Oxygen Toxicity

Vol. 21, No. 4April 199920TH ANNIVERSARY

Refereed Peer Review

FOCAL POINTKEY FACTS

5

Although prolonged exposureto high alveolar oxygen (O

2

)concentrations can lead topulmonary injury, O

2

therapyshould not be withheld fromhypoxemic patients.

Oxygen Toxicity

Dove Lewis Emergency Animal HospitalTufts UniversityPortland, Oregon

Steven Mensack, VMDRobert Murtaugh, DVM, MS

ABSTRACT:

Molecular oxygen (O

2

) manifests its toxic effects through the production of freeradicals. If an animal breathes a high fractional inspired O

2

concentration (Fi

O

2

), the increasedproduction of free radicals can overwhelm the endogenous antioxidant systems. Dependingon the atmospheric pressure by which O

2

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 ofbreathing, decreased tidal volume, and increased arteriovenous shunting are manifestations ofO

2

toxicity. Although there is no therapy, several methods are being investigated to amelioratethe pathologic changes associated with prolonged exposure to toxic O

2

concentrations. Untiltreatment methods are available, judiciously limiting exposure to high Fio

2

is the key to pre-vention.

S

ince the discovery of oxygen (O

2

) in the late 18th century, scientists havepostulated that although it is necessary for life, too much exposure can bedetrimental. As human and veterinary critical care medicine have ad-vanced, the use of supplemental O

2

therapy has become more common. Withincreased O

2

use comes the need to recognize possible complications. This articleaddresses the biochemical and pathophysiologic effects of prolonged use of highO

2

concentrations. The primary focus is on the pulmonary effects of O

2

deliv-ered at normal atmospheric pressure (normobaric toxicity), although the toxicneurologic effects of hyperbaric (high-pressure) oxygen (HBO) therapy is alsoaddressed. Finally, prevention and therapy for O

2

toxicity and tolerance to highO

2

concentrations are discussed.

RATIONAL USE OF OXYGEN

The use of supplemental O

2

therapy has gained widespread acceptance in vet-erinary medicine. Indications for supplemental O

2

include providing supportivecare for anesthetized patients; increasing the O

2

content in blood during periodsof hypoxemia; and aiding in the healing of chronic complicated wounds, acutetraumatic 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 O

2

transport. One of the primary purposes of both the respira-tory and circulatory systems is the transport of O

2

from the outside environmentto tissues. In the lungs, O

2

diffuses down its concentration gradient from thealveolus into the blood. Once in the blood, O

2

is transported to the tissues, where it again diffuses down its concentration gradient to be used for normalcellular metabolism. The amount of O

2

delivered to a particular tissue depends

CE

V

s

Under normal conditions, O

2

supplementation has little benefitin increasing arterial O

2

content ifthe measured partial pressure ishigher than 70 mm Hg or thefraction of saturated hemoglobinis greater than 93%.

s

Prolonged use of high fractionalinspired O

2

concentrations (Fi

O

2

)can lead to tracheobronchialirritation, atelectasis, anddecreased ability to transportO

2

from the environment to thealveoli and from the alveoli tothe blood.

s

Positive end-expiratory pressureand continuous positive airwaypressure are two ventilatorymodalities that can lessen theneed for high Fi

O

2

.

s

Once changes begin in the lungs,higher O

2

concentrations may berequired to achieve desiredlevels in the blood, creating avicious cycle of O

2

-induced lunginjury.

on the amount entering the lungs, efficiency of pul-monary gas exchange, blood flow to the tissue, andability of blood to carry O

2

.Under standard conditions (barometric pressure[P

atm

], 760 mm Hg; fractional inspired oxygen concen-tration [Fi

O

2

] in room air, 21%), each 100 ml of arteri-al blood carries approximately 19.5 ml of O

2

,

1,2

whichcan be calculated by the following equation:O

2

content = (1.34

×

[Hb]

×

Sa

O

2

) + 0.003 Pa

O

2

where

1.34

= the amount (in ml) of O

2

carried by 1 gof hemoglobin (Hb),

Hb

= the concentration of he-moglobin in blood (normal, 15 mg/dl),

Sa

O

2

= the frac-tion of saturated Hb (normal, 93% to 97%), and

Pa

O

2

= the partial pressure of O

2

dissolved in arterial plasma(normal, 85 to 105 mm Hg).

1–6

As calculated by thisequation, the majority of O

2

carried by blood is boundto Hb (19.2 ml) and very little is dissolved in plasma(0.3 ml).

1–4

The Sa

O

2

can be measured by cooximetry or estimated by pulse oximetry, the Hb concentrationattributable to red blood cells (RBCs) can be measuredby a hemoglobinometer or estimated by multiplyingthe measured hematocrit by one third, and the Pa

O

2

can be measured by arterial blood gas analysis.The ability of blood to carry O

2

is profoundly affect-ed by the ability of Hb to bind O

2

. The oxyhemoglo-bin dissociation curve (Figure 1) is sigmoid shaped andrepresents the relationship between Sa

O

2

and the partialpressure of O

2

(P

O

2

).

1,3,4,7

Under normal conditions, theplateau of the curve occurs at a P

O

2

of approximately 70 mm Hg. An increase in the P

O

2

above this levelcauses a minimal increase in the O

2

saturation of Hb.However, decreases in P

O

2

below 60 mm Hg have in-creasingly negative effects on O

2

saturation of Hb.

5

The ability of Hb to bind O

2

can be altered by sever-al pathophysiologic variables: blood pH; body tempera-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 P

O

2

is needed for Hb to bind aspecific amount of O

2

. Increased body temperature, de-creased blood pH, and increased P

CO

2

all shift thecurve to the right.

1,3,4,7,8

An increased 2,3-DPG alsoshifts 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 chronichypoxia.

