Oxygen Toxicity

Oxygen
Oxygen, water, and food are of fundamental importance to the animal organism. Of these three basic essentials for the maintenance of life, the deprivation of oxygen leads to death most rapidly.
Therapy with oxygen is useful or necessary for life . Oxygen therapy has been used in the care of critically ill patients since the early years of this century.

Normal Oxygenation

Oxygen moves down a stepwise series of partial pressure gradients from the inspired air to the body's cells and their mitochondria. Air normally contains 20.9% oxygen.

Oxygen in blood is carried primarily in chemical combination with hemoglobin and to a small extent in physical solution in plasma. When fully saturated, each gram of hemoglobin binds about 1.3 ml of oxygen. Hemoglobin is about 98% saturated when air is breathed under normal circumstances

Therapeutic Uses

Correction of Hypoxia Oxygen as a Diluent Hyperbaric Oxygen Therapy The primary use for inhalation of oxygen is to reverse the effects of hypoxia; other consequences usually are minor. However, when oxygen is breathed in excessive amounts, toxic effects can occur

Respiration

Inhalation of higher than normal percentage of oxygen at 1 atmosphere or above causes a small degree of respiratory depression in normal subjects, presumably as a result of loss of tonic chemoreceptor activity. Within a few minutes, ventilation increases because of a paradoxical increase in the tension of carbon dioxide in tissues.

Oxygen toxicity is not a major factor in hyperventilating, as some people believe. The problems caused by hyperventilating are due to decreased carbon dioxide within the blood. With or without hyperventilating, it is impossible to develop oxygen toxicity breathing air at typical surface atmospheric pressure.

Carbon dioxide is carried by blood in the form of bicarbonate. This mechanism of carbon dioxide transfer operates more readily when a hydrogen ion acceptor, such as deoxyhemoglobin (a stronger base than oxyhemoglobin), is available. Oxygen at a high PO2, (e.g., during hyperbaric oxygenation), the amount of physically dissolved oxygen may be sufficient to satisfy the requirements of tissue. little or no oxygen is extracted from oxyhemoglobin, and deoxyhemoglobin is not formed. Carbon dioxide is then buffered less efficiently, and the PCO2 of the tissues rises by several mm Hg.

Oxygen Toxicity

The rate at which oxygen toxicity develops is directly related to the partial pressure of inspired oxygen. No toxicity is ordinarily detectable when the concentration of inspired oxygen is less than 50 percent. However, most data regarding the tolerable limits of oxygen breathing have been obtained from normal, healthy young subjects-not patients with cardiopulmonary diseases. Thus, the effects of underlying disease on the development of oxygen toxicity are largely unknown.

Oxygen Toxicity

Oxygen toxicity probably results from an increased production of reactive species such as superoxide anion, singlet oxygen, hydroxyl radical, and hydrogen peroxide. The oxidative damage initiated by these substances is propagated by lipid peroxidation and ultimately involves all components of the cell. Cell injury and death are presumed to result from loss of membrane integrity.

What are free radicals??

Free radicals are a chemical molecular species which are extremely reactive by virtue of having unpaired electrons. A free radical has an odd number of electrons and a single unpaired electron in an outer orbit of the nucleus. It is the unpaired electron which is responsible for the instability and reactivity characteristic of free radicals.

Oxygen Free Radicals

While oxygen is essential for our survival, the relatively high reactivity of oxygen enables it to form free radicals readily. It is the unique architecture of the oxygen molecule that accounts for much of its behaviour in free radical reactions which renders it particularly susceptible to one electron reductions which produce potentially toxic highly reactive derivatives, the so-called activated oxygen species.

A number of highly reactive free radicals are generated from oxygen in living systems as an unavoidable consequence of aerobic respiration.
- O2.- (superoxide), HO. (hydroxil radical) 1 O (singlet oxygen) H2O2 (hydrogen peroxide). All these are partially reduced species of oxygen that are all toxic.

