Hypoxic Drive Theory: Here are the evidence that disproves it

The hypoxic drive theory was established in 1960.  Since then many studies have shed doubt on this theory, in favor of the Haldane Effect and ventilation-perfusion mismatching.  Listed here is all the evidence that either proves or disproves these theories.

1. Hoyt, John. W., "Debunking the Myths of Chronic Obstructive Pulmonary Disease", Critical Care Medicine, 1997, Volume 25, Number 9, pages 1450-1451 (you'll have to obtain a prescription to view article)
2. Campbell, E.J.M, "Respiratory Failure,"  The British Medical Journal,  June 1965, 1451-1460 (article provided by link)
3. Arnottt, W.M, "Respiratory Failure,"  Lancet,  January 1960, Volume 25, Issue 7114, pages 1-7 (you'll have to subscribe to view article)
4. Campbell, E.J.M, "The J. Burns Amberson Lecture - Management of Acute Respiratory Failure in Chronic Bronchitis and Emphysema," The Journal of Occupational and Environmental Medicine, June 1968,  Volume 10, issue 6, pages 329-332  (You'll have to become a member to veiw article)
5. Campbell, E.J.M, "The J. Burns Amberson Lecture - Management of Acute Respiratory Failure in Chronic Bronchitis and Emphysema," American Review of Respiratory Diseases, October 1967, Volume 96, Issue 4 (no link available)
6. Scano,G, A. Spinelli,  R. Duranti, M. Gorini, F. Gigliott i, P. Goti, J. Milic-Emili, "Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia," Europe Respiratory Journal, 1995, Volume 8, pages 78-85 (full pdf provided by link)
7. Robinson, Tracy D  David B. Freiberg, Jeff A. Regnis and Iven H. Young, "The Role of Hypoventilation and Ventilation-Perfusion Redistribution in Oxygen-induced Hypercapnea during Acute Exacerbation of Chronic Obstructive Pulmonary Disease," American Journal of Respiratory and Critical Care Medicine, 2000, volume 161, pages 1524-1529 (full pdf provided by link)
8. Aubier, M, et al, "Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure", American Review of Respiratory Diseases,  1980, Volume 122, pages 747-754 (abstract available by link)
9. Hanson, et all, "Causes of hypercapnia with Oxygen Therapy in patients with Chronic Obstructive Pulmonary Disease," Critical Care medicine, 1996, volume 24, pages 23-28 (abstract available by link)
10. Lazic, D, et al, "The influence of oxygen therapy on the hypercapnia in patients with chronic obstructive pulmonary disease,"  July 2008, Volume 65, Issue 7, pages 521-524 (abstract available by link)
11. Sassoon, C.S., et al, "Hyperoxic-induced Hypercapnea in Stable Chronic Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1987, 144, pages526-530 (abstract available by link)
12. Chien, et al, "Uncontrolled Oxygen Administration and Respiratory Failure in Acute Asthma," Chest, March 2000, Volume 117, Issue 3, pages728-733 (abstract available by link, or pdf here)
13. Caruana-Montaldo, et al, "The Control of Breathing in Clinical Practice," January 2000, 117/1, pages 205-225 (Article available by link)
14. Dunn, et al, "Oxygen-Induced Hypercarbia in Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1991, 144, pages 526-530
15. Gosselink, R, H, Stam editors, Lung Function Testing, 2000 chapter 3, "Control of Breathing," , page 51 (chapter 5 provided for viewing only, supports Campbell)
16. Rudolf, et al, "(Hypothesis) Hypercapnea During Oxygen Therapy in Acute Exacerbation of Chronic Respiratory Failure," Lancet, September 3, 1977, pages 4483-486 (Abstract available by link, prescription needed to view article)
17. Stradling, J.R, "(Editorial) Hypercapnia during oxygen therapy in airways obstruction: a reappraisal," Thorax, December 1986, 41(12) pages 897-90202 (have to subscribe to veiw article)
18. Siafakas, N. M, editor, Mitrouska, I, N. Tzanakis, N.M. Siafakas, Management of Chronic Obstructive Pulmonary Disease, Chapter 18,  "Oxygen Therapy in Chronic Obstructive Pulmonary Disease," 2006, pages 302-308
19. Crossley, et al, "Influence of inspired oxygen concentration on deadspace, respiratory drive, and paCO2 in intubated patients with chronic obstructive pulmonary disease," Critical Care Medicine, 1997, volume 25, Number 9, pages 1522-1526 (abstract available by link)
20. Plantt, et al, "One year prevalence study of respiratory acidosis in acute exacerbations of COPD:  implications for the provision of non-invasive ventilation and O2 administration," Thorax, 2000, 55, pages 550-554 (full pdf available by link, for abstract click here).
21. Molfino, et al, "respiratory arrest in Near-Fatal Asthma," New England Journal of Medicine, 1991, 324: pages 285-288 (abstract available by link,  another abstract available here or full pdf available here)  Correspondence to this article from pages 205-206 here.
22. McFadden, "(Editorial) Fatal and Near Fatal Asthma," New England Journal of Medicine, 1991, 324: pages 409-411
