Oxygen Toxicity

<<Compend Contin Educ Pract Vet 21[4]:341-351 Apr'99 Review Article 67 Refs

* Steven Mensack, VMD & Robert Murtaugh, DVM, MS
* Dept. of Clinical Science, Tufts University School of Veterinary Medicine, North Grafton, MA

- 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 exhibited 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 prevention. (Author Abstract)

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VIN SUMMARY

This article discusses the biochemical and pathophysiologic effects of prolonged high concentration oxygen therapy.  The effects of normobaric & hyperbaric toxicities, the prevention & treatment of oxygen toxicities, and tolerance of high oxygen concentrations are discussed.  For specific intracellular and chemical reactions, please see the full text.

Rational Use of Oxygen

Indications for supplemental oxygen (O₂) use include: 

·         Providing supportive care for anesthetized patients.

·         Increasing the O₂ content in blood during periods of hypoxemia.

·         Aiding in the healing of chronic complicated wounds, acute traumatic soft tissue injuries, and serious skin wound infections (hyperbaric [HBO] therapy).

Oxygen Transport: Normal

1.       Primary purpose of both circulatory and respiratory systems is to transport O₂ from the environment to the body’s tissues.

·         Lungs: O₂ diffuses from the alveolus to the blood via a concentration gradient.

·         Circulation: O₂ circulates via the blood to the tissues.

·         Tissues: O₂ diffuses down a concentration gradient to be used in cellular metabolism.

2.       Amount of O₂ going to the tissues dependent on: amount of oxygen entering the lungs, efficiency of the pulmonary gas exchange, blood flow to the tissue, and the ability of blood to carry O₂.

·         Normal amount of O₂ carried in the blood:  major amount carried by hemoglobin, very small amount in plasma.

·         Pulse oximetry estimates the O₂ saturation of the hemoglobin. (Normal is 93 – 97%.)

·         Hemoglobin concentration attributed to RBCs can be measured by hemoglobinometer or estimated as 1/3 the measured hematocrit. (Normal is 15 mg/dl.)

·         Arterial blood gas analysis can measure the partial pressure of the O2 dissolved in arterial plasma. (Normal is 85 – 105 mm Hg.)

·         Under normal conditions, the plateau of the oxyhemoglobin dissociation curve occurs at a normal partial pressure of O₂ (PO₂) of 70 mm Hg.

·         An increase in the PO₂ (partial pressure of O₂) above this level causes a minimal increase in the O2 saturation of hemoglobin.

·         A decrease in the PO₂ below 60 mm Hg have increasingly negative effects on the O₂ saturation of Hb.

·         The ability of hemoglobin to bind O₂ directly affects the ability of the blood to carry O₂ to the tissues.

·         Affected by: blood pH; body temperature; partial pressure of carbon dioxide (PCO₂) dissolved in plasma; and (in dogs) the change of the RBC carbohydrate 2,3-diphosphoglycerate (2,3-DPG)

·         Increased body temp, increased PCO₂, decreased blood pH, and increased 2,3-DPG favor the off-loading of O₂ from the Hb molecule. This means an increased PO₂ is required for hemoglobin to bind a specific amount of O₂.

·         Decreased body temp, decreased PCO₂, increased blood pH, and decreased 2,3-DPG favor an increased affinity for O₂ to bind to hemoglobin. This results in a decreased O₂ delivery to the tissues.

Indications for Supplemental Oxygen Therapy

1.       Treatment for prevention of hypoxemia.

·         Hypoxemia is the relative deficiency of O₂ tension in arterial blood; this is more significant as the partial pressure of O₂ goes below 70 mm Hg.

Causes of Hypoxemia (these are not mutually exclusive)
Hypoventilation (decreased O2 delivery from the environment to the lungs)	Drugs (narcotics, barbiturates)
	Thoracic wall trauma
	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 mismatching (blood flow is inadequate at the alveolar level to allow gas exchange even though adequate fresh gas is being delivered or blood flow/gas exchange is adequate but fresh gas is not).	Atelectasis
	Alveolar pneumonia
	Pulmonary edema
	Pulmonary thromboembolism
	Asthma
Arteriovenous shunting (extreme form of pulmonary ventilation/perfusion mismatching that happens when pulmonary blood bypasses ventilated lung tissue before returning to circulation.	Atelectasis and lung lobe consolidation (O2 may help correct)
	Arteriovenous fistula (O2 may help correct)
	Right-to-left intracardiac shunt
Low fractional inspired oxygen concentration	High altitude
	Administration of nitrous oxide
Toxins	Carbon monoxide
	Methemoglobin

·         Hypoxia is a relative deficiency of O₂ in the tissues, and can be caused by many factors (including hypoxemia).