Spreading the damage

Simply by losing or gaining an electron, any non radical compound can be converted to a free radical form and thereby undergo dramatic changes in its physical and chemical properties. Once initiated, free radicals tend to propagate by taking part with other, usually less reactive species. These chain reaction compounds, generally have longer half lives and therefore extended potential for cell damage. Thus the toxicity of a single radical species may be amplified with subsequent reactions.

Antioxidant Defense System

Intracellular enzymes exist which eliminate the most toxic products. The prototypes of these antioxidant enzymes are the metalloproteins termed

superoxide dismutases (SOD), which neutralize superoxide by conversion

to hydrogen peroxide. Catalase and glutathione peroxidase are capable of subsequently degrading potentially toxic intracellular hydrogen peroxide to

water. Glutathione peroxidase is also capable of eliminating products of lipid

peroxidation. Two related cytoplasmic enzymes, glutathione reductase and glucose 6-phosphate dehydrogenase, participate in antioxidant defense by regenerating reduced glutathione (GSH) and reduced adenine nucleotides. These are referred to collectively as antioxidant enzymes; together they act as a defensive system, effectively protecting the lung from oxidant injury.

Nonenzymatic antioxidants including a-tocopherol, ascorbate, cysteine,

ceruloplasm and others are normally present in cells and extracellular fluid.

In hyperoxia, cellular production of superoxide and subsequent reaction products exceeds the capacity of the antioxidant enzymes to detoxify them, so highly reactive chemical species are generated within cells. Oxygen free radicals can inactivate enzymes, perturb membrane functions, and damage genetic material. The overall result is death and lysis of oxygensensitive cells, resulting in the microvascular and alveolar cell injury typical of oxygen toxicity. The increased endogenous production of oxygen free radicals accounts for the cell injury observed in hyperoxia.

Glutathione

Glutathione peroxidase

Gly + R-O-O-H

Gly

Gly

Cys

SH + NADPH

Cys

Cys

+ H2O

Glu

Glu

Glu

Glutathione reductase

Reduced form of glutathione (monomer)

Oxidized form of glutathione (dimer, disulphide)

Respiratory Tract

Pulmonary system first to exhibit toxicity; Symptoms of pulmonary oxygen poisoning begin slowly as a substernal irritation that becomes progressively more intense and widespread along with with increased coughing. Uncontrollable coughing occurs in severe cases, symptoms originating in the trachea and major bronchi associated with a constant burning sensation, which is worsened by inspiration.

Pulmonary function changes to hyperoxic O2 exposures include: 1. decreases in inspiratory and expiratory lung volumes 2. decreases in flow rates 3. decreases in carbon monoxide diffusing capacity 4. decrease in lung compliance.

Effects on CNS

Central Nervous System. CNS oxygen toxicity does not occur when the partial pressure of inspired oxygen is less than 2 atmospheres; its occurrence is thus limited to a small number of hyperbaric applications. CNS toxicity is observed before pulmonary toxicity when oxygen is administered at partial pressures above 2.5 atmospheres characterized by convulsions, which may be preceded by visual symptoms or muscular twitching

The effect on the central nervous system : muscle twitching and spasm nausea and vomiting dizziness vision (tunnel vision) and hearing difficulties (tinnitus) twitching of facial muscles irritability, confusion trouble breathing, anxiety unusual fatigue incoordination convulsion.

Effects on Eye
At increased atmospheric pressures, vision may be affected. Symptoms may include photophobia, amblyopia, mydriasis, bilateral progressive constriction of visual acuity was found after breathing pure oxygen for four and one-half hours at normal atmospheric pressures.

DEVELOPMENT OF O2 TOLERANCE

No effective pharmacologic means exist for lessening oxygen-induced lung damage in humans. However, in rats, agents which increase lung antioxidant enzyme activities diminish lung damage and prolong survival in hyperoxia. Animal models of increased oxygen tolerance have been developed, but no sufficiently nontoxic pharmacologic agent is currently available for modifying oxygen toxicity in humans.