1

The P

O

2

at tissue level is lower than it is in ar-terial blood.

5

Thus, a right shift favors the off-loadingof O

2

from the Hb molecule.

5

A left shift of the curve represents increased affinity of the Hb molecule for O

2

and decreased O

2

delivery totissues. Decreased body temperature, increased bloodpH, decreased P

CO

2

, and decreased RBC concentrationof 2,3-DPG shift the curve to the left.

1,3,4,7,8

StoredRBCs contain decreased amounts of 2,3-DPG.

3

Thisdecreased level is not a problem in stored feline bloodbecause the release of O

2

is independent of 2,3-DPG.

9

Indications for Supplemental Oxygen Therapy

The most common nonanesthetic use of supplemen-tal O

2

is for treating or preventing hypoxemia. Hypox-emia is a relative deficiency of O

2

tension in arterialblood (decreased Pa

O

2

) and becomes significant whenthe Pa

O

2

is lower than 70 mm Hg.

2,6

Hypoxia, anothercommon but not interchangeable condition, is a rela-tive deficiency of O

2

in tissues and can be caused by multiple factors, one of which is hypoxemia.

1,10

Multi-ple known causes of hypoxemia include low Fi

O

2

,hypo-ventilation,diffusion impairment, pulmonary ventila-tion/perfusion (V

•

/Q

•

) inequity, intrapulmonary shuntingof blood, and certain toxins that may inhibit O

2

uptakein the lungs (see Causes of Hypoxemia). These causes arenot mutually exclusive.Hypoventilation, which decreases O

2

delivery fromthe environment to the lungs, can be caused by drugs

Small Animal/Exotics20TH ANNIVERSARY

Compendium

April 1999

OXYHEMOGLOBIN DISSOCIATION CURVE

s

NONANESTHETIC OXYGEN SUPPLEMENTATION

10090807060504030201000102030405060708090100

O x y g e n S a t u r a t i o n o f H e m o g l o b i n ( % )

Partial Pressure of Oxygen (Po

2

) (mm Hg)

Sa

O

2

(normal)Sa

O

2

(left shift)Sa

O

2

(right shift)

Figure 1—

The oxyhemoglobin dissociation curve. A left shiftfrom normal is caused by decreased body temperature, in-creased blood pH (alkalosis), decreased partial pressure of carbon dioxide (P

CO

2

) 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 P

CO

2

, andincreased RBC concentration of 2,3-DPG (

O

2

= oxygen;

Sa

O

2

= fraction of saturated hemoglobin).

(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 abdominalcontent 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 equilibrationcannot occur between alveolar gas and pulmonary cap-illary blood because of a thickened alveolar wall ordecreased contact time between blood and gas in thealveolus.

7

Conditions such as pulmonary fibrosis andpulmonary edema can cause diffusion impairment.

11

Pulmonary V

•

/Q

•

inequity occurs when areas of thelungs 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 lungsare not receiving fresh gas from the environment butare receiving a normal supply of fresh blood for gas ex-change (V

•

/Q

•

lower than 1).

1,3

Conditions that lead toV

•

/Q

•

mismatching include atelectasis, alveolar pneumo-nia, pulmonary edema of any cause, and pulmonary thromboembolism.

7,11,12

Compendium

April 199920TH ANNIVERSARYSmall Animal/Exotics

HYPOVENTILATION

s

DIFFUSION IMPAIRMENT

s

INTRAPULMONARY SHUNTING

s

Hypoventilation

(less oxygen delivered from theenvironment to the lungs)— Drugs (narcotics and barbiturates)— Thoracic wall trauma (rib fractures)— Pleural space disease (pneumothorax,hemothorax, pleural effusion, diaphragmatichernia)— Central nervous system trauma— Upper airway obstruction (foreign body, laryngealparalysis, edema, neoplasia)— Neuromuscular disease (polyradiculoneuritis,myasthenia gravis)— Diffusion impairment (thickened alveolar septaor decreased transit time of blood throughpulmonary capillaries prevents equilibrationof oxygen between alveolus and blood)— Pulmonary edema— Pulmonary fibrosis

s

Ventilation/perfusion (V

•

/Q

•

) mismatching

(excessiveblood flow to a region of underventilated lung [V

•

/Q

•

lower than 1] or excessive capillary blood low [V

•

/Q

•

higher than 1])

—

Atelectasis

—

Alveolar pneumonia

—

Pulmonary edema

—

Pulmonary thromboembolism

—

Asthma

s

Arteriovenous shunting

(blood in pulmonarycirculation bypasses ventilated lung tissue beforereturning to systemic circulation)

—

Atelectasis and lung lobe consolidation

—

Arteriovenous fistula

—

Right-to-left intracardiac shunt

s

Low fractional inspired oxygenconcentration

—

High altitude

—

Administration of nitrous oxide

s

Toxins

—

Carbon monoxide

—

Methemoglobin

Causes of Hypoxemia

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, arteriovenousfistulas, and right-to-left intracardiac shunts.

11,12

O

2

therapy can be beneficial to some extent in correctinghypoxemia caused by any of these pathophysiologicprocesses except intrapulmonary shunting.

1,3

Supplemental O

2

therapy may also have limited benefitfor severe anemia and acute hemorrhage.

11

As indicated by the equation presented earlier, approximately 97% of O

2

in blood is in the form of oxyhemoglobin, whereas the re-mainder is dissolved in plasma. With severe anemia oracute hemorrhage, the amount of Hb is reduced and therelative contribution of dissolved O

2

to overall O

2

contentin blood is greater. For each increase of 100 mm Hg inPa

O

2

,the overall increase of dissolved O

2

in blood is very small (approximately 0.3 ml O

2

per 100 ml blood).

1