23. Burnell, et al, "(Case Report) Extreme Obesity Associated with Alveolar Hypoventilation- A Pickwickian Syndrome," , American Journal of Medicine, 1956, 21:811-818 (abstract available by link)
24. Wagner, et al, "Ventilation-perfusion inequality in chronic obstructive pulmonary disease," The Journal of Clinical investigations, February 1977, Volume 59, pages 203-216 (full article available by link)
25. Dick, et al, "O2-Induced changes in Ventilation and Ventilatory Drive in COPD," American Journal of Critical Care Medicine, 1997, Volume 115, pages 609-614 (abstract available by link)
26. Gasparini, et al, "Inter-Individual Variability of the Response to Oxygen Administration in Hypercapneic Patients," European Journal of Respiratory Disease,  1986, 69 (suppl 146) 427-443 (no abstract or pdf availaable)
27. Schiavi, "Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease," Clinical Pulmonary Medicine, May 1998
28. Gomersall, Charles D, et al, "Oxygen therapy for hypercapnic patients with chronic obstructive pulmonary disease and acute respiratory failure: A randomized, controlled pilot study," Critical Care Medicine, January 2002, 1: 113-116 (abstract available by link)
29. Simpson, Stephen Q, "(Editorial) Oxygen-induced acute hypercapnia in chronic obstructive pulmonary disease: What's the problem?" Critical Care Medicine, January 2002, 1, page 258
30. Day, Rene A, Beverly Williams, Brunner and Suddarth's Textbook of Canadian Medical-Surgical Nursing, 2009, page 654
31. French, William A, "The Hypoxic Drive Theory Revisited," RT:  For Decision Makers in Respiratory Care, " February/ March, 2000
32. "Hypoxic Drive Theory: A Myth -- the why and how," Myparamedicblog.wordpress.com, 2009, http://paramedicblog.wordpress.com/2009/11/19/hypoxic-drive-theory-myth-the-why-and-how/
33. Siobal, Mark, "Hypoxic Drive in Chronic Obstructive Lung Disease: Is the fear of oxygen therapy based on fact or myth," UCSF San Fransisco General Hospital," power point presentation: PPT
34.  Beachey, Will, "Breathing Control in Chronic Hypercapnia," RT:  For Decision Makers in Respiratory Care, " June/ July, 2000
35. "Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients prehospital setting: randomized controlled trial," British Medical Journal, 2010, page 341, C5462
36. Correspondence (Aubier and Stradling regarding study cited in #8 above), American Review of Respiratory Disease, Oct. 16, 1986
37. Aubier, et al, "Central Respiratory Drive in Acute Respiratory Failure of Patients with Chronic Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1980, Volume 122, pages 191-99
38. Grief, Robert, et al, "Supplemental perioperative oxygen to reduce the incidence of surgical wound infection," The New England Journal of Medicine, Jan. 20, 2000, volume 342, no. 3
39. Jonnson K, et al, "Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients," Ann Surg, Nov. 1991, 214 (5), pages 605-13
40. La Van, FB, TK Hunt, "Oxygen and wound healing," Clin Plast Surg, July, 1990, 17 (3), pages 463-72
41. Bartells, Matthew N., John M. Gonzales, Woojin Kim, Ronald E. De Meersman, "Oxygen Supplementation and Cardiac-Autonomic Modulation in COPD, Chest, 2000, 118, pages 691-6
42. Noriaki, et al, "the relationship between chronic hypoxemia and activation of the tumor necrosis factor-x- system in Patients with Chronic Obstructive Pulmonary Disease, American Journal of Respiratory and Critical Care Medicine, April, 2000, Vol. 161, Number 4, pages 1179-1184
43. Mannix, ET, F. Manifredi, MO Farb er, "Elevated O2 cost of ventilation contributes to tissue wasting in COPD," Chest, March, 1999, volume 115, no. 3, pages 708-13
44. Macnee, Skwarski, "The pathogenisis of peripheral edema in Chronic Obstructive Pulmonary Disease," Clinical Pulmonary Medicine, Nov., 1997
45. "Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema.  Report of the Medical Research Council Working Party, Lancet, 1981, 1(8222), pages 681-6
46. Plywaczewski, et al, "Incidence of nocturnal desaturation while breathing oxygen in COPD patients undergoing long-term oxygen therapy," Chest, 2000, 117, pages 679-83
47. Burnell, et al, "(Case Report) Extreme obesity associated with aleolar hypoventilation -- a pickwickian syndrome," American Journal of Medicine, 1956, 21, pages 811-18
48. Steven M., Scharf, Michael R. Pinsky, Sheldon Magder, ed., "Respiratory-circulatory interactions in health and disease," 2005, New York, pages 656-658.  This provides a great review of all the evidence that disproves the hypoxic drive theory up to this date.  Great read for those interested. 
49. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24
50. Moulton, Chris, David W. Yates, "Lecture notes:  Emergency Medicine," 3rd ed., 2006, pages 215-16
51. Savi, Augusto, et al, "Influence of FiO2 During Noninvasive Ventilation in Patients with COPD," Respiratory Care, March, 2014, Volume 59, Number 3, pages 383-387
52. Young

