic intermediate because it
contains no unpaired electrons. Thus, it is not an O2-
derived FR in the truest sense. However, it is highly re-
active and does have the capacity to cross biologic
membranes, enabling the more damaging FRs to form
at sites away from where the toxic intermediates are ini-
tially produced.26,27 Because FRs are products of normal
cellular metabolism, biochemical defense mechanisms
protect the organism from excessive FR damage.
THE ANTIOXIDANT SYSTEMS
Two types of defense mechanisms protect cells from
damage by O2-derived FRs: intracellular enzymatic sys-
tems and FR scavengers. The primary enzymatic defens-
es consist of superoxide dismutase (SOD), catalase, and
glutathione peroxidase (GPO).2,13,22–24 These enzymes
eliminate O2– and H2O2 and prevent FR chain reactions
by decreasing the available levels of FRs that initiate the
process.2,24,25 SODs act on the superoxide anion to pro-
duce H2O2.22,28 This system is found in both the mito-
chondria and cytosol of cells. Catalase acts on H2O2 to
form water and an O2 molecule without the creation of
OH–.22,23 The GPO system also acts on H2O2 to directly
form water and molecular O2.22,23 Unlike catalase, GPO
can recycle itself through an energy-dependent mecha-
nism that involves glutathione reductase.22
Free-radical scavengers include α-tocopherol (vitamin
CELLULAR METABOLISM ■ TOXIC FREE RADICALS ■ ANTIOXIDANTS
Small Animal/Exotics
E), ascorbic acid (vitamin C), niacin (vitamin B6), ri-
boflavin (vitamin B 2), vitamin A, and plasma pro-
teins.2,22,25 These antioxidants, which act to stop FR
chain reactions by accepting electrons, are mainly
found in extracellular fluid and plasma and are primari-
ly effective at stopping lipid peroxidation of cellular
membranes.24 When exposed to increased O2 concen-
trations, both intracellular and extracellular defense sys-
tems are overwhelmed by the increased production of
O2-derived FRs and increased cellular injury occurs.
CELLULAR
OXYGEN INJURY
Inside cells and tissues, O2-derived FRs disrupt numer-
ous cellular processes.2,22,24,29 The targets of oxidative at-
tacks include lipids, proteins, and nucleic acids. Lipids
(e.g., pulmonary surfactant and those found in biologic
membranes) react with these FRs to produce lipid perox-
ides.5,22,24,25,29 These products lead to increased membrane
permeability, inactivation of surfactant, and inhibition of
normal cellular enzyme processes and can damage pro-
teins and intracellular membranes.5,22,30 Proteins are also
subject to direct damage. Protein synthesis may be de-
creased through inhibition of ribosomal translation, or
formed proteins may be destroyed through oxidative
processes.22,24,30 Consequently, inactivation of intracellu-
lar enzymes and transport proteins occurs, leading to im-
paired cellular metabolism and accumulation of cellular
waste products.30 O2-derived FRs can cause breaks in
DNA and inhibit the enzyme systems involved in repair-
ing or replicating DNA.22,24,30 All this damage culminates
in cellular death.
PULMONARY OXYGEN TOXICITY
The lungs are the primary organ affected by high
FiO2 because they act as a barrier that prevents the re-
mainder of the body from experiencing high O2 con-
centrations. The amount and type of damage that oc-
curs in the lungs depend on the FiO2 and the duration
of exposure to high O2 concentrations. Based on cur-
rent data, the sequence of morphologic changes that
occur in the lungs in response to toxic O2 concentra-
tions is apparently conserved across species.31–35 Howev-
er, the severity and time to onset of pulmonary changes
show both species and individual variation.36 These
data need to be interpreted cautiously because most of
the research has been conducted in laboratories on rats,
primates, and healthy humans and on neonatal or ter-
minal human patients in clinical settings.
