Oxygen toxicity

Oxygen toxicity or oxygen toxicity syndrome (also known as the "Paul Bert effect" or the "Lorrain Smith effect") is severe hyperoxia caused by breathing oxygen at elevated partial pressures.^[1]^[2]^[3] These above-normal concentrations of oxygen within the body can cause cell damage in two principal regions: the central nervous system (CNS); and the lungs (pulmonary).^[4] Over time, it can also cause damage to the retina and may be implicated in some retinopathic conditions.^[5]^[6]

The damage may be caused by long exposure (days) to lower concentrations of oxygen or by shorter exposure (minutes or hours) to high concentrations. Long exposures to partial pressure of oxygen above 0.5 bar (50 kPa) can result in pulmonary oxygen toxicity and are a concern for patients breathing pure oxygen for extended periods.^[7]^[8]^[9] Short exposures to partial pressure of oxygen above 1.6 bar (160 kPa) are usually associated with CNS oxygen toxicity and are most likely to occur among divers and those undergoing hyperbaric oxygen therapy.^[10]^[11]^[12]

Prevention of oxygen toxicity is an important precaution whenever oxygen is breathed at greater than normal partial pressures. This has led to protocols for avoidance of hyperoxia being used in such fields as diving, hyperbaric therapy and human spaceflight. Although it may appear that hyperventilation might lead to hyperoxia, this does not happen since oxygen toxicity never occurs when breathing air at atmospheric pressure.

Hyperoxia

Hyperoxia is excess oxygen in body tissues or higher than normal partial pressure of oxygen. Hyperoxia is caused by breathing gas at pressures greater than normal atmospheric pressure or by breathing oxygen-rich gases at normal atmospheric pressure for a prolonged period of time.

Mechanism

The high concentration of oxygen damages cells.^[4] The precise mechanism(s) of the damage caused by these reactive oxygen species are not known, but oxygen gas has a propensity to react with certain metals to form superoxide which may attack double bonds in many organic systems, including the unsaturated fatty acid residues in cells. High concentrations of oxygen are known to increase the formation of free-radicals which harm DNA and other structures (see nitric oxide, peroxynitrite, and trioxidane). Normally, the body has many defense systems against such damage (see glutathione, catalase, and superoxide dismutase) but at higher concentrations of free oxygen, these systems are eventually overwhelmed with time, and the rate of damage to cell membranes exceeds the capacity of systems which control or repair it. Cell damage and cell death then results. Note similarity to Reperfusion injury.

Types

Central nervous system (CNS) oxygen toxicity

CNS oxygen toxicity manifests as symptoms such as visual changes, ringing in the ears, nausea, twitching (especially on the face), irritability (personality changes, anxiety, confusion, etc.), dizziness, and convulsions.^[1]^[2] The onset depends upon partial pressure of oxygen (ppO₂) in the breathing gas and exposure duration.

Background to CNS oxygen toxicity

CNS Toxicity was first described by Paul Bert in 1878.^[1]^[13]^[14] He showed that oxygen was toxic to insects, arachnids, myriapods, molluscs, earthworms, fungi, germinating seeds, birds, and other animals. The first recorded human exposure was recorded in 1910 by Bornstein when two men breathed oxygen at 2.8 atm (280 kPa) for 30 minutes while he went on to 48 minutes with no symptoms.^[15] In 1912, Bornstein developed cramps in his hands and legs while breathing oxygen at 2.8 atm (280 kPa) for 51 minutes.^[16] Behnke et. al. were the first to observe visual field contraction (tunnel vision) on dives between 1.0 atm (100 kPa) and 4.0 atm (410 kPa).^[17]^[18] During World War II, Donald and Yarbrough et. al. performed many studies on oxygen toxicity to support the initial use of closed circuit oxygen rebreathers.^[10]^[11]^[19]^[20] They discovered the effects of underwater immersion and exercise. In the decade following World War II, Lambertsen et. al. made further discoveries on the effects of oxygen at pressure as well as methods of prevention.^[21]^[22] In the years since, research on CNS toxicity has centered around methods of prevention and safe extension of tolerance.^[23]

Clinical relevance of CNS oxygen toxicity

As CNS toxicity is caused by breathing oxygen at elevated ambient pressures, patients undergoing hyperbaric oxygen therapy are at risk of suffering hyperoxic seizures.^[1]^[12]^[24] Treatment of seizures during treatment consists of removing the patient from oxygen, thereby dropping the partial pressure of oxygen delivered.^[2]

