Debunking The Hypoxic Drive Theoery: The Truth About The Affects Of Oxygen On COPD

Originally published January 6, 2016.

I was recently interviewed by Rebecca Knutsen, a staff writer working for Advance for Respiratory Therapists.  She said she was working on a brief article that explores when to administer oxygen to hypoxemic patients with chronic obstructive pulmonary disorder.

The following are her questions followed by my answers.  

1.  Please describe hypoxic and hypercapnic drive:

Hypercapnic Drive: The central chemoreceptors on the medulla monitors the partial pressure of arterial CO2 (PaCO2). A normal PaCO2 level is 35-45 mmHG. When PaCO2 is high (>45 mmHg) a signal is sent to the medulla oblongata at the base of the brain to speed up breathing in order to blow off excess PaCO2. When PaCO2 levels are low (<35 mmHg) a signal is sent to the medulla oblongata at the base of the brain to decrease breathing in order to allow PaCO2 to accumulate. This is the main drive to breathe.

Hypoxic Drive: The peripheral chemoreceptors located at the bifurcations of the aortic arteries and the aortic arch monitor partial pressure of arterial oxygen (PaO2). This drive only becomes active when the PaO2 is less than 60 mmHg. This hypoxic response is far slower than signals sent by central chemoreceptors, and therefore the hypoxic drive has only a minor role in breathing.

2.  What tests does your organization use and what do they measure?

ABG: This is a blood draw from the radial, brachial or femoral artery that measures PaO2, PaCO2 and arterial pH.

Pulse oximeter: It’s a noninvasive device that slips over a finger, toe, or ear lobe. It determines the SpO2, which is an estimation of hemoglobin in the blood that are saturated with oxygen. This percentage can be used to estimate PO2. Generally, an SpO2 of 90 indicates the PO2 is about 60.

End Tidal CO2 Monitor: It’s a noninvasive device that can be connected to special nasal cannulas or endotracheal tubes. It determines the ETCO2, which is an estimation of the amount of CO2 exhaled. This percentage can be used to estimate PaCO2. In a person with healthy lungs, the EtCO2 is about 2-5 mmHg less than PaCO2.

3.  When is it recommended to administer oxygen to hypoxemic patients with COPD? 

Most medical experts now recommend administering the lowest amount of oxygen needed to maintain an SpO2 of 88-92%, or as directed by a physician.

4.  Why is hypoxic drive so controversial? 

The hypoxic drive is not controversial, it’s the hypoxic drive theory that’s controversial. To understand why it is so controversial it’s important to understand a little of the history of it. 

Back in the late 1940s and 50s, when oxygen first started to be used for patients with chronic obstructive pulmonary disease, it was observed that some of them became lethargic or lapsed into a coma after receiving high levels of oxygen.

Initial studies showed a decrease in ventilation in 26 of 35 patients with COPD given oxygen therapy, with a rise in CO2 and a fall in pH. A further study showed that stopping and starting oxygen therapy led to a fall and rise in CO2 respectively.

The concern became so great that in the 1950s a study was performed that ultimately lead Dr. EJM Campbell to give a lecture to pulmonologists in 1960 about the dangers of giving too much oxygen to COPD patients. It was this lecture that forever linked hypoxic drive with COPD, and gave birth to the hypoxic drive theory.

What is the hypoxic drive theory? The hypoxic drive theory states that some patients with COPD develop chronically elevated arterial CO2 levels, and so their hypercapnic drive becomes blunted, so they use their hypoxic drive to breathe instead. 

Therefore, giving high amounts of oxygen to these patients may blunt the hypoxic drive as well, thus completely blunting their drive to breathe. This may cause PaCO2 levels to rise to critical levels, resulting in narcosis and possible death. For this reason, COPD patients with suspected CO2 retention are limited to 2-3 lpm by nasal cannula, or 40% by venturi mask.

What’s wrong with this theory? The problem with this theory is that it’s a myth concocted on incomplete evidence. The study cited by Campbell included only four patients with COPD, and later studies failed to validate this theory. Yet it has continued to be a gold standard theory when dealing with COPD patients.

Under the guise of this theory, many patients who desperately need higher levels of supplemental oxygen to survive are deprived of it. Plus, as many respiratory therapists, nurses, and physicians have observed, when these patients are given the oxygen they need, rarely does this lead to complications.