Morphologic changes in lungs exposed to hyperoxic
conditions follow a sequence of phases: initiation, inflam-
mation, destruction, proliferation, and fibrosis (see Phases
of Pulmonary Oxygen Toxicity). During initiation, the
Small Animal/Exotics 20TH ANNIVERSARY
Phases of Pulmonary Oxygen Toxicity
■ Initiation
— Increased production of toxic oxygen (O2)
metabolites
— Depleted antioxidant stores
— No evidence of lung injury
■ Inflammation
— Destruction of pulmonary endothelial lining
— Increased inflammatory mediators to the site of
injury
— Development of pulmonary edema
■ Destruction
— Release of soluble inflammatory mediators
— Amplification of destruction of pulmonary
endothelial lining
— Phase of O2 toxicity most associated with mortality
production rate of toxic FRs in lung tissue increases con-
siderably37 because of increased O2 metabolism in the
cells,38 which depletes cellular storage of enzymes, vita-
mins, and other substances involved in combating FR-de-
rived injury. However, there is no morphologic evidence
of pulmonary injury.25 During this time, the flow of tra-
cheal mucus decreases, which may impair the clearance of
debris from the lower airway and predispose the patient
to respiratory infection. The length of the initiation phase
varies inversely with the concentration of O2 delivered; in
rats, the time course is 24 hours at an FiO2 of 100%, 72
hours at 85% FiO2, and up to 7 days at 60% FiO2.31,32
The remaining phases follow in sequential order until
the patient either dies from respiratory compromise or
the hyperoxic conditions are resolved. Morphologic
changes in the lungs represent a continuum. The first
change is accumulation of plasma in the pericapillary
spaces secondary to damage of the endothelial lining.31,33
Accumulation of platelets and then of neutrophils in the
pulmonary vasculature and interstitium follows (inflam-
mation phase).13,30,31,33,39 These cells, along with pul-
monary macrophages and damaged capillary endothelial
cells, release soluble mediators of inflammation, thereby
amplifying the destruction of endothelial cells (destruc-
tion phase).13,30,31,33,39 If a patient survives the destruction
phase, the remaining capillary endothelial cells hyper-
trophy and other cell lines proliferate. The number of
monocytes and type II (surfactant-secreting) alveolar ep-
ithelial cells increases (proliferation phase; (Figure
3).13,30,31,33,39 Finally, collagen deposition in the lung in-
terstitium, thickness of the alveolar interstitial space,
OXIDATIVE ATTACKS ■ SEQUENCE OF TOXIC PHASES
Compendium April 1999
■ Proliferation
— Evident after prolonged exposure to less than
100% O2 concentrations (60% to 85% fractional
inspired oxygen concentration)
— Increased monocytes
— Increased type II alveolar epithelial cells
(surfactant secreting)
■ Fibrosis
— Permanent lung damage
— Collagen deposition in lung interstitium
— Increase in the thickness of pulmonary interstitial
space
— Increase in interstitial fibrosis
and interstitial fibrosis all increase (fibrosis phase).13,31,35
These changes occur in rodents and nonhuman pri-
mates after 48 to 96 hours of 100% O2 exposure.23 Be-
cause these changes are very similar to those described
for patients with acute respiratory distress syndrome and
because of the uniform use of supplemental O2 during
respiratory failure, the histopathologic diagnosis of
purely O2-induced pulmonary injury is very difficult.