Note:  Various individuals contributed to this list, most notably Jeffrey Whitnack and Dana Oachs. 

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COPD-CO2 retainers: How should they be managed?

The evidence suggests that supplemental oxygen may increase CO2 levels in some COPD patients, particularly CO2 retainers.  While rare, it is still something that should weigh on the minds of medical professionals.

Based on this evidence, Schmidt and Hall recommended COPD-CO2 retainers be maintained on as little oxygen as possible to maintain an adequate oxygen saturation, or an SpO2 of 88-92%.  Many modern textbooks, including the Textbook of Canadian Medical-Surgical Nursing, support this view. (1)(2)

On the other hand, Schmidt and Hall also remind us that oxygen is essential to survival.  Oxygenation at or below critical levels, such as a PO2 of 40 and SPO2 of 70, this increases the risk of an anoxic brain injury that may cause life altering changes, including death.

For this reason, they recommend COPD-CO2 retainers be monitored and treated based on clinical assessment and work of breathing "rather than by arbitrary laboratory values."

Likewise, Chris Moulton and David W. Yates in their 2006 book "Lecture notes:  Emergency Medicine" recommend setting a goal "to raise the PaO2 above 50 mmHg without worsening the acidosis."  (17)

Savi et al, in 2014, reported that, while "the PaCO2 commonly rises somewhat when a patient with COPD receives supplemental oxygen... carbon dioxide narcosis due to oxygen therapy is uncommon, and patients should not be kept hypoxemic for fear that oxygen therapy could aggravate carbon dioxide." (4, page 385)

Moreover, the report notes: "This expected rise (in PaCO2) should not be specifically treated unless it is excessive, resulting in a trend toward acute respiratory acidosis on serial arterial blood gas analysis, with central nervous system or cardiovascular side effects." (4, pages 385-386)

They also reiterate the obvious: "Carbon dioxide narcosis may occur with excessive FiO2, but is much less likely with low-flow, controlled oxygen therapy." (4, page 386)

Generally, if a COPD-CO2 retainers lose their drive to breathe, it's going to occur whether in the presence of oxygen or not.  Therefore, it is essential to closely monitor oxygenation levels and adjust them accordingly.