2.       Severe anemia and acute hemorrhage, where the amount of hemoglobin is reduced and the relative contribution of dissolved O₂ to overall O₂ content in blood is greater, followed by therapy.

·         Therapy for severe anemia requires replacement of hemoglobin (RBCs and/or O₂ carrying plasma-phase hemoglobin solution such as OxyglobinÒ)

·         Supplemental oxygen may not be beneficial for the above cases, if the patient also has low cardiac output, hypotension, hyperthermia, or problems with cellular O₂ uptake. Correction of the underlying circulatory problem via intravascular volume expansion, positive inotropes, or pressor agents is necessary.

Oxygen Delivery

·         Based on fractional inspired O₂ (FiO₂) required, the patient’s condition, and equipment available.

·         Endotracheal intubation (or tracheostomy tube) connected to an oxygen source can achieve 100% FiO₂.

·         O₂ delivery via mask, or Elizabethan collar fronted with plastic wrap, can achieve 60% FiO₂; a well fitting mask and reservoir bag can reach nearly 100% FiO₂.

·         Nasal cannulation efficacy depends upon O₂ flow rate, patient tolerance, and number of cannulas (1 or 2) used, but can achieve up to 90% FiO₂.

·         Intratracheal catheterization uses lower flow rates than nasal cannulation, and can achieve up to 80 – 90% FiO₂.

·         Commercial oxygen cages usually do not exceed 50% FiO₂.

Hyperbaric Oxygen

Patients are placed in an oxygenation chamber and the chamber is filled with 100% O₂ at pressures greater than 1 atm at sea level  (760 mm Hg).  Commonly, O₂ is given at 2.0 – 2.4 atm (1520 – 1800 mm Hg) for 40 – 60 minutes SID – BID.

·         Aids in healing chronic complicated wounds, acute traumatic soft tissue injuries, and serious skin wound infections. 

·         Sufficient O₂ carried by the blood may not reach these areas of reduced blood circulation.

·         Hyperbaric oxygen increases the amount of plasma O₂ (which diffuses into the tissues more easily).

·         Increased O₂ supply to damaged tissue leads to increased antimicrobial effects, induction and propagation of angiogenesis, vasoconstriction without tissue O₂ loss (preventing edema), and fewer tissue bubbles.

·         May be helpful in treating certain toxicoses (cyanide or carbon monoxide poisoning).

Oxygen Metabolism and Production of Toxic Oxygen Metabolites

Normal cellular metabolism involves the addition of 4 single electrons to the O₂ molecule. During normal partial pressure (100 mg Hg), 95% of the molecules will be reduced to H₂0 and 5% will be partially reduced (toxic metabolites).

·         Toxic metabolites have a high affinity for the electrons in nearby molecules; this can lead to oxidative damage to the molecules.

·         Toxic metabolites are called “free radicals” (FRs).

·         FRs leak into the cytosol, and out from the cell. FRs cause much of the cellular damage seen in O₂ toxicity.

The Antioxidant Systems – Defense mechanisms

·         Intracellular enzymatic systems:  Superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPO).  These enzymes prevent FR chain reactions (due to decreased numbers of FRs).

·         FR scavengers: a-tocopheral (vitamin E), ascorbic acid (vitamin C), niacin (vitamin B₆), riboflavin (vitamin B₂), vitamin A, and plasma proteins.  These stop FR chain reactions by accepting elections.

·         When O₂ concentrations are increased, both intracellular and extracellular defense systems may be overwhelmed by increased numbers of O₂-derived FRs; this leads to increased cellular injury

Cellular Oxygen Injury

FRs attack the lipids, proteins, and nucleic acids of the cells and tissues.

·         Lipids (e.g. pulmonary surfactant) react with FRs to produce lipid peroxides.

·         Lipid peroxides cause increased membrane permeability, inactivation of surfactant, and inhibition of normal cellular enzyme processes and can damage proteins and intracellular membranes.

·         Proteins reacting with FRs results in a decreased protein synthesis (due to inhibition of ribosomal translation) or destruction of formed proteins (by oxidative processes).

·         These reactions ultimately cause inactivation of intracellular enzymes and transport proteins; this leads to impaired cellular metabolism and the accumulation of cellular waste products.

FRs can cause breaks in DNA; they can also disrupt enzyme systems designed for the repair or replication of DNA.

*Ultimate result is cell death.