Clinically, O2 toxicity may be more difficult to define
in veterinary patients because pulmonary function tests
are difficult to perform. In healthy human volunteers ex-
posed to 100% O2, clinical signs of substernal soreness,
cough, sore throat, nasal congestion, and painful inspira-
tion developed within 12 to 14 hours.5,23,38,40,41 Mucocil-
iary clearance was shown to decrease in humans after 3
to 6 hours of 100% O2 exposure23,30,41 and in healthy
dogs42 and cats43 after 72 hours, which can lead to an in-
creased risk for pneumonia (a common complication in
mechanically ventilated patients). During the initial 6- to
12-hour period in healthy humans, no changes in vital
capacity (total amount of gas exhaled after a full inspira-
tion), alveolar–arterial O2 gradient, pulmonary artery
pressure, or total lung water were noted.25,44
The first clinically measured change in human volun-
teers was decreased vital capacity, which occurred with-
in 24 hours after beginning to breathe 100% O2.23,30,40
This decrease became progressively more severe after 60
hours of exposure.5,23 In normal baboons, this decrease
became evident after breathing 100% O2 for 48 hours,
and total lung capacity was less than 50% of normal by
day 6.33,45 After healthy human subjects breathed 100%
Small Animal/Exotics 20TH ANNIVERSARY Compendium April 1999

O 2 for approximately 30 ple enzyme systems is de-

hours, the gas-diffusing ca- pressed by an undefined
pacity (a measure of gas ex- mechanism not involving
change in the lungs) de- FR generation. Decreased
creased.46 enzymatic activity ultimate-
These changes in lung ly leads to seizure activity.
function are postulated to Seizures induced by
occur from progressive at- HBO therapy are rare, with
electasis attributed to reports of seizures occurring
washout of normal lung ni- in 0.03% 48 to 0.21% 49 of
trogen, decreased surfactant treatments in humans. When
activity, and edema sec- seizure activity is noted, pa-
ondary to endothelial cell tients should be removed
damage. 5 The effects and Figure 3—This photomicrograph from a 3-year-old spayed from the chamber but not
clinical time course of O2- female German shepherd with suspected oxygen (O2) toxicity until the seizure activity has
induced functional changes demonstrates the proliferative phase of toxicity. The dog had ceased. Decompression of a
in diseased lungs have not a history of chronic pneumonia, had been on a ventilator on patient during the tonic
been elucidated because of two separate occasions, and had received high-concentration phase of the seizure can put
O2 therapy for extended periods before being euthanatized.
the confounding influence Note the similarity to changes associated with acute respira- the patient at risk for air or
of various disease processes tory distress syndrome. Thin arrows = type II alveolar epithe- oxygen embolus. 20 There
that occur in lung tissue. lial cells; thick arrow = hyaline membrane deposition. (Cour- has been no report of long-
Lower FiO2 (60% to 85%) tesy of Michael Hawes, DVM, Tufts University) term clinical sequelae to
has also been implicated in HBO-induced seizures. 21
causing pulmonary damage However, pathologic CNS
in rodents, primates, and humans, although to a lesser changes have been noted in experimental animals,17 in-
extent and over a longer period (days to weeks).25,31,32,39,47 cluding white matter necrosis with either pyknosis and
Although these lower concentrations can cause perma- hyperchromatosis of the neurons, vacuolization of the
nent lung damage, they have not been shown to lead di- cytoplasm, and simultaneous swelling of the perineural
rectly to death. glial processes or lysis within the nerve cell’s cytoplasm
and karryorhexis.
NEUROLOGIC OXYGEN TOXICITY Several factors have been shown to predispose a pa-
The potential toxic effects of O2 are not limited to tient to seizure activity while receiving HBO therapy.
the lungs. The CNS, primarily the brain, has been Candidates for this therapy should not be febrile or aci-
shown to respond adversely to abnormally high PaO2, dotic because both states have been associated with a
which is normally achieved using HBO therapy. One higher prevalence of seizure activity17,18; should not re-
of the major clinical manifestations of neurologic O2 ceive high concentrations of supplemental O2 just be-
toxicity is generalized seizures.3,17,18,20,21,48,49 Although fore HBO therapy because seizure activity and pul-
the exact process leading to hyperoxia-induced seizure monary damage are more likely; and should not have a
activity is unknown, three mechanisms may be in- history of previous seizure activity.18 Seizure activity as-
17
volved. The first is decreased cerebral metabolism, sociated with HBO therapy has not been reported in
leading to a decreased level of γ-aminobutyric acid the veterinary literature.