Diving relevance of CNS oxygen toxicity

CNS oxygen toxicity is a deadly but entirely avoidable event while diving. The diver generally experiences no warning signs because the brain primarily monitors carbon dioxide levels. The symptoms are sudden convulsions and unconsciousness,^[1]^[2] during which the victim can lose his/her regulator and drown. There is an increased risk of CNS oxygen toxicity on deep dives, long dives or dives where oxygen-rich breathing gases are used. Divers are taught to calculate a maximum operating depth for oxygen-rich breathing gases. Cylinders containing such mixtures must be clearly marked with that depth.

In some diver training courses for these types of diving, divers are taught to plan and monitor what is called the "oxygen clock" of their dives. This clock is a notional alarm clock, which "ticks" more quickly at increased ppO₂ and is set to activate at the maximum single exposure limits recommended in the NOAA Diving Manual. The maximum single exposure limits recommended in the NOAA Diving Manual are 45 minutes at 1.6 bar (160 kPa), 120 minutes at 1.5 bar (150 kPa), 150 minutes at 1.4 bar (140 kPa), 180 minutes at 1.3 bar (130 kPa) and 210 minutes at 1.2 bar (120 kPa), but is impossible to predict with any reliability whether or when CNS symptoms will occur.^[1]^[2]^[25]^[26] Many Nitrox-capable dive computers also calculate this "Oxygen Loading".

The aim is to avoid activating the alarm by reducing the ppO₂ of the breathing gas or the length of time breathing gas of higher ppO₂. As the ppO₂ depends on the fraction of oxygen in the breathing gas and the depth of the dive, the diver can obtain more time on the oxygen clock by diving at a shallower depth, by breathing a less oxygen-rich gas or by shortening the exposure to oxygen-rich gases.

Pulmonary oxygen toxicity

Background to pulmonary oxygen toxicity

Pulmonary oxygen toxicity was first described by Lorrain Smith in 1899 when he noted CNS toxicity and discovered in experiments in mice and birds that 0.42 atm (43 kPa) had no effect but 0.74 atm (75 kPa) of oxygen was a pulmonary irritant.^[27] He then went on to show that intermittent exposure permitted the lungs to recover and delayed the onset of toxicity.^[27] Lambertsen et. al. made further discoveries on the effects of oxygen effects at pressure as well as methods of prediction and prevention.^[1]^[2]^[21] Their work on intermittent exposures for extension of oxygen tolerance^[28] and model for prediction of pulmonary oxygen toxicity based on pulmonary function^[29] are key documents in the development of operational oxygen procedures. In 1988, Hamilton et. al. wrote procedures for NOAA to establish oxygen exposure limits for habitat operations.^[1]^[30]^[31]^[32] Models for the prediction of pulmonary oxygen toxicity do not explain the results of all exposures to high partial pressures of oxygen.^[33]

Clinical relevance of pulmonary oxygen toxicity

The risk of bronchopulmonary dysplasia ("BPD") in infants,^[7]^[8] or adult respiratory distress syndrome in adults,^[9] begins to increase with exposure for over 16 hours to oxygen partial pressures of 0.5 bar (50 kPa) or more. At sea-level, 0.5 bar (50 kPa) is exceeded by gas mixtures having oxygen fractions greater than 50%. Lung oxygen toxicity damage-rates at sea-level pressure rise non-linearly between the 50% threshold of toxicity, and the rate of damage on 100% oxygen. For this reason, intensive care patients requiring more than 60% oxygen, and especially patients at fractions near 100% oxygen, are considered to be at especially high risk. If the situation is not corrected, the treatment may begin to cause lung damage which exacerbates the original problem requiring the high-oxygen mixture. Care must be used in distinguishing oxygen mole fraction from oxygen partial pressure. Partial pressures between 0.2 bar (20 kPa) (normal at sea level) and 0.5 bar (50 kPa) usually are considered non-toxic. BPD is reversible in the early stages during "break" periods on lower oxygen pressures, but it may eventually result in irreversible lung damage, if allowed to progress to severe damage. Usually several days of exposure without "oxygen breaks" are needed to cause severe lung damage.

Oxygen toxicity is a potential complication of mechanical ventilation with pure oxygen, where it is called the respiratory lung syndrome.

