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Editorials: Point and Counterpoint |

POINT: Does Low-Dose Oxygen Expose Patients With COPD to More Radiation-Like Risks Than Patients Without COPD? Yes FREE TO VIEW

Vincent J. Kopp, MD; Joseph M. Stavas, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: J. M. S. consults for Cook, Inc. (West Lafayette, IN) and Excelerate Health Ventures, Inc. (Durham, NC). None declared (V. J. K.).

CORRESPONDENCE TO: Vincent J. Kopp, MD, Department of Anesthesiology, Campus Box 7010, N2198 UNC Hospitals, Chapel Hill, NC 27599-7010


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(2):303-306. doi:10.1016/j.chest.2015.10.073
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Published online

We argue that low-dose oxygen therapy (LDOT) does expose patients with COPD to more radiation-like risks than patients without COPD. Three considerations subtend our assertion: radiation and oxygen share oxidative stress mechanisms that constitute radiation-oxygen injury homology (ROIH); patients with COPD have higher, more problematic exposure rates to LDOT vs patients without COPD; and patients with COPD vs patients without COPD have disease burdens that amplify ROIH from LDOT. Thus, LDOT, independent of benefits, poses radiation-like risks with pernicious results that follow stochastic patterns.,

We use LDOT, low-flow oxygen therapy (LFOT), and long-term oxygen therapy (LTOT) as synonymous terms throughout this article.

COPD arises when oxidative stress in susceptible individuals manifests as structural and functional failures with clinical manifestations that ramify along a biopsychosocial continuum. Implicitly, the Global Initiative for Chronic Obstructive Lung Disease, the American Thoracic Society-European Respiratory Society, and the American College of Physicians COPD classifications and treatment guidelines endorse this perspective.

In 2013, the Centers for Disease Control and Prevention reported 6.4% of US adults (about 15.7 million adults) were “told” by any health professional that they had COPD. Further, 22.1% of patients with COPD (vs 6.7% of those without) used “special equipment to manage health problems,” without specifying LDOT devices. These Centers for Disease Control and Prevention data do not offer a granular view of LDOT use.

Nishi et al, using Medicare Parts A and B records, showed that any oxygen use among COPD beneficiaries rose from 33.7% in 2001 to 40.5% in 2010, whereas sustained oxygen use varied from 19.5% in 2001 to 26.9% in 2008 when service reimbursement formulae changed, before dropping to 18.5% in 2010. These data endorse problematic LDOT use influenced by sociopolitical factors. They also found LDOT was highest among non-Hispanic, white women with two or more comorbidities and low socioeconomic status, engendering questions about the applicability of classic LDOT life extension studies to this population. Further questioning the applicability of these studies to other populations is appropriate.

ROIH was first recognized more than 70 years ago. In 1934, de Almedia noted histological homologies in x-irradiated and hyperoxia-exposed testes. Gerschman, in 1954, postulated free radicals as the “…common mechanism between oxygen poisoning and x-irradiation….” In 1962, Noell, studying vision, noted that cumulative “oxygen poisoning” resembles “x-irradiation effects.” Gilbert, in 1972, reiterated that radiation catalyzes oxygen toxicity. Mensel, in 1970, underscored that ozone—an oxygen allotrope—causes radiation-like damage. Microbiologists postulate that radiation resistance via antioxidant-like mechanisms developed before atmospheric oxygen accummulated. That free radicals and reactive oxygen species cause molecular and submolecular damage and govern multiple, often competing translational/transcriptional events, is axiomatic. Regression analysis shows not smoking and lower atmospheric oxygen tension secondary to higher elevation as inverse predictors for lung cancer.

Figure 1 depicts ways ROIH can incite cellular injury. Oxygen partial pressure variations from evolutionarily determined (physoxic) levels produce adaptive and pathological responses.

