1. Limitations of O2 Therapy Dr. Ahmet U. Demir Hacettepe University Dept. of Chest Diseases

2. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

3. Therapy…

4. COPD Mortality  COPD is the only major disease with increased mortality during the last ~30 years  Mannino DM, Kiriz VA. Int J Chron Obstruct Pulmon Dis. 2006;1(3):219-33. Review.

5. Benefits  O2: decreases pulmonary hypertension, decreases the eryhtrocyte mass, improves exertional capacity  1980’s: NOTT (Nocturnal Oxygen Therapy Trial) and MRC (Medical Research Council) studies showed that LTOT was the only treatment with survival benefit in COPD and respiratory failure.  Patients were receiving O2 for at least 18 hours a day.

6.  MRC: in hypoxemic COPD, the major benefit among those using O2 >19 h/day  Nocturnal Oxygen Therapy Trial Group  Ann Inter Med 1981, 93:391–8; 1981.  Lancet, 1980:681–5.  Abbreviations: MRC, Medical Research Council; NIH, National Institutes of Health;  NOTT, Nocturnal Oxygen Therapy Trial.

7. Other Treatments  None of them has a demonstrated effect on mortality!  Chest. 2008;133(6):1451-62

8.  This finding has been supported by other studies  Other benefits: o Stabilizing the progression of Pulmonary hypertenson o Decreased rate of arrythmia and myocardial ischaemia o Increased exertional capacity o Improvement in neuropsychiatric function o Improvement in quality of life o Decreased exacerbation and hospitalization o Improvement in hypoxemia  benefits: depend on compliance and length of administartion

9.  Most of the patients in the trials are COPD, but other chronic lung diseases are also included  Eur Respir J. 2007 Nov;30(5):993-1013

10. References  169 Miyamoto K, Aida A, Nishimura M, et al. Gender effect  on prognosis of patients receiving long-term home  oxygen therapy. Am J Respir Crit Care Med 1996; 152:  972–976.  170 Waterhouse JC, Nichol J, Howard P. Survey on domiciliary  oxygen by concentrator in England and Wales.  Eur Respir J 1994; 7: 2021–2025.  171 Chailleux E, Fauroux B, Binet F, Dautzenberg B, Polu JM.  Predictors of survival in patients receiving domiciliary  oxygen therapy or mechanical ventilation. A 10-year  analysis of ANTADIR Observatory. Chest 1996; 109:  741–749.  172 Neri M, Melani AS, Miorelli AM, et al. Long-term oxygen  therapy in chronic respiratory failure: a Multicenter Italian  Study on Oxygen Therapy Adherence (MISOTA). Respir  Med 2006; 100: 795–806.

11. Exertional capacity  Meta-analysis of RCT’S comparing ambulatory O2 treatment with breathing roo air (crossover)  O2: 3-7 L/min, 30%-75%  Dyspnea has improved

12. Exertional capacity short term  O2 arm: ~25 m increase in the distance

13. Exertional capacity short term  O2 arm: ~2.5 min increase in duration

14. Exertional capacity short term  O2 arm: maximum duration of exercise increased by ~1 min

15. Exertional capacity short term  O2 arm: maximum exercise distance increased by ~32 m

16. Exertion  COPD patients without severe exertional hypoxemia vere enrolled to an exercise program with O2 therapy (7 weeks, 21 times) those with O2 could do more intense exercise and increased perfomance after the program  Long term effect?  Proc Am Thorac Soc 2007 Oct 1;4(7):549- 53.

17. Cost effectiveness  Cost effectiveness: ICER (incremental cost- effectiveness ratios)  ICER: in compariosns cost/quality adjusted life year (QALY)  ICER >> Cost effective  Survival data of trials were used to construct a model  QALY estimated according to FEV1  No adjustment for exacerbation  O2 equipment: 198$/mo,  concentator (continuous): 30$/mo, nocturnal: 11 $/mo

18. Continuous O2 therapy (16 h/d)  Cost effective

19. Nocturnal O2 therapy (9 h/d)  Not Cost effective  (PaO2: 56-65 mmHg, Sao2 30% of total sleep time or < %90 + minimum %85)

20. Other treatments  Am J Manag Care. 2009 Feb;15(2):97-104.  Nocturnal O2 is expensive than the other treatments except for alfa1 antitrypsin

21. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

22. Addiction  No previous finding related to addiction!

23. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

24. O2 Harm…  Retinal blood flow : influenced by O2 pressure and blood pressure  Hyperoxia>>> retinal vasoconstriction (adult and newbırn)  In the newborn choroidal vessels do not consrict like in adults >>> increased toxic level of O2 in the retina  Hyperoxygenization >>> peroxidation >>> microvascular injury >>> ischeamia >>> vasoproliferative retinopati  VEGF-A has a major role  Pharmacol Rep. 2005;57 Suppl:169-90.

25. O2 Harm…  100% O2 breathing >>> coronary blood flow decrease by 20%-30%, vascular resistance increases by 23%-40%  Large conduit arteries’ dimaters do not change  Effect on coronary vascular endothelium:reactive O2 species, rapid degradation of NO  Production of free O2 radicals >>> reperfusion injury in heart  Reperfusion provided by thrombolytic therapy and percutaneous coronary plasty is relevant for thşs effect  Wijesinghe M, Perrin K, Ranchord A, Simmonds M, Weatherall M, Beasley R. Heart. 2009 Mar;95(3):198-202

26. O2 Harm…  6 studies from 4 publications that met the inclusion criteria, with 6 healthy subjects and 61 subjects with cardiac disease.  high-concentration oxygen therapy resulted in hyperoxia, with a range in mean Pao(2) of 273 to 425 mm Hg.  Hyperoxia caused a significant reduction in coronary blood flow (mean change -7.9% to -28.9%, n = 6 studies).  Hyperoxia caused a significant increase in coronary vascular resistance (mean change 21.5% to 40.9%, n = 4 studies) and a significant reduction in myocardial oxygen consumption (mean change -15.3% to -26.9%, n = 3 studies).  Farquhar H, Weatherall M, Wijesinghe M, Perrin K, Ranchord A, Simmonds M, Beasley R. Am Heart J. 2009;158(3):371-7.