Although, should the patient's drive to breathe become tapped out, with CO2 levels rising to critical levels, the best treatment option may be to support ventilations with positive pressure breaths by noninvasive positive pressure ventilation or mechenical ventilation.

References:

1. Schmidt, Greggory A., Jesse B. Hall M.D "Oxygen Therapy and Hypoxic Drive to Breath: Is There Danger in the patient with COPD?" Critical Care Digest, 1989, 8, pages 52-53
2. Day, Rene A, Beverly Williams, Brunner and Suddarth's Textbook of Canadian Medical-Surgical Nursing, 2009, page 654. Source #8 above also supports the veiw that the hypoxic drive is not responsible for hypercarbia in COPD patients given too much oxygen, and likewise supports the Haldane and V/Q mismatching theories (Cooper, op cit, page 24)
3. Moulton, Chris, David W. Yates, "Lecture notes:  Emergency Medicine," 3rd ed., 2006, pages 215-16
4. Savi, Augusto, et al, "Influence of FiO2 During Noninvasive Ventilation in Patients with COPD," Respiratory Care, March, 2014, Volume 59, Number 3, pages 383-387

What evidence proves the hypoxic drive theory wrong?

Ironically, and surprisingly, there has never been a real scientific study done to prove the hypoxic drive theory.  On the contrary, many studies have shown the theory to be nothing more than a myth.

For instance, in 1989 Greggory A. Schmidt M.D. and Jesse B. Hall M.D. wrote an article, "Oxygen Therapy and Hypoxic Drive to Breath:  Is There Danger in the patient with COPD?" that was published in Critical Care Digest questioning the popular hypoxic drive theory.  (1)

Schmidt and Hall reported that little science was used in coming up with this theory.  No COPD patients were given oxygen and had their ventilations simultaneously measured.  (1)

In fact, they report that in one study COPD patients were given oxygen and they found that "the rise in CO2 could not be accounted for by hypoventilation."

Likewise, a follow up study determined that supplemental oxygen to COPD patients caused decreased ventilation in some, unchanged ventilation in some, and normal ventilation in some. They wrote that "The commonest pattern was of early hypoventilation followed by a return to baseline.

Schmidt and Hall "attributed the rise in CO2 to an increase in the dead space to tidal volume ratio (also referred to as ventilation/ perfusion mismatching) consequent to oxygen therapy, though the mechanism for this change is unclear."

Abier et al in 1980 showed that 20 COPD patients in acute respiratory failure receiving 5lpm oxygen for 30 minutes showed a 14% reduction in minute ventilation with only a small rise in PaCO2, despite a large rise in PaO2.  They concluded that there was no correlation with the rise in PaCO2 and the fall in ventilation. (2)

Abier et al in 1980 also studied the effects of 100% oxygen on minute ventilation in COPD patients presenting with acute respiratory failure.  The concluded, once again, that despite the slight rise in CO2 and drop in minute ventilation, there was no correlation with the rise in PaCO2 and the fall in ventilation. (3)

In a 2000 study by Robinson et al, 22 COPD patients were given 100% oxygen and ventilations fell by an average of 20% for those who were CO2 retainers, yet the cause was determined to be due to ventilation/ perfusion mismatching, "not just a failure of ventilatory response to the increase in PaCO2."  (4)

A 2007 by Dick et al showed that oxygen induced hypercarbia was not caused by knocking out the drive to breathe.  In stable patients with COPD given 100% oxygen over a period of 15 minutes, oxygen saturations increased by about 7.6% and PaCO2 rose by about 6.6 mmgH, while minute ventilation was unchanged in all those studied. (5)

A 2014 study by Savi et all concluded the following:

Our results support the hypothesis that increasing the FiO2 in CO2-retaining COPD subjects on NIV does not cause any clinically important change in CO2 retention.  (6)

The also note:

The PaCO2 commonly rises somewhat when a patient with COPD receives supplemental oxygen, but carbon dioxide narcosis due to oxygen therapy is uncommon, and patients should not be kept hypoxemic for fear that oxygen therpay could aggravate carbon dioxide retention. The increase in CO2 is probably due to a change in dead space or shift of the hemoglobin-oxygen binding curve, rather than decreased respiratory drive.  The expected rise should not be specifically treated unless it is excessive, resulting in a trend toward acute respiratory acidosis on serial arterial blood gas analysis, with cenetral nervous system or cardiovascular side effects.  Carbon dioxide narcosis may occur with excessive FiO2, but is much less likely with low flow, controlled oxygen therapy.(6)

Despite all these studies, the hypoxic drive theory continues to be the gold standard theory regarding treatment of patients with COPD.  However, enough evidence now exists to support that supplemental oxygen is not as detrimental to COPD-CO2 retainers as once suspected.