When these patients go into respiratory failure, it’s going to happen regardless of how much oxygen they receive. And while higher levels of oxygen may cause CO2 to rise, it’s not due to oxygen blunting their hypoxic drive, which the hypoxic drive theory postulates, it’s due to either the Haldane effect or V/Q mismatching.

The Haldane effect: This was postulated by John Haldane, a pioneer in oxygen therapy. He proved that the Deoxygenation of arterial blood increases its ability to carry carbon dioxide. In other words, as fewer oxygen molecules are attaching to hemoglobin, more CO2 are attaching to hemoglobin.

Oxygen is more soluble in water and therefore has a higher affinity for hemoglobin, so if you increase oxygen in the blood, CO2 molecules are forced off hemoglobin and oxygen takes its place. This causes an increase PaCO2.

Add into this the fact that patients with COPD have limited reserves to increase their respiratory rate to blow off excessive CO2. Also add into this that many COPD patients already have an elevated hemoglobin levels, and so these patients are going to have lots of extra arterial CO2 molecules.

Out of respect for this theory, COPD patients should be maintained on the lowest level of oxygen required to maintain an oxygen saturation between 88-92%.

The Haldane effect was proven by a study described in 1996 in Critical Care Medicine, "Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease."

V/Q Mismatching: The air passages of COPD lungs become narrow due to remodeling, increased mucus production, and bronchospasm. Where this occurs the lungs are perfused but poorly ventilated. CO2 returning to these areas remain in arterial bloodstream, thus causing PaCO2 to rise.

Add into this that when alveoli are poorly ventilated the vasculature around them will constrict so oxygen goes to alveoli that are ventilated well. This is how these patients make efficient use of their diseased lungs.

Now add 100% oxygen and you screw up this naturally occurring phenomenon. Now the vasculature around that non-ventilating alveoli dilates, and this causes blood to be sent to the non functioning alveoli. Now you have even greater V/Q mismatching and more CO2 that doesn't get out of arterial blood. The end result is an increase in PaCO2.

If a patient with COPD is going to fail this is going to be the reason. If they need oxygen you give it to them, because doing otherwise will further compromise them. If they go into respiratory failure, you treat it with either noninvasive ventilation or mechanical ventilation.

V/Q Mismatching was proven via a study completed in 1980 and reported in American Review of Respiratory Disorders, "Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure,"

Conclusion: Modern evidence suggests that the hypercapnic drive is never completely blunted, and therefore even COPD patients with chronically elevated PaCO2 will not stop breathing in the presence of higher oxygen levels. There is such a thing as the hypoxic drive, but the hypoxic drive theory is a myth.

To read the final published version of my interview read "Oxygen and COPD: Debunking the hypoxic drive theory."

Further References:

• 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)
• Campbell, E.J.M, "Respiratory Failure," The British Medical Journal, June 1965, 1451-1460 (article provided by link)
• 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

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Medicine based on consensus, not science

Medicine is an art based on science.  Much of medicine is based on flawed science. Or, as Richard Feynman once said, science is the belief in the ignorance of experts. 

Much of science is not even science: it's consensus.  It's basically the world's leading experts voting on what they think is fact, rather than waiting for the evidence to reveal the truth.  It's creating theories and voting on which ones should be in the forefront of our minds.  So when deciding on what to believe, we must never forget that "science is about evidence, not consensus."  

It is so hard in the medical profession to separate consensus from science.  In fact, one of the things that fascinated me most about the medical profession is it's loose relationship with science.  In fact, early on in my studies I learned that medicine is loosely based on science, and more so based on consensus, which is not science at all. 

Look at the hypoxic drive theory.  It was based on a study of four COPD patients, and became a gold standard based on a presentation by EJM Campbell to pulmonologists in 1960 about the results of a study based on only four COPD patients.  So basically the hypoxic drive theory, or hoax as I like to call it, was based on a consensus of experts, and had nothing to do with science. 

So basically physician's under oxygenated their patients for over 70 years, and many still do, based on a consensus.