(GABA), an inhibitory neurotransmitter. This prem-
ise is based on the fact that a decrease in the amount THERAPY, PREVENTION, AND TOLERANCE
of GABA in the brain occurs before the onset of seizure The only fully effective way of managing O2 toxicity
activity and that the critical atmospheric pressures for is to avoid it. Veterinarians can manage patients at risk
onset of seizure activity and reduction in GABA oc- for pulmonary toxicity by maintaining the lowest FiO2
cur concomitantly.17 The second postulated mecha- compatible with achieving adequate systemic and tissue
nism involves the generation of toxic FRs, which can oxygenation. There are, however, occasions when the
lead to cellular membrane lipid peroxidation, inactiva- need for prolonged ventilation with an FiO2 of 60% or
tion of enzyme systems, and DNA denaturation. The higher is required to maintain sufficient systemic oxy-
changes induced by this damage lead to seizure activi- genation. In these patients, it is important to attempt to
ty. The third postulated mechanism involves enzyme reduce the FiO2 by small increments to below this criti-
inhibition. With HBO therapy, the activity of multi- cal level as soon as is safely possible and to monitor for

HISTOPATHOLOGIC DIAGNOSIS ■ HYPEROXIA-INDUCED SEIZURES

 Compendium April 1999 20TH ANNIVERSARY Small Animal/Exotics

hypoxemia by serial arterial blood gas measurements.
Several strategies have been proven useful in decreas-
ing the need for toxic FiO2. The most common are pos-
itive end-expiratory pressure (PEEP) and continuous
positive airway pressure (CPAP) delivered while the pa-
tient is receiving O2 from a ventilatory circuit.50 PEEP
is supplied while the ventilator is performing the work
of breathing, whereas CPAP is supplied while the pa-
tient is breathing spontaneously. With either mode,
positive pressure is being maintained to the airways
throughout the duration of the respiratory cycle, there-
by preventing complete expiration. By preventing com-
plete expiration, small airways remain open, alveolar
size increases, and more alveoli are available for gas ex-
change. Because the majority of gas exchange between
the blood and alveolus occurs • •
during expiration, these
measures help improve V/Q matching and decrease in-
trapulmonary shunting, leading to improved arterial
oxygenation.
Sound medical practice can also lower the FiO2 re-
quired. This includes maintaining proper sedation, cor-
recting anemia, optimizing cardiac output to improve
O2 delivery to tissues, treating fever or hyperthermia to
decrease tissue O2 demands, diagnosing and treating in-
fections, supplying proper nutrition, and providing
good nursing care.51
MP
ENDIU Nutrition is very impor-
M’
associated with O2 toxicity in lung or CNS tissue. Mul-
tiple strategies to prevent or ameliorate the toxic effects
of acute pulmonary toxicity are currently under labora-
tory investigation. Investigations in rats and mice have
shown that pentoxifylline (a methylxanthine deriva-
tive),54 high doses of magnesium sulfate,55 acetylcys-
teine, 56,57 liposomal-encapsulated antioxidant en-
zymes,58,59 deferoxamine (an iron chelating agent),29,60
and recombinant human tumor necrosis factor61 all
provide some protection against pathologic changes in
the lungs of rats or mice exposed to lethal O2 concen-
trations. Exogenous surfactant administration has been
shown to prevent rabbits from developing pulmonary
damage.62 The value of these drugs in the clinical set-
ting awaits further investigation.