References:

1. Schmidt, Greggory A., Jesse B. Hall M.D "Oxygen Therapy and Hypoxic Drive to Breath:  Is There Danger in the patient with COPD?" Critical Care Digest, 1989, 8, pages 52-53
2. Aubier M., Murciano D, Fournier M, Milic-Emili J, Pariente R, Derenne JP, "Central respiratory drive in acute respiratory failure of patients with chronic obstructive pulmonary disease, American Review of Respiratory Disease, 1980 volume 122, number 2, pages 191-199
3. Aubier M, Murciano D, Milic-Emil J, Touaty E, Daghfous J, Pariente R, Derenne JP, "Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure," American Review of Respiratory Disorders, 1980, volume 122, number 5, pages 747-754
4. Robinson, Tracey D., et al, "The Role of Hypoventilation and Ventilation-Perfusion Redistribution in Oxygen-induced Hypercapnia during Acute Exacerbations of Chronic Obstructive Pulmonary Disease," American Journal of Respiratory adn Critical Care Medicine, 2000, volume 161, pages 1524-1529
5. Dick, C.R., et al, "O2-induced change in ventilation and ventilatory drive in COPD," American Journal of Respiratory and Critical Care Medicine," volume 155, no. 2, Feb., 1997, pages 609-614
6. Savi, Augusto, et al, "Influence of FiO2 During Noninvasive Ventilation in Patients with COPD," Respiratory Care, March, 2014, Volume 59, Number 3, pages 383-387

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Hypoxic Drive Theory: Here is your evidence

The hypoxic drive theory was established in 1960.  Since then many studies have shed doubt on this theory, in favor of the Haldane Effect and ventilation-perfusion mismatching.  Listed here is all the evidence that either proves or disproves these theories.