Figure 1
Figure Jump LinkFigure 1 Pro-oxidant effects of radiation (RAD) and oxygen (O2) produce reactive oxygen and nitrogen species (RONS) that cause direct molecular and submolecular injury with lipid, protein, and nucleic acid structural consequences; RONS also participate in transcriptional/translational events that reset homeostasis. Oxidative phosphorylation (OXPHOS) exerts its powerful influence on RONS generation, antioxidant level control (not shown), and codon and gene product activation, especially hypoxia inducible factors (HIF-1), nuclear factor kappa B (NFκB), protein 53 (p53), and tumor necrosis factor alpha (TNFα). Antioxidants regulate and counterregulate pro-oxidant effects to produce “molecular whiplash” because antioxidants may become reactive species in and of themselves. Because mitochondria are primary RONS sites, mitochondrial genomes are more susceptible to injury than nuclear genomes because of proximity and marginal protection/repair mechanisms, which is only compensated for by heteroplasmy. DS-DNA = double-stranded DNA; SS-DNA = single-stranded DNA.Grahic Jump Location

Electrons (e-) and reactive oxygen and nitrogen species (RONS) that generate free radicals are ROIH common denominators., Hydroxyl radicals, hydrogen peroxide, superoxide, and singlet oxygen species produced by oxidative phosphorylation and nonrespiratory enzymatic and nonenzymatic oxygen activation have parallels in water irradiation. These moieties react with nitric oxide to produce RONS such as peroxynitrite, which also cause injury and/or translational/transcriptional events that reset homeostasis.

Regarding ionizing radiation, health professional and consumer concerns about medical imaging radiation exposure risks, especially in children, reflects both postulated and proven harm. The US government and medical societies recommend “radiation reduction” strategies such as “as low as reasonably achievable” (ALARA), also reflected in The American Board of Internal Medicine Foundation’s “Choosing Wisely” campaign. To date, oxygen has escaped equivalent attention, though risk awareness is increasing. Notably, the Occupational Safety and Health Administration and Food and Drug Administration regulate oxygen, depending on intended use, industrial or medical, respectively.

Our review suggests that patients with COPD have (1) higher exposure rates to LDOT/LFOT/LTOT and (2) more problematic exposures than patients without COPD.

Our PubMed search using “low-dose oxygen therapy for COPD patients” and “low-dose oxygen therapy for non-COPD patients” for LDOT; “low-flow oxygen therapy for COPD patients” and “low-flow oxygen therapy for non-COPD patients” for LFOT; and “long-term oxygen therapy for COPD patients” and “long-term oxygen therapy for non-COPD patients” for LTOT is summarized in Table 1. We were surprised by the paucity of results for all search terms, particularly LDOT and LFOT.

Table Graphic Jump Location
Table 1 PubMed Search Results (July 16, 2015, 12:00-12:15 am, and July 19, 2015 2:20 pm)
a Any language. LDOT = low-dose oxygen therapy; LFOT = low-flow oxygen therapy; LTOT = long-term oxygen therapy.

In 2000, Zieliński noted no controlled trials assessed LTOT in patients without COPD comparable to the Nocturnal Oxygen Therapy Trial or the British Medical Research Trial, two acknowledged 1980s trials still used to model life-saving COPD oxygen therapy. He catalogued COPD/non-COPD LTOT use in seven different countries finding variations from 39%/61% in Japan to 93.4%/6.6% in the Czech Republic. In the United States, where about 80% of LTOT users are Medicare recipients, rates were 76%/24% COPD/non-COPD. The non-COPD pulmonary conditions associated with LTOT were tuberculous sequelae, interstitial pulmonary fibrosis, pneumoconiosis, kyphoscoliosis, bronchiectasis, and cystic fibrosis; in children, these were restrictive lung disease conditions associated with neuromuscular disease and bronchopulmonary dysplasia. Although these conditions share oxygen use with COPD, none evince the total COPD pathophysiologic spectrum. Cystic fibrosis, OSA, and pulmonary hypertension associated with COPD and congestive heart failure constitute other LTOT populations.

Chaney et al evaluated 283 LTOT “follow-up” users in an outpatient clinic. Their distribution was 75%/ 25% for patients with COPD/patients without COPD. The patients without COPD had 8.1%/16.9% interstitial lung disease/“other diagnosis.” About one-third of subjects (n = 94) warranted LTOT discontinuation on initial follow-up; about 17% (n = 47) of subjects scheduled for follow-up died beforehand, while still on LTOT.