Tolerance to high O2 concentrations has been report-
ed. Rats have been able to increase the antioxidant de-
fenses in their lungs after being exposed to an FiO2 of
85%.31 On subsequent exposure to lethal doses (100%
FiO2), many survived prolonged exposures.31 However,
lower toxic doses (60% FiO2) did not increase antioxi-
dant defenses or prolong survival with subsequent ex-
posure to lethal concentrations.25,63 A threshold of FR
exposure is possibly needed to induce tolerance. Toler-
ance has not been shown to develop in dogs, mice, and
guinea pigs, apparently making this a species-specific
phenomenon.64

20th tant in helping to prevent

CO

S

1 9 7
9 - 1
9 9 9
ANNIVERSARY
A LookBack
The discovery of sequential
stages of oxygen-induced
damage has helped to fuel
dramatic advances in the field
of oxygen toxicity research over
the past 20 years. Delineation
of these stages has allowed
researchers to make comparisons
across species, evaluate the
efficacy of various therapeutic
interventions, and assess the
ability of lung tissue to recover
from oxygen-derived damage.
the toxic effects of O2, es-
pecially in ventilator-de-
pendent patients.52 Vitamin
or trace mineral deficien-
cies increase the suscepti-
bility of organs to FR
damage secondary to de-
pleted stores of SODs or
FR scavengers. Protein de-
ficiency potentiates toxici-
ty from hyperoxic expo-
sure because of a lack of
sulfur-containing amino
acids, which are necessary
for glutathione synthesis.
Because patients that re-
ceive high FiO2 are usually
on mechanical breathing
circuits, total or partial
parenteral nutrition must
be provided intravenously
or enteral nutrition through
a feeding tube.53
No therapy currently ex-
ists to prevent or treat changes
CONCLUSION
The need for supplemental O2 therapy should always
take precedence over concerns regarding toxic effects in
the acute management of veterinary patients. The low-
est FiO2 necessary to achieve adequate arterial oxygena-
tion should be used. Arterial blood gas and pulse
oximetry monitoring should be used to guide O2 ad-
ministration. If prolonged periods of high FiO2 are an-
ticipated, ventilatory adjuncts (e.g., CPAP or PEEP)
should be initiated, even though toxic changes to the
lungs sometimes occur. Once changes begin in the
lungs, higher O2 concentrations may be required to
achieve desired levels in the blood, creating a vicious
cycle of O2-induced lung injury.
Because O2 toxicity studies seldom use dogs and cats,
guidelines for safe administration have been extrapolat-
ed from studies on other species. Current recommenda-
tions for safe administration are up to 24 hours with
100% O2 and up to 48 hours with 60% O2. These rec-
ommendations are based on current data that suggest
hyperoxia-induced injury does not occur before these
time intervals.27,45,52,64
The recovery time for pets with clinical changes at-
tributed to O2 toxicity remains undefined. Once safe
levels (60% or less FiO2) are being administered, any

SOUND MEDICAL PRACTICE ■ NUTRITION ■ OXYGEN TOLERANCE

Small Animal/Exotics 20TH ANNIVERSARY
lung injury may take several weeks to partially re-
solve.45,65–67 Even when administering lower levels of O2,
some permanent pulmonary damage may remain. Be-
cause there is no therapy to prevent or reverse the toxic
pulmonary changes, avoidance is essential. Several
strategies and drugs that may eventually allow higher
concentrations of O2 to be delivered for longer periods
are being investigated.
REFERENCES
1. Ganong WF: Review of Medical Physiology. Norwalk, CT,
Appleton & Lange, 1995, pp 608–611, 627–635.
2. Marino PL: The ICU Book. Baltimore, Williams & Wilkins,
1998, pp 19–22, 32–50, 388–400.
3. West JB: Respiratory Physiology. Baltimore, Williams &
Wilkins, 1995, pp 51–88.
4. Bryan-Brown CW, Gutierrez G: Pulmonary gas exchange,
transport, and delivery, in Shoemaker WC, Ayers SM, Gren-
vik A, Holbrook PR (eds): Textbook of Critical Care. Phila-
delphia, WB Saunders Co, 1995, pp 776–784.
5. Jenkinson SG: Oxygen toxicity. New Horizons 1(4):504–511,
1993.
6. O’Connor BS, Vender JS: Oxygen therapy. Crit Care Clinics
11(1):67–78, 1995.