Diving relevance of pulmonary oxygen toxicity

Pulmonary oxygen toxicity is entirely avoidable event while diving. The time-factor and the naturally intermittent nature of most diving makes this a relatively rare (and even then, reversible) complication for divers. Guidelines have been established that allow divers to calculate when they are at risk of pulmonary toxicity.^[1]^[2]^[28]^[30]^[31]^[32]

In the treatment of Decompression Sickness, divers are exposed to long periods of oxygen breathing under hyperbaric conditions. This exposure coupled with that from the dive that preceded the symptoms can be a significant cumulative oxygen exposure and pulmonary toxicity may occur.^[12]

Space relevance of pulmonary oxygen toxicity

As noted earlier in this article, the toxicity is from high partial pressure. This is illustrated by oxygen use in spacesuits and other low-pressure applications (historically, for example, the Gemini spacecraft and Apollo spacecraft). High fraction oxygen is non-toxic even at breathing mixture oxygen fractions approaching 100%, because the oxygen partial pressure is not allowed to chronically exceed 0.35 bar (35 kPa) in these applications.

Retinopathic oxygen toxicity

Prolonged exposure to high inspired fractions of oxygen causes damage to the retina. Oxygen may be a contributing factor for the disorder called retrolental fibroplasia.^[5] Hyperoxic myopia has occurred in closed circuit oxygen rebreather divers with prolonged exposures.^[6]

Hyperventilation

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.