Look at all the breathing treatments we give based on a consensus that albuterol cures every lung ailment you can think of. Our new healthcare law insists that a lung patient must be sick enough to need 3 breathing treatments for reimbursement criteria to be met. This includes COPD, CHF, Asthma, Pneumonia, etc. So 3 breathing treatments are ordered on all these patients, and it's assumed they are needed. What's wrong with this picture? It certainly has nothing to do with science. 

Other examples of consensus over science include:

• BiPAP pushes fluid out of lungs
• The earth is flat
• Man made global warming
• The continents cannot drift
• Stress causes ulcers
• Asthma is one of the seven pychosomatic disorders
• Phlogiston was necessary for combustion to take place

All of these theories are, or were, so widespread, and so well accepted, that they caused people to focus on treatments and therapies that probably did more harm than good (like under oxygenating COPD patients). As in the case with asthma, consensus caused experts to focus so much on a dead end path that it prevented the advancement of knowledge to the detriment of those who suffered from it (i.e., experts focused on treating asthma with psychosomatic medicines when they should have been looking treatments for inflammation and bronchospasm). 

So when you're thinking about whether or not you want to believe something is true, consider the evidence and not the consensus.  The fact that a majority of people believe something to be true does not make it so. In other words, it's okay to oppose the majority opinion, so long as the evidence is on your side. 

When a doctor orders something, it's your job as a therapist, or a nurse, to do as you are instructed.  For instance, if a doctor orders you to give a breathing treatment, then you must give it regardless that you know it is a waste of time.  As the old saying goes, "It can't hurt." 

Still, it really does hurt, because you're putting medicine into someone that doesn't need to be there, and, even though we can't always see them, all medicines come with side effects.  And then there's also the side effect of second hand ventolin on those who are doling it out all day long.

However, when a doctor orders for you to maintain an SpO2 in the low 80s because of the hypoxic drive myth, it's time to rise up and challenge the consensus for the benefit of the patient, because, Lord knows, oxygen is beneficial to the living heart. Thankfully the hypoxic drive consensus/hoax is slowly fading, and COPD patients are actually being oxygenated these days. 

Further reading.

• Rush Limbaugh: Peer Reviewed Science Exposed as Fraud
• NY TIMES:  Many Psychology Findings Not As Strong As Claimed, Study Says
• Wall Street Journal: Science is About Evidence, Not Consensus
• RT Cave: Second Hand Albuterol

Interview: Debunking the Hypoxic Drive Theory

The following post was originally published at Advance for Respiratory Care and Sleep Medicine, and written by Rebecca Mayer Knutsen on January 12, 2015.

Oxygen and COPD: Debunking the hypoxic drive theory

In patients with chronic obstructive pulmonary disorder (COPD), inflammatory changes impact their ability to breathe properly. Patients will eventually retain carbon dioxide (CO2) as their efforts to maintain normal CO2 levels proves difficult. Experts have long debated whether chronically elevated carbon dioxide levels affect how a patient handles oxygen. As a result, a theory developed that administering oxygen obliterated the drive to breathe.

The problem with the Hypoxic Drive Theory is that it's a myth concocted on incomplete evidence and often elicits a controversial response, according to John Bottrell, RT, Spectrum Health Ludington Hospital, and COPD/asthma expert for healthcentral.com.

For hypoxemic patients with COPD, most medical experts now recommend administering the lowest amount of oxygen needed to maintain SpO2 of 88% to 92%, according to Bottrell.

The Controversy of Hypoxic Drive Theory

In hypoxic drive, Bottrell told ADVANCE, the peripheral chemoreceptors located at the bifurcations of the aortic arteries and the aortic arch monitor partial pressure of arterial oxygen (PaO2). This drive only becomes active when the PaO2 is less than 60 mmHg. "This hypoxic response is far slower than signals sent by central chemoreceptors, and therefore the hypoxic drive has only a minor role in breathing," he explained.

When patients with COPD need oxygen, healthcare practitioners should give it to them because doing otherwise will further compromise their health, Bottrell observed. "If the patient goes into respiratory failure, then he should be treated with either noninvasive ventilation or mechanical ventilation," he shared.

Spectrum Health Ludington Hospital tests include arterial blood gas (ABG) collection, pulse oximeter and end tidal CO2 monitor. End tidal CO2 monitor is a noninvasive device that can be connected to special nasal cannulas or endotracheal tubes. The test determines the ETCO2, which is an estimation of the amount of CO2 exhaled. This percentage can be used to estimate PaCO2. In a person with healthy lungs, the EtCO2 is about 2 to 5 mmHg less than PaCO2.