7. Drobatz KJ, Hackner S, Powell S: Oxygen supplementation,
in Bonagura JD (ed): Kirk’s Current Veterinary Therapy XII.
Philadelphia, WB Saunders Co, 1995, pp 175–179.
8. Shappel SD: Adaptive, genetic, and iatrogenic alterations of
the oxyhemoglobin dissociation curve. Anesthesiology 37:
178–206, 1972.
9. Harvey JW: Erythrocyte metabolism, in Kaneko JJ (ed):
Clinical Biochemistry of Domestic Animals. San Diego, Aca-
demic Press, 1989, pp 185–234.
10. Court MH: Respiratory support of the critically ill small ani-
mal patient, in Murtaugh RJ, Kaplan PM (eds): Veterinary
Emergency and Critical Care Medicine. St. Louis, Mosby Year
Book, 1992, pp 575–584.
11. Court MH, Dodman NH, Seeler DC: Inhalation therapy:
Oxygen administration, humidification, and aerosol therapy.
Vet Clin North Am Small Anim Pract 15(5):1041–1059,
1985.
12. Filuk RB, Anthonisen NR: Administering oxygen effectively
to critically ill patients. J Crit Illness 1(2):21–27, 1986.
13. Coalson JJ: Pathophysiologic features of infant and adult re-
spiratory distress syndromes, in Shoemaker WC, Ayers SM,
Grenvik A, Holbrook PR (eds): Textbook of Critical Care. Phil-
adelphia, WB Saunders Co, 1995, pp 797–805.
14. Fitzpatrick RK, Crowe DT: Nasal oxygen administration in
dogs and cats: Experimental and clinical investigations. JAAHA
22:293–300, 1986.
15. Mann FA, Wagner-Mann C, Allert JA, Smith J: Comparison
of intranasal and intratracheal oxygen administration in
healthy awake dogs. Am J Vet Res 53(5):856–860, 1992.
16. Elkins AD: Hyperbaric oxygen therapy: Potential veterinary
applications. Compend Contin Educ Pract Vet 19 (5):607–
612, 1997.
17. Fischer B, Jain KK, Braun E, Lehrl S: Handbook of Hyperbaric
Oxygen Therapy. Berlin, Springer-Verlag, 1988, pp 4–58.
18. Foster JH: Hyperbaric oxygen therapy: Contraindications
and complications. J Oral Maxillofac Surg 50:1081–1086,
1992.
Compendium April 1999
19. Hosgood G, Elkins AD, Hill RK: Hyperbaric oxygen thera-
py: Mechanism and potential applications. Compend Contin
Educ Pract Vet 12(11):1589–1594, 1990.
20. Schafer SE: Fundamentals of hyperbaric oxygen therapy.
Orthop Nurs 11(6):9–15, 1992.
21. Tibbles PM, Edelsberg JS: Hyperbaric–oxygen therapy. N
Engl J Med 334(25):1642–1648, 1996.
22. Hitt ME: Oxygen-derived free radicals: Pathophysiology and
implications. Compend Contin Educ Pract Vet 10(8):939–
946, 1988.
23. Jackson RM: Oxygen therapy and toxicity, in Shoemaker
WC, Ayers SM, Grenvik A, Holbrook PR (eds): Textbook of
Critical Care. Philadelphia, WB Saunders Co, 1995, pp 784–
789.
24. Rochat MC: An introduction to reperfusion injury. Com-
pend Contin Educ Pract Vet 13(6):35–41, 1991.
25. Klein J: Normobaric pulmonary oxygen toxicity. Anesth
Analg 70:195–207, 1990.
26. Rubanyl GM: Vascular effects of oxygen-derived free radi-
cals. Free Radic Biol Med 4:107–120, 1988.
27. Stogner SW, Payne DK: Oxygen toxicity. Ann Pharmacother
26:1554–1561, 1992.
28. Freeman BA, Crapo JD: Biology of disease. Free radicals and
tissue injury. Lab Invest 47:412–426, 1982.