Pulmonary Oxygen Toxicity

·         The lungs are the primary organ affected by high fractional inspired oxygen (FiO₂).

·         The lungs act as the barrier to keep the rest of the body from receiving elevated O₂ concentrations

·         The amount and type of damage done to the lungs is dependent on the fractional inspired O₂ and duration of exposure to high O₂ consumption.

·         The amount of damage done, and the time to onset of changes, shows both species and individual variation.

Phases of Pulmonary Oxygen Toxicity
1. Initiation	·         Increased production of toxic oxygen (O2) metabolites ·         Depleted antioxidant (enzymes, vitamins, etc.) stores ·         No evidence of lung injury ·         Decreases flow of tracheal mucus, leading to decreased clearance of debris from lower airway, predisposing to infection ·         Length of this phase varies inversely with O2 concentration delivered (In rats, it's 1 day at FiO2 of 100%, 3 days at FiO2 of 85%, and up to 7 days at FiO2 of 60%.)
2. Inflammation	·         Destruction of pulmonary endothelial lining ·         Increased inflammatory mediators to the site of injury ·         Development of pulmonary edema
3. Destruction	·         Amplification of destruction of pulmonary endothelial lining (accumulation of platelets, then neutrophils, in pulmonary vasculature and interstitium) ·         Release of soluble inflammatory mediators ·         Phase of O2 toxicity most associated with mortality
4. Proliferation	·         Evident after prolonged exposure to less than 100% O2 concentrations (60 – 85% fractional inspired oxygen concentration ·         Hypertrophy of remaining capillary endothelial cells ·         Increased monocytes ·         Increased type II alveolar epithelial cells (They secrete surfactant.)
5. Fibrosis	·         Permanent lung damage ·         Collagen deposition in lung interstitium ·         Increase in the thickness of pulmonary interstitial space ·         Increase in interstitial fibrosis

Neurologic Oxygen Toxicity

The CNS, especially the brain, responds adversely to excessively high O₂ concentrations (e.g. during hyperbaric therapy).

·         Seizures are the most common manifestation of this toxicity.

·         Postulated mechanisms

1.       Decreased cerebral metabolism leads to decreased g-aminobutyric acid (GABA).

2.       Generated FRs lead to cellular membrane lipid peroxidation, inactivation of enzyme systems, and DNA denaturation; the changes from this damage lead to seizures.

3.       Decreased activity in multiple enzyme systems.

·         If HBO induced, remove patient from chamber after seizure has stopped. Decompression of a patient during the tonic phase of the seizure can put the patient at risk for air or oxygen embolus.

·         Pathologic CNS signs seen in study animals may include white matter necrosis with either pyknosis and hyperchromatosis of the neurons, vacuolization of the cytoplasm, and simultaneous swelling of the perineural glial processes or lysis within the nerve cell’s cytoplasm and karryorhexis.

·         Prospective HBO patients should not be febrile or acidotic (may induce seizures); should not receive high concentrations of O₂ prior to therapy (may increase chances of  seizures or pulmonary damage); and should not have a previous history of seizures.

·         Seizures have not been reported with HBO therapy in veterinary medicine

Therapy , Prevention, and Tolerance

Primary means of managing O₂ toxicity is to PREVENT it. There is no therapy to reverse toxic pulmonary changes.

Prevention includes:

1.       Maintaining the lowest fractional inspired O₂ concentrations compatible with adequate systemic and tissue oxygenation.

2.       Reducing the level of fractional inspired O₂ in small increments as soon as possible, if prolonged ventilation with an FiO₂ of 60% or higher is required to maintain systemic oxygenation. (Monitor for several weeks after ceasing use of high concentrations of O₂ as the tissue injury may take a long time to partially resolve. Permanent damage may remain even with lower levels of administration.)

3.       Reducing the need for toxic FiO₂.

·         Use positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). These systems prevent complete expiration, allowing airways to remain open, alveolar size to increase, and keep more alveoli available for gas exchange.

·         Use sound medical practices. Maintain proper sedation, correct anemia, optimize cardiac output, treat fever/hyperthermia, diagnose & treat infections, supply proper nutrition, and provide good nursing care.

The need for supplemental O₂ therapy should always take precedence over concern about toxic effects. Arterial blood gas and pulse oximetry monitoring should be used to guide O₂ administration.  Guidelines for safe administration to dogs and cats have been extrapolated from studies on other species. Current recommendations are: up to 24 hours with 100% O₂, and up to 48 hours with 60% O₂.

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vinid = JA013527, date0599
Journal info: ISSN 0193-1903; ID=J005, CCE


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