27. O2 Harm…  O2 >>> hypercapnia  Hypoventilation (abolishing hypoxemic stimulus from peripheral chemoreceptors))  Ventilation perfusion changes (abolishing hypoxic pulmonary vasokonstriction, perfusion of hypoventialted lung regions)  Haldane effect (O2 binding to Hb releases CO2)

28. Sleep and Respiration  Due to alveolar hypoventilation PaCO 2 increase by 3-7 mmHg, PaO 2 decrease by 3.5- 9.4 mmHg, SaO2 decreases by ~2%  These changes are not clinically significant  However individuals with compromised lung funciton during the day have difficulty during sleep (COPD) especially during REM sleep

29. Sleep and Respiration  Decreased Tidal volume, changes in the ventilation perfusion due to lying, decreased mucocilliary clearance azalma >>> aggrevated hypoventilation

30. Sleep and Respiration  Sleep hypercapnia was observed in a high percentage of COPD patients, 43% and 59%, respectively,  was likely due to the oxygen therapy.  Tárrega J, Güell R, Antón A, et al. Respir Care 2002., 47:882–6.  O´Donoghue F, Catcheside P, Ellis E, et al.. Eur Respir J 2003;21:977–84.

31. Sleep and Respiration  Nocturnal flow rate was increased by 1 liter and this induced sleep hypercapnia and respiratory acidosis in a significant number of patients (34.2% vs. 23.7% of patients)  Samolski D, Tárrega J, Antón A, Mayos M, Martí S, Farrero E, Güell R. Respirology. 2010 Feb;15(2):283-8

32. Sleep and Respiration  If patients present with sleep hypercapnia then: o early mornig PaO2 o test for the presence of OSAS. o Once OSAS is ruled out, the best way to treat thesepatients with SH under oxygen therapy may be to use the o Venturi mask or noninvasive ventilation.  Pulmon Dis. 2008;3(2):231-7.

33. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

34. Early Treatment  Twenty-seven patients completed blinded N-of-1 RCTs, each comprising three pairs of 2-week home treatment periods, with oxygen provided during one period of each pair and a placebo mixture during the other.  Patients: COPD, limited their daily activities due to dyspnea, 2 consecutive minutes with SaO2 88% or less in 6 minute walk test  O2 treatment: no effect on quality of life  5 minute walk test significant improvement with O2: 427 vs 412 steps  2 patients responded (improvement in chronic respiratory questionnaire compared to placebo in all 3 pairs)  Nonoyama ML, Brooks D, Guyatt GH, Goldstein RS. Am J Respir Crit Care Med 2007; 176: 343–349

35.  None of the QOL scores (dyspnea, fatigue, emotion and mastery) changed significantly

36. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

37. Prescribing…  In many European countries patients are tested in supine rather than sitting position  target SaO2 varies from 90% to 92%  not all countries measure arterial blood gases or test SaO2 during sleep.  Lack of standardization

38. Questions to consider in practical life  Do you give this to treat?  Does it cause addiction?  Does it have a harmful effect?  If it is so beneficial why don’t we recommend it earlier?  Is arterial blood gas analysis required to prescribe long term oxygen treatment?  Is there problems related to the use of oxygen?

39. Treatment Compliance and Problems  Adherence: 45%-70%*  concentrator: suspicions about their efficacy**  Compliance rate could be lower than estimated **  Control visits could improve the compliance**  *: Chron Respir Dis. 2006;3(4):217-22.  **: Respir Care. 2000 Feb;45(2):223-8

40. Treatment Compliance and Problems  Early studies were performed before portable systems were widely used  COPD patients: limited by slight exertion (eating etc) and have dyspnea  Data is scanty about 24 h use  International Journal of COPD 2008:3(2) 231–237

41. Treatment Compliance and Problems  meta-synthesis of qualitative studies of O2 treatrment  formulated four themes : adapting oxygen to life's circumstances, living in a restricted world, self- management is fostered by oxygen  two major results: persons prescribed oxygen rationalize its use while negotiating lifestyle interference and physical restrictions and the drive to care for one's self is conflicted.  Patient develops dependency to O2  each oxygen user faces tremendous physical, psychological, and emotional challenges.  They strive to adapt and maintain mastery but eventually oxygen dependency results.  These challenges affect the patient's ability to adhere to their treatment guidelines. These barriers and challenges are seldom addressed and are under-treated.  J Adv Nurs 2009 Mar;65(3):634-41

42. Increase Nocturnal O2?  Thirty eight patients (63% men) of mean (SD) age 73.5 (8.04) years and mean (SD) forced expiratory volume in 1 second 0.77 (0.35) l were evaluated.  Overnight desaturation occurred in six (16%; 95% CI 4 to 27).  Desaturators had mean (SD) resting oxygen saturation on room air of 88 (4.2)% compared with 90 (4.1)% in non-desaturators  HRQL and sleep quality were poor but did not differ between desaturators and non-desaturators.  Thorax 2006;61(9):779-82.

43. Conclusions  The following should be addressed in further studies: o Compliance with O2 treatment o O2 treatment to improve exertional capacity o Usage of O2 during sleep o Long term effects of O2 treatment