1. Hoyt, John. W., "Debunking the Myths of Chronic Obstructive Pulmonary Disease", Critical Care Medicine, 1997, Volume 25, Number 9, pages 1450-1451 (you'll have to obtain a prescription to view article)
2. Campbell, E.J.M, "Respiratory Failure,"  The British Medical Journal,  June 1965, 1451-1460 (article provided by link)
3. Arnottt, W.M, "Respiratory Failure,"  Lancet,  January 1960, Volume 25, Issue 7114, pages 1-7 (you'll have to subscribe to view article)
4. Campbell, E.J.M, "The J. Burns Amberson Lecture - Management of Acute Respiratory Failure in Chronic Bronchitis and Emphysema," The Journal of Occupational and Environmental Medicine, June 1968,  Volume 10, issue 6, pages 329-332  (You'll have to become a member to veiw article)
5. Campbell, E.J.M, "The J. Burns Amberson Lecture - Management of Acute Respiratory Failure in Chronic Bronchitis and Emphysema," American Review of Respiratory Diseases, October 1967, Volume 96, Issue 4 (no link available)
6. Scano,G, A. Spinelli,  R. Duranti, M. Gorini, F. Gigliott i, P. Goti, J. Milic-Emili, "Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia," Europe Respiratory Journal, 1995, Volume 8, pages 78-85 (full pdf provided by link)
7. Robinson, Tracy D  David B. Freiberg, Jeff A. Regnis and Iven H. Young, "The Role of Hypoventilation and Ventilation-Perfusion Redistribution in Oxygen-induced Hypercapnea during Acute Exacerbation of Chronic Obstructive Pulmonary Disease," American Journal of Respiratory and Critical Care Medicine, 2000, volume 161, pages 1524-1529 (full pdf provided by link)
8. Aubier, M, et al, "Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure", American Review of Respiratory Diseases,  1980, Volume 122, pages 747-754 (abstract available by link)
9. Hanson, et all, "Causes of hypercapnia with Oxygen Therapy in patients with Chronic Obstructive Pulmonary Disease," Critical Care medicine, 1996, volume 24, pages 23-28 (abstract available by link)
10. Lazic, D, et al, "The influence of oxygen therapy on the hypercapnia in patients with chronic obstructive pulmonary disease,"  July 2008, Volume 65, Issue 7, pages 521-524 (abstract available by link)
11. Sassoon, C.S., et al, "Hyperoxic-induced Hypercapnea in Stable Chronic Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1987, 144, pages526-530 (abstract available by link)
12. Chien, et al, "Uncontrolled Oxygen Administration and Respiratory Failure in Acute Asthma," Chest, March 2000, Volume 117, Issue 3, pages728-733 (abstract available by link, or pdf here)
13. Caruana-Montaldo, et al, "The Control of Breathing in Clinical Practice," January 2000, 117/1, pages 205-225 (Article available by link)
14. Dunn, et al, "Oxygen-Induced Hypercarbia in Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1991, 144, pages 526-530
15. Gosselink, R, H, Stam editors, Lung Function Testing, 2000 chapter 3, "Control of Breathing," , page 51 (chapter 5 provided for viewing only, supports Campbell)
16. Rudolf, et al, "(Hypothesis) Hypercapnea During Oxygen Therapy in Acute Exacerbation of Chronic Respiratory Failure," Lancet, September 3, 1977, pages 4483-486 (Abstract available by link, prescription needed to view article)
17. Stradling, J.R, "(Editorial) Hypercapnia during oxygen therapy in airways obstruction: a reappraisal," Thorax, December 1986, 41(12) pages 897-90202 (have to subscribe to veiw article)
18. Siafakas, N. M, editor, Mitrouska, I, N. Tzanakis, N.M. Siafakas, Management of Chronic Obstructive Pulmonary Disease, Chapter 18,  "Oxygen Therapy in Chronic Obstructive Pulmonary Disease," 2006, pages 302-308
19. Crossley, et al, "Influence of inspired oxygen concentration on deadspace, respiratory drive, and paCO2 in intubated patients with chronic obstructive pulmonary disease," Critical Care Medicine, 1997, volume 25, Number 9, pages 1522-1526 (abstract available by link)
20. Plantt, et al, "One year prevalence study of respiratory acidosis in acute exacerbations of COPD:  implications for the provision of non-invasive ventilation and O2 administration," Thorax, 2000, 55, pages 550-554 (full pdf available by link, for abstract click here).
21. Molfino, et al, "respiratory arrest in Near-Fatal Asthma," New England Journal of Medicine, 1991, 324: pages 285-288 (abstract available by link,  another abstract available here or full pdf available here)  Correspondence to this article from pages 205-206 here.
22. McFadden, "(Editorial) Fatal and Near Fatal Asthma," New England Journal of Medicine, 1991, 324: pages 409-411
23. Burnell, et al, "(Case Report) Extreme Obesity Associated with Alveolar Hypoventilation- A Pickwickian Syndrome," , American Journal of Medicine, 1956, 21:811-818 (abstract available by link)
