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Vol. 21, No.

4 April 1999 V 20TH ANNIVERSARY

CE Refereed Peer Review

Oxygen Toxicity
FOCAL POINT Dove Lewis Emergency Animal Hospital
Tufts University Portland, Oregon
★Although prolonged exposure Steven Mensack, VMD Robert Murtaugh, DVM, MS
to high alveolar oxygen (O2 )
concentrations can lead to 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
pulmonary injury, O2 therapy
production of free radicals can overwhelm the endogenous antioxidant systems. Depending
should not be withheld from
on the atmospheric pressure by which O2 is delivered, clinical signs of toxicity may be exhibit-
hypoxemic patients. 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
KEY FACTS 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
■ Under normal conditions, O2 treatment methods are available, judiciously limiting exposure to high Fio2 is the key to pre-
supplementation has little benefit vention.
in increasing arterial O2 content if

S
the measured partial pressure is ince the discovery of oxygen (O2) in the late 18th century, scientists have
higher than 70 mm Hg or the postulated that although it is necessary for life, too much exposure can be
fraction of saturated hemoglobin detrimental. As human and veterinary critical care medicine have ad-
is greater than 93%. vanced, the use of supplemental O2 therapy has become more common. With
increased O2 use comes the need to recognize possible complications. This article
■ Prolonged use of high fractional addresses the biochemical and pathophysiologic effects of prolonged use of high
inspired O2 concentrations (FiO2) O2 concentrations. The primary focus is on the pulmonary effects of O2 deliv-
can lead to tracheobronchial ered at normal atmospheric pressure (normobaric toxicity), although the toxic
irritation, atelectasis, and neurologic effects of hyperbaric (high-pressure) oxygen (HBO) therapy is also
decreased ability to transport addressed. Finally, prevention and therapy for O2 toxicity and tolerance to high
O2 from the environment to the O2 concentrations are discussed.
alveoli and from the alveoli to
the blood. RATIONAL USE OF OXYGEN
The use of supplemental O2 therapy has gained widespread acceptance in vet-
■ Positive end-expiratory pressure erinary medicine. Indications for supplemental O2 include providing supportive
and continuous positive airway care for anesthetized patients; increasing the O2 content in blood during periods
pressure are two ventilatory of hypoxemia; and aiding in the healing of chronic complicated wounds, acute
modalities that can lessen the traumatic soft tissue injuries, and serious skin wound infections (HBO therapy).
need for high FiO2.
Oxygen Transport
■ Once changes begin in the lungs, To understand when supplemental therapy is necessary, it is important to un-
higher O2 concentrations may be derstand normal O2 transport. One of the primary purposes of both the respira-
required to achieve desired tory and circulatory systems is the transport of O2 from the outside environment
levels in the blood, creating a to tissues. In the lungs, O2 diffuses down its concentration gradient from the
vicious cycle of O2-induced lung alveolus into the blood. Once in the blood, O2 is transported to the tissues,
injury. 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 20TH ANNIVERSARY Compendium April 1999

can be measured by arterial blood gas analysis.


100
The ability of blood to carry O2 is profoundly affect-
90
ed by the ability of Hb to bind O2. The oxyhemoglo-
Oxygen Saturation of Hemoglobin (%)