29. Ward PA, Johnson KJ, Till GO: Animal models of oxidant
lung injury. Respiration 50:1, 5–12, 1986.
30. Fulmer JD, Snider GL: ACCP-NHLBI national conference
on oxygen therapy. Chest 86(2):240–241, 243–244, 1984.
31. Crapo JD, Barry BE, Foscue HA, Shelburne J: Structural
and biochemical changes in rat lungs occurring during expo-
sures to lethal and adaptive doses of oxygen. Am Rev Respir
Dis 122:123–143, 1980.
32. Crapo JD, Peters-Golden M, Marsh-Salin J, et al: Pathologic
changes in the lungs of oxygen adapted rats: A morphomet-
ric analysis. Lab Invest 39(6):640–653, 1978.
33. De las Santos R, Seidenfeld JJ, Anzueto A, et al: One hun-
dred percent oxygen lung injury in adult baboons. Am Rev
Respir Dis 136:657–661, 1987.
34. Kamponei Y, Tosco R, Eggerman J, et al: Oxygen pneu-
monitis in man. Chest 62:162–169, 1972.
35. Thet LA, Parra SC, Shelburne JD: Sequential changes in
lung morphology during the repair of acute oxygen-induced
lung injury in adult rats. Exp Lung Res 11:209–228, 1986.
36. Frank L, Bucher JR, Roberts RJ: Oxygen toxicity in neonatal
and adult animals of various species. J Appl Physiol 45(5):
699–704, 1978.
37. Jamieson D, Chance B, Cadenas E, Boveris A: The relation-
ship of free radical production to hyperoxia. Ann Rev Physiol
48:703–719, 1986.
38. Freeman BA, Toppolsky MK, Crapo JD: Hyperoxia increas-
es oxygen radical production in rat lung homogenates. Arch
Biochem Biophys 216:477–484, 1982.
39. Barry BE, Crapo JD: Pattern of accumulation of platelets
and neutrophils in rat lungs during exposure to 100% and
85% oxygen. Am Rev Respir Dis 132:548–555, 1985.
40. Comroe JH, Dripps RD, Dumke PR, Deming M: Oxygen
toxicity. The effect of inhalation of high concentrations of
oxygen for twenty-four hours on normal men at sea level
and at a simulated altitude of 18,000 feet. JAMA 128:710–
717, 1945.
41. Sackner M, Landa J, Hirsch J, et al: Pulmonary effects of oxy-
gen breathing. A six-hour study in normal men. Ann Intern
Med 82:40–43, 1975.
Compendium April 1999 20TH ANNIVERSARY
42. Wolfe WG, Eeret PA, Sabiston DC Jr: Effect of high oxygen
tension on mucociliary function. Surgery 72(2):246–252, 1972.
43. Lauenzi GA, Yin S, Guarneri JJ: Adverse effect of oxygen on
tracheal mucus flow. N Engl J Med 279(7):333–339,1968.
44. Van der Water JN, Kagey KS, Miller IT, et al: Response of
the lung to six to 12 hours of 100 percent oxygen inhalation
in normal man. N Engl J Med 283:621–626, 1970.
45. Jenkinson SG: Pulmonary oxygen toxicity. Clin Chest Med
3(1):109–119,1982.
46. Caldwell P, Lee W, Schildkraut H, et al: Changes in lung
volume, diffusing capacity, and blood gases in men breath-
ing oxygen. J Appl Physiol 21:1477–1483, 1966.
47. Hayatdavoudi G, O’Neil JJ, Barry BE, et al: Pulmonary in-
jury in rats following continuous exposure to 60% O2 for 7
days. J Appl Physiol 51:1220–1231, 1981.
48. Grim PS, Gottlieb LJ, Boddie A, et al: Hyperbaric oxygen
therapy. JAMA 263:2216–2220, 1990.