Historical Perspective on Hypoxic Drive Theory

Oxygen was first used for patients with COPD in the late 1940s and 1950s. Around that time, experts observed that some patients became lethargic or lapsed into a coma after receiving high levels of oxygen, Bottrell told ADVANCE. Initial studies showed a decrease in ventilation in 26 of 35 patients with COPD given oxygen therapy, with a rise in CO2and a fall in pH. A further study showed that stopping and starting oxygen therapy led to a fall and rise in CO2 respectively.

The concern became so great that a study was performed in the 1950s that ultimately led Dr. EJM Campbell to give a lecture to pulmonologists in 1960 about the dangers of giving too much oxygen to COPD patients. "It was this lecture that forever linked hypoxic drive with COPD, and gave birth to the hypoxic drive theory," explained Bottrell.

"The hypoxic drive theory states that some patients with COPD develop chronically elevated arterial CO2 levels, and as a result, their hypercapnic drive becomes blunted, causing them to use their hypoxic drive to breathe instead," Bottrell said. "Therefore, giving high amounts of oxygen to these patients may blunt the hypoxic drive as well, thus completely blunting their drive to breathe."

This occurrence may cause PaCO2 levels to rise to critical levels, resulting in narcosis and possible death. For this reason, COPD patients with suspected CO2 retention are limited to 2 to 3 lpm by nasal cannula, or 40% by venturi mask.

According to Bottrell, the study cited by Campbell included only four patients with COPD, and later studies failed to validate this theory. "Yet it has continued to be a gold standard theory when dealing with COPD patients," he observed.

"Under the guise of this theory, many patients who desperately need higher levels of supplemental oxygen to survive are deprived of it," Bottrell relayed. "Plus, as many respiratory therapists, nurses, and physicians have observed, when these patients are given the oxygen they need, rarely does this lead to complications."

Bottrell believes patients might go into respiratory failure regardless of how much oxygen they receive. "And while higher levels of oxygen may cause CO2 to rise, it's not due to oxygen blunting their hypoxic drive, which the hypoxic drive theory postulates, it's due to either the Haldane effect or V/Q mismatching," he said.

The Haldane effect was postulated by John Haldane, a pioneer in oxygen therapy. He proved that the deoxygenation of arterial blood increases its ability to carry carbon dioxide. "In other words, as fewer oxygen molecules are attaching to hemoglobin, more CO2 are attaching to hemoglobin," Bottrell said.

Oxygen is more soluble in water, and therefore, has a higher affinity for hemoglobin. "So if you increase oxygen in the blood, CO2 molecules are forced off hemoglobin and oxygen takes its place," Bottrell shared. "This causes an increase in PaCO2."

Out of respect for this theory, according to Bottrell, COPD patients should be maintained on the lowest level of oxygen required to maintain an oxygen saturation between 88% to 92%.

According to Bottrell, modern evidence suggests that the hypercapnic drive is never completely blunted, and therefore even COPD patients with chronically elevated PaCO2 will not stop breathing in the presence of higher oxygen levels. "There is such a thing as the hypoxic drive, but the hypoxic drive theory is a myth," he said.

Rebecca Mayer Knutsen is on staff at ADVANCE.

To view the complete interview, read my post "How does too much oxygen effect COPD?"

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

Alternatives to the hypoxic drive theory

Since 1960, several studies have demonstrated what really happens when CO2 retainers are exposed to supplemental oxygen.  The best explanation comes from John Haldane himself in what is now referred to as the Haldane Effect, and another process we refer to as ventilation/ perfusion (V/Q) mismatching.

1.  The Haldane effect:   This law was created by John Haldane, a pioneer of oxygen therapy.  He proved that as Deoxygenation of the blood increases its ability to carry carbon dioxide.  Thus, the less oxygen on hemoglobin, the more CO2 on hemoglobin.  CO2 attaches to unsaturated hemoglobin molecules. Oxygen is more soluble in water and therefore has a higher affinity for hemoglobin, so if you increase oxygen in the blood by supplemental oxygen, CO2 molecules are forced off hemoglobin and oxygen takes its place.  This causes an increase in CO2 in the blood, or an increased PaCO2.