LDOT is used for patients with and patients without COPD dyspnea. Notably, not all dyspnea reveals hypoxemia. Uronis et al noted LFOT use for COPD dyspnea relief yielded interesting results: 41% of “oxygen responders” (dyspnea relieved by LFOT) desired no further therapy because of “inconvenience and poor tolerability.” This suggests that some LFOT is influenced by biopsychosocial factors that defy classical medical rationalizations.

The role of oxidative stress in COPD is established. Oxidative stress injures lipids, proteins, and nucleic acids and through transcriptional/translational events promotes cellular apoptosis, senescence, and death. COPD, in our opinion, is a disease phenotype in which oxidative stress manifests as gas conductance impairment over gas diffusion capacity. Adding oxidative stress stimulus via LDOT without improving gas conductance increases ROIH risks, especially where hypoxemia and low antioxidant capacity coexist, irrespective of benefit.

Faschino-Barbaro et al showed LFOT produces antioxidant defense impairment ameliorated experimentally by N-acetyl-cysteine (NAC) vs placebo administration. Oxidative stress biomarkers measured in the Global Initiative for Chronic Obstructive Lung Disease III volunteers exposed to 18 h of 2 L/min oxygen before and after NAC administration included erythrocyte reduced/oxidized glutathione and erythrocyte and plasma thiol and carbonyl proteins. They concluded that (1) LTOT/LFOT worsens COPD oxidative stress and (2) 1,800 mg/day NAC reduces oxidative stress.

Alternatively, de Matos Cavalcante et al followed 8-isoprostane levels in a randomized, double-blind, placebo controlled study of melatonin in COPD. They noted subjects with the greatest decreases in 8-isoprontane levels had the greatest decrease in dyspnea. In addition to direct antioxidant effects, the authors noted melatonin-induced sleep improvement and in vitro evidence of antibacterial activity as reasons to further investigate melatonin’s place in COPD management.

Finally, Houghton notes epidemiological links between COPD and lung cancer development independent of cigarette smoking dosages. Because shared links between ROIH and cancer genesis at the molecular level are not straightforward, it should be considered that some LDOT COPD life extension may evince late progression toward lung cancer.

Although no “gold standard” trials prove or disprove our position, interdisciplinary evidence and clinical observations suggests LDOT in COPD is not risk-free. Gas conductance improvement coupled with oxidative stress reduction strategies should precede LDOT to lessen ROIH. Noting irradiation’s ALARA practices, adopting “lowest oxygen level acceptable” practices as the primary antioxidant strategy for indicated medical oxygen use is advisable.

Dainiak N. . Radiation dose and stochastic risk from exposure to medical imaging. Chest. 2013;144:1431-1433 [PubMed]journal. [CrossRef] [PubMed]
 
Simeonov K.P. .Himmelstein D.S. . Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. Peer J. 2015;13:e705- [PubMed]journal
 
Engel G.L. . The clinical application of the biopsychosocial model. Am J Psychiatry. 1980;137:535-544 [PubMed]journal. [CrossRef] [PubMed]
 
Niewoehner D.E. . Outpatient management of severe COPD. N Engl J Med. 2010;362:1407-1416 [PubMed]journal. [CrossRef] [PubMed]
 
Wheaton A.G. .Cunningham T.J. .Ford E.S. .Croft J.B. . Employment and activity limitations among adults with chronic obstructive pulmonary disease—United States, 2013. MMWR Morb Mort Wkly Rep. 2015;64:289-295 [PubMed]journal
 
Nishi S.P.E. .Zhang W. .Kuo Y.-F. .Sharma G. . Oxygen therapy use in older adults with chronic obstructive pulmonary disease. PLoS One. 2015;10:e0120684- [PubMed]journal. [CrossRef] [PubMed]
 
Lim S. .Lam D.C. .Muttalif A.R. .et al Impact of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. Asia Pac Fam Med. 2015;14:4- [PubMed]journal. [CrossRef] [PubMed]
 
Gerschman R. . Historical introduction to the “free radical theory” of oxygen toxicity.Gilbert D.L.. Oxygen and Living Processes: An Interdisciplinary Approach.  :44-46 [PubMed]journal
 