49. Rettenmaier PA, Whittaker B, Myers RAM: Acute oxygen
toxicity during hyperbaric oxygen therapy. Crit Care Med
14(4):394, 1986.
50. Hendricks JC: Respiratory conditions in critical patients.
Vet Clin North Am 19(6):1167–1188, 1989.
51. Brown LH: Pulmonary oxygen toxicity. Focus Crit Care 17(1):
68–75, 1990.
52. Jenkinson SG: Oxygen toxicity. J Intensive Care Med 3(3):
137–152, 1988.
53. Davenport DJ: Enteral and parenteral nutritional support in
Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Inter-
nal Medicine: Diseases of the Dog and Cat, ed 4. Philadelphia,
WB Saunders Co, 1995, pp 244–252.
54. Lindsey HJ, Kisala JM, Ayala A, et al: Pentoxifylline attenuates
oxygen-induced lung injury. J Surg Res 56:543–548, 1994.
55. Flink EB, Dedhia HV, Dinsmore J, et al: High-dose magne-
sium sulfate attenuates pulmonary oxygen toxicity. Crit Care
Med 20(12):1692–1698, 1992.
56. Patterson CE, Butler JA, Byrne FD, Rhodes ML: Oxidant
lung injury: Intervention with sulfhydryl reagents. Lung 163:
23–32, 1985.
57. Sarnstrand B, Tunek A, Sjodin K, Hallberg A: Effects of N-
acetylcysteine stereoisomers on oxygen-induced lung injury
in rats. Chem-Biol Interact 94:157–164, 1995.
Small Animal/Exotics
58. Padmanabhan R, Gudapaty R, Liener I, et al: Protection
against pulmonary oxygen toxicity in rats by the administra-
tion of liposome encapsulated superoxide dismutase or cata-
lase. Am Rev Respir Dis 132(1):164–167, 1985.
59. Turrens J, Crapo JD, Freeman BA: Protection against oxy-
gen toxicity by intravenous injection of liposome-encapsulat-
ed catalase and superoxide dismutase. J Clin Invest 73:87–
95, 1984.
60. Boyce NW, Campbell D, Holdsworth SR: Modulation of
normobaric pulmonary oxygen toxicity by hydroxyl radical
inhibition. Clin Invest Med 10:316–320, 1987.
61. Jensen JC, Pogrebniak HW, Pass HI, et al: Role of tumor
necrosis factor in oxygen toxicity. J Appl Physiol 72(5):
1902–1907, 1992.
62. Matalon S, Holme B, Notter R: Modification of pulmonary
hyperoxic injury by administration of exogenous surfactant.
J Appl Physiol 62(2):756–761, 1987.
63. Frank L: Endotoxin reverses the decreased tolerance of rats
to greater than 95% O2 after pre-exposure to lower O2. J
Appl Physiol 51:577–583, 1981.
64. Jenkinson SG: Oxygen toxicity. J Intensive Care Med 3:137–
152, 1988.
65. Davis WB, Rennard SI, Bitterman PB, Crystal RG: Pul-
monary oxygen toxicity: Early reversible changes in human
alveolar structures induced by hyperoxia. N Engl J Med
309(15):878–883, 1983.
66. Durr R, Dubayba B, Thet LA: Repair of chronic hyperoxic
lung injury: Changes in lung ultrastructure and matrix. Exp
Mol Pathol 47:219–240, 1987.
67. Jackson RM: Molecular, pharmacologic and clinical aspects of
oxygen-induced lung injury. Clin Chest Med 11(1):73–86, 1990.
About the Authors
Dr. Mensack is affiliated with the Department of Clinical
Science, Tufts University School of Veterinary Medicine,
North Grafton, Massachusetts. Dr. Murtaugh is Director of
Critical Care at the Dove Lewis Emergency Animal Hospi-
tal in Portland, Oregon, and is a Diplomate of the American
College of Veterinary Internal Medicine and of the Ameri-
can College of Veterinary Emergency and Critical Care.