80 bin dissociation curve (Figure 1) is sigmoid shaped and


70 represents the relationship between SaO2 and the partial
60
pressure of O2 (PO2).1,3,4,7 Under normal conditions, the
plateau of the curve occurs at a PO2 of approximately
50
70 mm Hg. An increase in the PO2 above this level
40
causes a minimal increase in the O2 saturation of Hb.
30 However, decreases in PO2 below 60 mm Hg have in-
20 creasingly negative effects on O2 saturation of Hb.5
10
The ability of Hb to bind O2 can be altered by sever-
al pathophysiologic variables: blood pH; body tempera-
0
0 10 20 30 40 50 60 70 80 90 100 ture; the partial pressure of carbon dioxide (P CO 2 )
Partial Pressure of Oxygen (Po2) (mm Hg) dissolved in plasma; and in dogs, changes in the con-
SaO2 (normal) centration of the RBC carbohydrate 2,3-diphospho-
SaO2 (left shift)
SaO2 (right shift) glycerate (2,3-DPG).5 A right shift of the curve indi-
cates that an increased PO2 is needed for Hb to bind a
Figure 1—The oxyhemoglobin dissociation curve. A left shift
specific amount of O2. Increased body temperature, de-
from normal is caused by decreased body temperature, in- creased blood pH, and increased P CO 2 all shift the
creased blood pH (alkalosis), decreased partial pressure of curve to the right.1,3,4,7,8 An increased 2,3-DPG also
carbon dioxide (PCO2) in blood, or decreased red blood cell shifts the curve to the right.1,3,4,7,8 Conditions that in-
(RBC) concentration of 2,3-diphosphoglycerate (2,3-DPG). crease the RBC concentration of 2,3-DPG include hy-
A right shift from normal is caused by increased body tem- perthyroidism, anemia, chronic exercise, and chronic
perature; decreased blood pH (acidosis), increased PCO2, and hypoxia.1 The PO2 at tissue level is lower than it is in ar-
increased RBC concentration of 2,3-DPG (O2 = oxygen; terial blood.5 Thus, a right shift favors the off-loading
SaO2 = fraction of saturated hemoglobin). 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
on the amount entering the lungs, efficiency of pul- tissues. Decreased body temperature, increased blood
monary gas exchange, blood flow to the tissue, and pH, decreased PCO2, and decreased RBC concentration
ability of blood to carry O2. of 2,3-DPG shift the curve to the left.1,3,4,7,8 Stored
Under standard conditions (barometric pressure RBCs contain decreased amounts of 2,3-DPG.3 This
[Patm], 760 mm Hg; fractional inspired oxygen concen- decreased level is not a problem in stored feline blood
tration [FiO2] in room air, 21%), each 100 ml of arteri- because the release of O2 is independent of 2,3-DPG.9
al blood carries approximately 19.5 ml of O2,1,2 which
can be calculated by the following equation: Indications for Supplemental Oxygen Therapy
The most common nonanesthetic use of supplemen-
O2 content = (1.34 × [Hb] × SaO2) + 0.003 PaO2 tal O2 is for treating or preventing hypoxemia. Hypox-
emia is a relative deficiency of O2 tension in arterial
where 1.34 = the amount (in ml) of O2 carried by 1 g blood (decreased PaO2 ) and becomes significant when
of hemoglobin (Hb), Hb = the concentration of he- the PaO2 is lower than 70 mm Hg.2,6 Hypoxia, another
moglobin in blood (normal, 15 mg/dl), SaO2 = the frac- common but not interchangeable condition, is a rela-
tion of saturated Hb (normal, 93% to 97%), and PaO2 tive deficiency of O2 in tissues and can be caused by
= the partial pressure of O2 dissolved in arterial plasma multiple factors, one of which is hypoxemia.1,10 Multi-
(normal, 85 to 105 mm Hg).1–6 As calculated by this ple known causes of hypoxemia include low FiO2, hypo-
equation, the majority of O2 carried by blood is bound ventilation, diffusion
• •
impairment, pulmonary ventila-
to Hb (19.2 ml) and very little is dissolved in plasma tion/perfusion (V/Q) inequity, intrapulmonary shunting
(0.3 ml).1–4 The SaO2 can be measured by cooximetry of blood, and certain toxins that may inhibit O2 uptake
or estimated by pulse oximetry, the Hb concentration in the lungs (see Causes of Hypoxemia). These causes are
attributable to red blood cells (RBCs) can be measured not mutually exclusive.
by a hemoglobinometer or estimated by multiplying Hypoventilation, which decreases O2 delivery from
the measured hematocrit by one third, and the PaO2 the environment to the lungs, can be caused by drugs