24. Wagner, et al, "Ventilation-perfusion inequality in chronic obstructive pulmonary disease," The Journal of Clinical investigations, February 1977, Volume 59, pages 203-216 (full article available by link)
25. Dick, et al, "O2-Induced changes in Ventilation and Ventilatory Drive in COPD," American Journal of Critical Care Medicine, 1997, Volume 115, pages 609-614 (abstract available by link)
26. Gasparini, et al, "Inter-Individual Variability of the Response to Oxygen Administration in Hypercapneic Patients," European Journal of Respiratory Disease,  1986, 69 (suppl 146) 427-443 (no abstract or pdf availaable)
27. Schiavi, "Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease," Clinical Pulmonary Medicine, May 1998
28. Gomersall, Charles D, et al, "Oxygen therapy for hypercapnic patients with chronic obstructive pulmonary disease and acute respiratory failure: A randomized, controlled pilot study," Critical Care Medicine, January 2002, 1: 113-116 (abstract available by link)
29. Simpson, Stephen Q, "(Editorial) Oxygen-induced acute hypercapnia in chronic obstructive pulmonary disease: What's the problem?" Critical Care Medicine, January 2002, 1, page 258
30. Day, Rene A, Beverly Williams, Brunner and Suddarth's Textbook of Canadian Medical-Surgical Nursing, 2009, page 654
31. French, William A, "The Hypoxic Drive Theory Revisited," RT:  For Decision Makers in Respiratory Care, " February/ March, 2000
32. "Hypoxic Drive Theory: A Myth -- the why and how," Myparamedicblog.wordpress.com, 2009, http://paramedicblog.wordpress.com/2009/11/19/hypoxic-drive-theory-myth-the-why-and-how/
33. Siobal, Mark, "Hypoxic Drive in Chronic Obstructive Lung Disease: Is the fear of oxygen therapy based on fact or myth," UCSF San Fransisco General Hospital," power point presentation: PPT
34.  Beachey, Will, "Breathing Control in Chronic Hypercapnia," RT:  For Decision Makers in Respiratory Care, " June/ July, 2000
35. "Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients prehospital setting: randomized controlled trial," British Medical Journal, 2010, page 341, C5462
36. Correspondence (Aubier and Stradling regarding study cited in #8 above), American Review of Respiratory Disease, Oct. 16, 1986
37. Aubier, et al, "Central Respiratory Drive in Acute Respiratory Failure of Patients with Chronic Obstructive Pulmonary Disease," American Review of Respiratory Disease, 1980, Volume 122, pages 191-99
38. Grief, Robert, et al, "Supplemental perioperative oxygen to reduce the incidence of surgical wound infection," The New England Journal of Medicine, Jan. 20, 2000, volume 342, no. 3
39. Jonnson K, et al, "Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients," Ann Surg, Nov. 1991, 214 (5), pages 605-13
40. La Van, FB, TK Hunt, "Oxygen and wound healing," Clin Plast Surg, July, 1990, 17 (3), pages 463-72
41. Bartells, Matthew N., John M. Gonzales, Woojin Kim, Ronald E. De Meersman, "Oxygen Supplementation and Cardiac-Autonomic Modulation in COPD, Chest, 2000, 118, pages 691-6
42. Noriaki, et al, "the relationship between chronic hypoxemia and activation of the tumor necrosis factor-x- system in Patients with Chronic Obstructive Pulmonary Disease, American Journal of Respiratory and Critical Care Medicine, April, 2000, Vol. 161, Number 4, pages 1179-1184
43. Mannix, ET, F. Manifredi, MO Farb er, "Elevated O2 cost of ventilation contributes to tissue wasting in COPD," Chest, March, 1999, volume 115, no. 3, pages 708-13
44. Macnee, Skwarski, "The pathogenisis of peripheral edema in Chronic Obstructive Pulmonary Disease," Clinical Pulmonary Medicine, Nov., 1997
45. "Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema.  Report of the Medical Research Council Working Party, Lancet, 1981, 1(8222), pages 681-6
46. Plywaczewski, et al, "Incidence of nocturnal desaturation while breathing oxygen in COPD patients undergoing long-term oxygen therapy," Chest, 2000, 117, pages 679-83
47. Burnell, et al, "(Case Report) Extreme obesity associated with aleolar hypoventilation -- a pickwickian syndrome," American Journal of Medicine, 1956, 21, pages 811-18
48. Steven M., Scharf, Michael R. Pinsky, Sheldon Magder, ed., "Respiratory-circulatory interactions in health and disease," 2005, New York, pages 656-658.  This provides a great review of all the evidence that disproves the hypoxic drive theory up to this date.  Great read for those interested. 
49. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24
50. Moulton, Chris, David W. Yates, "Lecture notes:  Emergency Medicine," 3rd ed., 2006, pages 215-16
51. Savi, Augusto, et al, "Influence of FiO2 During Noninvasive Ventilation in Patients with COPD," Respiratory Care, March, 2014, Volume 59, Number 3, pages 383-387

Various individuals contributed to this list, including Jeff Whitnack, Dana Oachs and even Dr. Google.