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Brubakk, A. O.; T. S. Neuman (2003). Bennett and Elliott's physiology and medicine of diving, 5th Rev ed.. United States: Saunders Ltd., 800. ISBN 0702025712.
^ ^a ^b ^c ^d ^e ^f ^g ^h (2006) US Navy Diving Manual, 6th revision. United States: US Naval Sea Systems Command. Retrieved on 2008-04-24.
^ ^a ^b Acott, C. (1999). "Oxygen toxicity: A brief history of oxygen in diving". South Pacific Underwater Medicine Society journal 29 (3). ISSN 0813-1988. OCLC 16986801. Retrieved on 2008-04-29.
^ ^a ^b Bitterman N (2004). "CNS oxygen toxicity". Undersea Hyperb Med 31 (1): 63–72. PMID 15233161. Retrieved on 2008-04-29.
^ ^a ^b Nichols CW, Lambertsen C (July 1969). "Effects of high oxygen pressures on the eye". N. Engl. J. Med. 281 (1): 25–30. PMID 4891642.
^ ^a ^b Butler FK, White E, Twa M (1999). "Hyperoxic myopia in a closed-circuit mixed-gas scuba diver". Undersea Hyperb Med 26 (1): 41–5. PMID 10353183. Retrieved on 2008-04-29.
^ ^a ^b Bancalari E, Claure N, Sosenko IR (February 2003). "Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition". Semin Neonatol 8 (1): 63–71. doi:10.1016/S1084-2756(02)00192-6. PMID 12667831. Retrieved on 2008-04-30.
^ ^a ^b Tin W, Gupta S (March 2007). "Optimum oxygen therapy in preterm babies". Arch. Dis. Child. Fetal Neonatal Ed. 92 (2): F143–7. doi:10.1136/adc.2005.092726. PMID 17337663. Retrieved on 2008-04-30.
^ ^a ^b Thiel M, Chouker A, Ohta A, et al (June 2005). "Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury". PLoS Biol. 3 (6): e174. doi:10.1371/journal.pbio.0030174. PMID 15857155. Retrieved on 2008-04-30.
^ ^a ^b Donald K. W. (1947). "Oxygen and the diver: Part I". Br Med J 1(4506): 667–672. Retrieved on 2008-04-29.
^ ^a ^b Donald K. W. (1947). "Oxygen and the diver: Part II". Br Med J 1(4506): 712–717. Retrieved on 2008-04-29.
^ ^a ^b ^c Smerz RW (2004). "Incidence of oxygen toxicity during the treatment of dysbarism". Undersea Hyperb Med 31 (2): 199–202. PMID 15485081. Retrieved on 2008-04-30.
^ Bert, P. (originally published 1878). "Barometric Pressure: researches in experimental physiology". Translated by: Hitchcock MA and Hitchcock FA. College Book Company; 1943.
^ Sport Diving, British Sub Aqua Club, ISBN0091638313, page 110
^ Bornstein, A. (1910). "Versuche uber die Prophylaxe der Pressluftkrankheit". Pflug Arch 4: 1272–1300.
^ Bornstein, A. and Stroink M. (1912). "Ueber Sauerstoff vergiftung". Dtsch med Wschr 38: 1495–1497.
^ Behnke A. R., Johnson F. S., Poppen J. R., and Motley E. P. (1935). "The effect of oxygen on man ar pressures from 1 to 4 atmospheres". Am J Physiol 110: 565–572. Retrieved on 2008-04-29.
^ Behnke A. R., Forbes H. S., and Motley E. P. (1935). "Circulatory and visual effects of oxygen at 3 atmospheres pressure". Am J Physiol 114: 436–442. Retrieved on 2008-04-29.
^ Donald, K. W. (1992). Oxygen and the diver.. UK: Harley Swan, 237. ISBN 1854211765.
^ Yarbrough, O. D., Welham W., Brinton E.S. and Behnke, A. R. (1947). "Symptoms of Oxygen Poisoning and Limits of Tolerance at Rest and at Work". US Naval Experimental Diving Unit Technical Report NEDU-47-01. Retrieved on 2008-04-29.
^ ^a ^b Lambertsen, C. J., J. M. Clark, R. Gelfand (2000). "The Oxygen Research Program, University of Pennsylvania: Physiologic Interactions of Oxygen and Carbon Dioxide Effects and Relations to Hyperoxic Toxicity, Therapy, and Decompression. Summation: 1940 to 1999". Environmental Biomedical Stress Data Center, Institute for Environmental Medicine, University of Pennsylvania Medical Center EBSDC-IFEM Report No. 3-1-2000.
^ Vann RD (2004). "Lambertsen and O2: beginnings of operational physiology". Undersea Hyperb Med 31 (1): 21–31. PMID 15233157. Retrieved on 2008-04-29.
^ Natoli, M. J. and Vann R. D. (1996). Factors Affecting CNS Oxygen Toxicity in Humans Report to the US Office of Naval Research. Durham, NC: Duke University. Retrieved on 2008-04-29.
^ Hampson NB, Simonson SG, Kramer CC, and Piantadosi CA (December 1996). "Central nervous system oxygen toxicity during hyperbaric treatment of patients with carbon monoxide poisoning". Undersea Hyperb Med 23 (4): 215–9. PMID 8989851. Retrieved on 2008-04-29.
^ Butler FK, Thalmann ED (June 1986). "Central nervous system oxygen toxicity in closed circuit scuba divers II". Undersea Biomed Res 13 (2): 193–223. PMID 3727183. Retrieved on 2008-04-29.
^ Butler FK (2004). "Closed-circuit oxygen diving in the U.S. Navy". Undersea Hyperb Med 31 (1): 3–20. PMID 15233156. Retrieved on 2008-04-29.
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^ ^a ^b Clark JM (2004). "Extension of oxygen tolerance by interrupted exposure". Undersea Hyperb Med 31 (2): 195–8. PMID 15485080. Retrieved on 2008-04-29.
^ Clark, J. M. and Lambertsen, C. J. (1970). Pulmonary Oxygen Tolerance in Man and Derivation of Pulmonary Oxygen Tolerance Curves IFEM Report No. 1-70. Retrieved on 2008-04-29.
^ ^a ^b Hamilton R. W., Kenyon D. J., Peterson R. E., Butler G. J., Beers D. M. (1988). Repex habitat diving procedures: Repetitive vertical excursions, oxygen limits, and surfacing techniques. Technical Report 88-1A. Retrieved on 2008-04-29.
^ ^a ^b Hamilton R. W., Kenyon D. J., Peterson R. E. (1988). Repex habitat diving procedures: Repetitive vertical excursions, oxygen limits, and surfacing techniques. Technical Report 88-1B. Retrieved on 2008-04-29.
^ ^a ^b Hamilton R. W. (1997). "Tolerating oxygen exposure". South Pacific Underwater Medicine Society journal 27 (1). ISSN 0813-1988. OCLC 16986801. Retrieved on 2008-04-29.
^ Shykoff, B (2007). Performance of Various Models in Predicting Vital Capacity Changes Caused by Breathing High Oxygen Partial Pressures. NEDU-TR-07-13. Retrieved on 2008-06-06.

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