OXYHEMOGLOBIN DISSOCIATION CURVE ■ NONANESTHETIC OXYGEN SUPPLEMENTATION


Compendium April 1999 20TH ANNIVERSARY Small Animal/Exotics

• •
(e.g., narcotics and barbiturates that depress the respira- Intrapulmonary shunting, an extreme form of V/Q
tory centers of the brain),3,6,11,12 thoracic wall trauma,3,7 mismatching, occurs if blood in the pulmonary circula-
pleural space disease (e.g., pneumothorax, hemothorax, tion totally bypasses ventilated lung • •
tissue before re-
pleural effusion, diaphragmatic hernia with abdominal turning to systemic circulation (V/Q = infinity).1,3,11,12
content displaced into the pleural space),7,11 central ner- Conditions that cause intrapulmonary shunting of
vous system (CNS) trauma,12 upper airway obstruc- blood include lung lobe consolidation, arteriovenous
tion,7,11 and neuromuscular disease (e.g., polyradicu- fistulas, and right-to-left intracardiac shunts.11,12 O2
loneuritis, myasthenia gravis).3,7 therapy can be beneficial to some extent in correcting
Diffusion impairment develops when equilibration hypoxemia caused by any of these pathophysiologic
cannot occur between alveolar gas and pulmonary cap- processes except intrapulmonary shunting.1,3
illary blood because of a thickened alveolar wall or Supplemental O2 therapy may also have limited benefit
decreased contact time between blood and gas in the for severe anemia and acute hemorrhage.11 As indicated by
alveolus.7 Conditions such as pulmonary fibrosis and the equation presented earlier, approximately 97% of O2
pulmonary edema • •
can cause diffusion impairment.11 in blood is in the form of oxyhemoglobin, whereas the re-
Pulmonary V/Q inequity occurs when areas of the mainder is dissolved in plasma. With severe anemia or
lungs are receiving adequate fresh gas from the environ- acute hemorrhage, the amount of Hb is reduced and the
ment but• blood

flow is inadequate to effect gas ex- relative contribution of dissolved O2 to overall O2 content
change (V/Q higher than 1) or when areas of the lungs in blood is greater. For each increase of 100 mm Hg in
are not receiving fresh gas from the environment but PaO2, the overall increase of dissolved O2 in blood is very
are receiving
• •
a normal supply of fresh blood for gas ex- small (approximately 0.3 ml O2 per 100 ml blood).1 Ulti-
change
• •
(V/Q lower than 1).1,3 Conditions that lead to mately, therapy for severe anemia involves replacing Hb in
V/Q mismatching include atelectasis, alveolar pneumo- the form of RBCs and/or an O2-carrying plasma-phase
nia, pulmonary edema of any cause, and pulmonary Hb solution (Oxyglobin®; Biopure, Cambridge, MA). In
thromboembolism.7,11,12 the interim, supplemental O2 therapy may help stabilize a

Causes of Hypoxemia
• •
■ Hypoventilation (less oxygen delivered from the lower than 1] or excessive capillary blood low [V/Q
environment to the lungs) higher than 1])
— Drugs (narcotics and barbiturates) — Atelectasis
— Thoracic wall trauma (rib fractures) — Alveolar pneumonia
— Pleural space disease (pneumothorax, — Pulmonary edema
hemothorax, pleural effusion, diaphragmatic — Pulmonary thromboembolism
hernia) — Asthma
— Central nervous system trauma
■ Arteriovenous shunting (blood in pulmonary
— Upper airway obstruction (foreign body, laryngeal
circulation bypasses ventilated lung tissue before
paralysis, edema, neoplasia)
returning to systemic circulation)
— Neuromuscular disease (polyradiculoneuritis,
— Atelectasis and lung lobe consolidation
myasthenia gravis)
— Arteriovenous fistula
— Diffusion impairment (thickened alveolar septa
— Right-to-left intracardiac shunt
or decreased transit time of blood through
pulmonary capillaries prevents equilibration ■ Low fractional inspired oxygen concentration
of oxygen between alveolus and blood) — High altitude
— Pulmonary edema — Administration of nitrous oxide
— Pulmonary fibrosis
■ Toxins
• •
■ Ventilation/perfusion (V/Q) mismatching (excessive — Carbon monoxide
• •
blood flow to a region of underventilated lung [V/Q — Methemoglobin