Makarova K.S. .Aravind L. .Koonin E.V. .Daly M.J. . Genome of the extremely radiation-resistant bacterium Deinococcus radiodurans viewed from the perspective of comparative genomics. Microbiol Mol Biol Rev. 2001;65:44-79 [PubMed]journal. [CrossRef] [PubMed]
 
Semenza G.L. . Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol Mech Dis. 2014;9:47-71 [PubMed]journal. [CrossRef]
 
Gupta K. .Madan E. .Sayyid M. .et al Oxygen regulates molecular mechanisms of cancer progression and metastasis. Cancer Metastasis Rev. 2015;33:183-215 [PubMed]journal
 
Kim J.H. .Jenrow K.A. .Brown S.L. . Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiat Oncol J. 2014;32:103-115 [PubMed]journal. [CrossRef] [PubMed]
 
Sjöberg F. .Singer M. . The medical use of oxygen: a time for critical reappraisal. J Intern Med. 2013;274:505-528 [PubMed]journal. [CrossRef] [PubMed]
 
Zieliński J. . Long-term oxygen therapy in conditions other than chronic obstructive pulmonary disease. Respir Care. 2000;45:172-176 [PubMed]journal. [PubMed]
 
Chaney J.C. .Jones K. .Grathwohl K. .Olivier K.N. . Implementation of an oxygen therapy clinic to manage users of long-term oxygen therapy. Chest. 2002;122:1661-1667 [PubMed]journal. [CrossRef] [PubMed]
 
Uronis H.E. .Ekström M.P. .Currow D.C. .McCrory D.C. .Samsa G.P. .Abernathy A.P. . Oxygen for relief of dyspnoea in people with chronic obstructive pulmonary disease who would not qualify for home oxygen: a systematic review and meta-analysis. Thorax. 2015;70:492-494 [PubMed]journal. [CrossRef] [PubMed]
 
Domej W. .Oettl K. .Renner W. . Oxidative stress and free radicals in COPD—implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 2014;17:1207-1224 [PubMed]journal
 
Foschino-Barbaro M.P. .Serviddio G. .Resta O. .et al Oxygen therapy at low flow causes oxidative stress in chronic obstructive pulmonary disease: prevention by n-acetyl cysteine. Free Radical Res. 2005;39:1111-1118 [PubMed]journal. [CrossRef]
 
de Matos Cavalcante A.G. .de Bruin P.F. .de Bruin V.M. .et al Melatonin reduces lung oxidative stress in patients with chronic obstructive pulmonary disease: a randomized, double-blind, placebo-controlled study. J Pineal Res. 2012;53:238-244 [PubMed]journal. [CrossRef] [PubMed]
 
Houghton A.M. . Mechanistic links between COPD and lung cancer. Nat Rev Cancer. 2013;13:233-245 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Pro-oxidant effects of radiation (RAD) and oxygen (O2) produce reactive oxygen and nitrogen species (RONS) that cause direct molecular and submolecular injury with lipid, protein, and nucleic acid structural consequences; RONS also participate in transcriptional/translational events that reset homeostasis. Oxidative phosphorylation (OXPHOS) exerts its powerful influence on RONS generation, antioxidant level control (not shown), and codon and gene product activation, especially hypoxia inducible factors (HIF-1), nuclear factor kappa B (NFκB), protein 53 (p53), and tumor necrosis factor alpha (TNFα). Antioxidants regulate and counterregulate pro-oxidant effects to produce “molecular whiplash” because antioxidants may become reactive species in and of themselves. Because mitochondria are primary RONS sites, mitochondrial genomes are more susceptible to injury than nuclear genomes because of proximity and marginal protection/repair mechanisms, which is only compensated for by heteroplasmy. DS-DNA = double-stranded DNA; SS-DNA = single-stranded DNA.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 PubMed Search Results (July 16, 2015, 12:00-12:15 am, and July 19, 2015 2:20 pm)
a Any language. LDOT = low-dose oxygen therapy; LFOT = low-flow oxygen therapy; LTOT = long-term oxygen therapy.