HYPOVENTILATION ■ DIFFUSION IMPAIRMENT ■ INTRAPULMONARY SHUNTING


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 Small Animal/Exotics

Cellular O2 metabolism involves the addition of single E), ascorbic acid (vitamin C), niacin (vitamin B6), ri-
electrons to molecular O2, yielding sequential reactive O2 boflavin (vitamin B 2), vitamin A, and plasma pro-
intermediates.5,23,24 The addition of the first electron teins.2,22,25 These antioxidants, which act to stop FR
yields the superoxide anion (O2–), a very reactive prod- chain reactions by accepting electrons, are mainly
uct. The addition of a second electron (in the presence of found in extracellular fluid and plasma and are primari-
hydrogen atoms) yields hydrogen peroxide (H2O2 ), a less ly effective at stopping lipid peroxidation of cellular
reactive intermediate. The addition of a third electron membranes.24 When exposed to increased O2 concen-
yields the very highly reactive hydroxyl radical (OH–) trations, both intracellular and extracellular defense sys-
and a molecule of water; through the addition of the tems are overwhelmed by the increased production of
fourth electron, OH– is finally reduced to water. Within O2-derived FRs and increased cellular injury occurs.
the mitochondria, cytochrome oxidases that contain cop-
per or iron bind most of the molecules involved in the CELLULAR
reduction reactions, preventing the escape of reactive O2 OXYGEN INJURY
species generated during the reactions.2,22,23 Inside cells and tissues, O2-derived FRs disrupt numer-
Under normal cellular conditions, approximately 5% ous cellular processes.2,22,24,29 The targets of oxidative at-
of the O2 metabolized within the mitochondria is only tacks include lipids, proteins, and nucleic acids. Lipids
partially reduced, generating toxic free radicals (FRs)2,22 (e.g., pulmonary surfactant and those found in biologic
that leak into the cytosol and out from the cell, possibly membranes) react with these FRs to produce lipid perox-
through anion channels.2,22 O2-derived FRs in the cy- ides.5,22,24,25,29 These products lead to increased membrane
tosol or outside the cell undergo further reactions. Two permeability, inactivation of surfactant, and inhibition of
superoxide anions can spontaneously react to form normal cellular enzyme processes and can damage pro-
H2O2. In the presence of iron or copper, O2– may react teins and intracellular membranes.5,22,30 Proteins are also
with existing H2O2 to produce OH– and singlet oxygen subject to direct damage. Protein synthesis may be de-
(1O2), a reaction known as the Fenton reaction.2,24,25 creased through inhibition of ribosomal translation, or
These FRs (O2–, OH–, 1O2) are believed to cause much formed proteins may be destroyed through oxidative
of the cellular damage observed with O 2 toxicity. 25 processes.22,24,30 Consequently, inactivation of intracellu-
H2O2 is a less reactive toxic intermediate because it lar enzymes and transport proteins occurs, leading to im-
contains no unpaired electrons. Thus, it is not an O2- paired cellular metabolism and accumulation of cellular
derived FR in the truest sense. However, it is highly re- waste products.30 O2-derived FRs can cause breaks in
active and does have the capacity to cross biologic DNA and inhibit the enzyme systems involved in repair-
membranes, enabling the more damaging FRs to form ing or replicating DNA.22,24,30 All this damage culminates
at sites away from where the toxic intermediates are ini- in cellular death.
tially produced.26,27 Because FRs are products of normal
cellular metabolism, biochemical defense mechanisms PULMONARY OXYGEN TOXICITY
protect the organism from excessive FR damage. The lungs are the primary organ affected by high
FiO2 because they act as a barrier that prevents the re-
THE ANTIOXIDANT SYSTEMS mainder of the body from experiencing high O2 con-
Two types of defense mechanisms protect cells from centrations. The amount and type of damage that oc-
damage by O2-derived FRs: intracellular enzymatic sys- curs in the lungs depend on the FiO2 and the duration
tems and FR scavengers. The primary enzymatic defens- of exposure to high O2 concentrations. Based on cur-
es consist of superoxide dismutase (SOD), catalase, and rent data, the sequence of morphologic changes that
glutathione peroxidase (GPO).2,13,22–24 These enzymes occur in the lungs in response to toxic O2 concentra-
eliminate O2– and H2O2 and prevent FR chain reactions tions is apparently conserved across species.31–35 Howev-
by decreasing the available levels of FRs that initiate the er, the severity and time to onset of pulmonary changes
process.2,24,25 SODs act on the superoxide anion to pro- show both species and individual variation.36 These
duce H2O2.22,28 This system is found in both the mito- data need to be interpreted cautiously because most of
chondria and cytosol of cells. Catalase acts on H2O2 to the research has been conducted in laboratories on rats,
form water and an O2 molecule without the creation of primates, and healthy humans and on neonatal or ter-
OH–.22,23 The GPO system also acts on H2O2 to directly minal human patients in clinical settings.
form water and molecular O2.22,23 Unlike catalase, GPO Morphologic changes in lungs exposed to hyperoxic
can recycle itself through an energy-dependent mecha- conditions follow a sequence of phases: initiation, inflam-
nism that involves glutathione reductase.22 mation, destruction, proliferation, and fibrosis (see Phases
Free-radical scavengers include α-tocopherol (vitamin of Pulmonary Oxygen Toxicity). During initiation, the