References

Dainiak N. . Radiation dose and stochastic risk from exposure to medical imaging. Chest. 2013;144:1431-1433 [PubMed]journal. [CrossRef] [PubMed]
 
Simeonov K.P. .Himmelstein D.S. . Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. Peer J. 2015;13:e705- [PubMed]journal
 
Engel G.L. . The clinical application of the biopsychosocial model. Am J Psychiatry. 1980;137:535-544 [PubMed]journal. [CrossRef] [PubMed]
 
Niewoehner D.E. . Outpatient management of severe COPD. N Engl J Med. 2010;362:1407-1416 [PubMed]journal. [CrossRef] [PubMed]
 
Wheaton A.G. .Cunningham T.J. .Ford E.S. .Croft J.B. . Employment and activity limitations among adults with chronic obstructive pulmonary disease—United States, 2013. MMWR Morb Mort Wkly Rep. 2015;64:289-295 [PubMed]journal
 
Nishi S.P.E. .Zhang W. .Kuo Y.-F. .Sharma G. . Oxygen therapy use in older adults with chronic obstructive pulmonary disease. PLoS One. 2015;10:e0120684- [PubMed]journal. [CrossRef] [PubMed]
 
Lim S. .Lam D.C. .Muttalif A.R. .et al Impact of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. Asia Pac Fam Med. 2015;14:4- [PubMed]journal. [CrossRef] [PubMed]
 
Gerschman R. . Historical introduction to the “free radical theory” of oxygen toxicity.Gilbert D.L.. Oxygen and Living Processes: An Interdisciplinary Approach.  :44-46 [PubMed]journal
 
Makarova K.S. .Aravind L. .Koonin E.V. .Daly M.J. . Genome of the extremely radiation-resistant bacterium Deinococcus radiodurans viewed from the perspective of comparative genomics. Microbiol Mol Biol Rev. 2001;65:44-79 [PubMed]journal. [CrossRef] [PubMed]
 
Semenza G.L. . Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol Mech Dis. 2014;9:47-71 [PubMed]journal. [CrossRef]
 
Gupta K. .Madan E. .Sayyid M. .et al Oxygen regulates molecular mechanisms of cancer progression and metastasis. Cancer Metastasis Rev. 2015;33:183-215 [PubMed]journal
 
Kim J.H. .Jenrow K.A. .Brown S.L. . Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiat Oncol J. 2014;32:103-115 [PubMed]journal. [CrossRef] [PubMed]
 
Sjöberg F. .Singer M. . The medical use of oxygen: a time for critical reappraisal. J Intern Med. 2013;274:505-528 [PubMed]journal. [CrossRef] [PubMed]
 
Zieliński J. . Long-term oxygen therapy in conditions other than chronic obstructive pulmonary disease. Respir Care. 2000;45:172-176 [PubMed]journal. [PubMed]
 
Chaney J.C. .Jones K. .Grathwohl K. .Olivier K.N. . Implementation of an oxygen therapy clinic to manage users of long-term oxygen therapy. Chest. 2002;122:1661-1667 [PubMed]journal. [CrossRef] [PubMed]
 
Uronis H.E. .Ekström M.P. .Currow D.C. .McCrory D.C. .Samsa G.P. .Abernathy A.P. . Oxygen for relief of dyspnoea in people with chronic obstructive pulmonary disease who would not qualify for home oxygen: a systematic review and meta-analysis. Thorax. 2015;70:492-494 [PubMed]journal. [CrossRef] [PubMed]
 
Domej W. .Oettl K. .Renner W. . Oxidative stress and free radicals in COPD—implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 2014;17:1207-1224 [PubMed]journal
 
Foschino-Barbaro M.P. .Serviddio G. .Resta O. .et al Oxygen therapy at low flow causes oxidative stress in chronic obstructive pulmonary disease: prevention by n-acetyl cysteine. Free Radical Res. 2005;39:1111-1118 [PubMed]journal. [CrossRef]
 
de Matos Cavalcante A.G. .de Bruin P.F. .de Bruin V.M. .et al Melatonin reduces lung oxidative stress in patients with chronic obstructive pulmonary disease: a randomized, double-blind, placebo-controlled study. J Pineal Res. 2012;53:238-244 [PubMed]journal. [CrossRef] [PubMed]
 
Houghton A.M. . Mechanistic links between COPD and lung cancer. Nat Rev Cancer. 2013;13:233-245 [PubMed]journal. [CrossRef] [PubMed]
 
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