CELLULAR METABOLISM ■ TOXIC FREE RADICALS ■ ANTIOXIDANTS


Small Animal/Exotics 20TH ANNIVERSARY Compendium April 1999

Phases of Pulmonary Oxygen Toxicity

■ Initiation ■ Proliferation
— Increased production of toxic oxygen (O2) — Evident after prolonged exposure to less than
metabolites 100% O2 concentrations (60% to 85% fractional
— Depleted antioxidant stores inspired oxygen concentration)
— No evidence of lung injury — Increased monocytes
— Increased type II alveolar epithelial cells
■ Inflammation
(surfactant secreting)
— Destruction of pulmonary endothelial lining
— Increased inflammatory mediators to the site of ■ Fibrosis
injury — Permanent lung damage
— Development of pulmonary edema — Collagen deposition in lung interstitium
— Increase in the thickness of pulmonary interstitial
■ Destruction
space
— Release of soluble inflammatory mediators
— Increase in interstitial fibrosis
— 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- and interstitial fibrosis all increase (fibrosis phase).13,31,35
siderably37 because of increased O2 metabolism in the These changes occur in rodents and nonhuman pri-
cells,38 which depletes cellular storage of enzymes, vita- mates after 48 to 96 hours of 100% O2 exposure.23 Be-
mins, and other substances involved in combating FR-de- cause these changes are very similar to those described
rived injury. However, there is no morphologic evidence for patients with acute respiratory distress syndrome and
of pulmonary injury.25 During this time, the flow of tra- because of the uniform use of supplemental O2 during
cheal mucus decreases, which may impair the clearance of respiratory failure, the histopathologic diagnosis of
debris from the lower airway and predispose the patient purely O2-induced pulmonary injury is very difficult.
to respiratory infection. The length of the initiation phase Clinically, O2 toxicity may be more difficult to define
varies inversely with the concentration of O2 delivered; in in veterinary patients because pulmonary function tests
rats, the time course is 24 hours at an FiO2 of 100%, 72 are difficult to perform. In healthy human volunteers ex-
hours at 85% FiO2, and up to 7 days at 60% FiO2.31,32 posed to 100% O2, clinical signs of substernal soreness,
The remaining phases follow in sequential order until cough, sore throat, nasal congestion, and painful inspira-
the patient either dies from respiratory compromise or tion developed within 12 to 14 hours.5,23,38,40,41 Mucocil-
the hyperoxic conditions are resolved. Morphologic iary clearance was shown to decrease in humans after 3
changes in the lungs represent a continuum. The first to 6 hours of 100% O2 exposure23,30,41 and in healthy
change is accumulation of plasma in the pericapillary dogs42 and cats43 after 72 hours, which can lead to an in-
spaces secondary to damage of the endothelial lining.31,33 creased risk for pneumonia (a common complication in
Accumulation of platelets and then of neutrophils in the mechanically ventilated patients). During the initial 6- to
pulmonary vasculature and interstitium follows (inflam- 12-hour period in healthy humans, no changes in vital
mation phase).13,30,31,33,39 These cells, along with pul- capacity (total amount of gas exhaled after a full inspira-
monary macrophages and damaged capillary endothelial tion), alveolar–arterial O2 gradient, pulmonary artery
cells, release soluble mediators of inflammation, thereby pressure, or total lung water were noted.25,44
amplifying the destruction of endothelial cells (destruc- The first clinically measured change in human volun-
tion phase).13,30,31,33,39 If a patient survives the destruction teers was decreased vital capacity, which occurred with-
phase, the remaining capillary endothelial cells hyper- in 24 hours after beginning to breathe 100% O2.23,30,40
trophy and other cell lines proliferate. The number of This decrease became progressively more severe after 60
monocytes and type II (surfactant-secreting) alveolar ep- hours of exposure.5,23 In normal baboons, this decrease
ithelial cells increases (proliferation phase; (Figure became evident after breathing 100% O2 for 48 hours,
3).13,30,31,33,39 Finally, collagen deposition in the lung in- and total lung capacity was less than 50% of normal by
terstitium, thickness of the alveolar interstitial space, day 6.33,45 After healthy human subjects breathed 100%

OXIDATIVE ATTACKS ■ SEQUENCE OF TOXIC PHASES


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

20th tant in helping to prevent


 CO

S

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

SOUND MEDICAL PRACTICE ■ NUTRITION ■ OXYGEN TOLERANCE


Small Animal/Exotics 20TH ANNIVERSARY Compendium April 1999

lung injury may take several weeks to partially re- 19. Hosgood G, Elkins AD, Hill RK: Hyperbaric oxygen thera-
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Science, Tufts University School of Veterinary Medicine,
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