Most people would simply increase their respiratory rate and blow off this CO2. Yet COPD retainers who are in respiratory distress may not have the capacity to increase their respiratory rate, so their respiratory rate remains the same.  This causes their PaCO2 to rise.

Now consider that this patient may have an elevated hemoglobin level after years of oxygen deprivation, and you're going to have lots of extra CO2 molecules roaming around the blood stream.  This may be on top the patients already elevated CO2 retention.

All these CO2 molecules are transported back to the lungs for ventilation to take place.  Yet because many alveoli are poorly ventilated (V/Q mismatching), and because the patients ability to increase ventilation is tapped out, PaCO2 levels will rise.

The Haldane effect was proven by a study described in 1996 in Critical Care Medicine, "Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease." (1)

2.  V/Q mismatching:  Consider that V = Ventilation and P = Perfusion.  So, generally this is Ventilation/ Perfusion mismatching.  It is caused by increased airway narrowing due to airway remodeling, bronchospasm, and increased sputum production.  Where this occurs, the lungs are perfused but poorly ventilated.  It means that in areas of the lungs where V/Q mismatching occurs do not allow CO2 to enter the lungs, and oxygen to enter.

When an alveoli is poorly ventilated the vasculature around it will constrict so oxygen goes to alveoli that are ventilated well.  This is how that patient's body has made efficient use of his diseased lungs.

Now add 100% oxygen and you screw up this naturally occurring phenomenon.  Now the vasculature around that non-ventilating alveoli dilates, and this causes blood to be sent to the non functioning alveoli.  Now you have even greater V/Q mismatching and more CO2 that doesn't get out of the blood.  The end result, therefore, is an increase in PaCO2.

This theory was proven via a study completed in 1980 and reported in American Review of Respiratory Disorders, "Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure," (2)

These two theories are far more viable than the hypoxic drive theory, and both have been proven by science.  Regardless, the hypoxic drive theory continues to be the gold standard theory.

References:

1. 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)  Source #3 above also indicates support for this theory (Caruano-Montaldo, ibid, page 218), and reference # 12 (Robinson, ibid, page 1527), and #13 (Dick, C.R., ibid)
2. 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) Source #3 above also indicates support for this theory (Caruano-Montaldo, ibid, page 218)

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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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How the hypoxic drive theory was born

While oxygen was discovered as early as the 18th century, it was not routinely used therapeutically until the early 21st century.  Still, it wasn't until the 1940s that physicains started realizing their were risks associated with its use, and 1960 when the hypoxic drive theory was born.

Oxygen was discovered in 1777 by Joseph Priestley. Despite its availability, it was not routinely used to treat medical conditions mainly because there was no convenient means of producing, storing, and delivering oxygen to patients.  Yet by the turn of the 21st century the first two of these obstacles were resolved, and it was up to John Haldane to resolve the third.

In 1922, Haldane wrote about his own research on oxygen in "The Therapeutic Administration of Oxygen."  During WWI he had developed a mask to conveniently deliver oxygen to soldiers suffering from pulmonary edema due to poison gas.  After the war he continued his experiments in hospitals.

Soon thereafter oxygen tanks became more and more common at the patient bedside, and oxygen was tried on patients with pulmonary edema and pneumonia, although sometimes for patients with cystic fibrosis, asthma, emphysema and chronic bronchitis.  (7)

Once oxygen was administered to COPD patients, it was soon realized that some of these patients became lethargic and lost their drive to breathe.  It was soon learned that it was the oxygen causing this because it caused their carbon dioxide (CO2) to rise.

In 1949 a case was documented where a man with emphysema "lapsed into a coma after receiving oxygen therapy but rapidly recovered after the oxygen was removed," according to Nicola Cooper, Kirsty Forrest, Paul Cramp in their 2006 textbook, "Essential guide to acute care."

The text also explains that "in 1954 a decrease in ventilation in 26 out of 35 patients with COPD given oxygen therapy, with a rise in PaCO2 and a fall in pH.  No patient with a normal baseline PO2 showed these changes.  In a further study it was showed that stopping and starting oxygen therapy led to a fall and rise of PaCO2, respectively."  (8)

The concern became so great that in the 1950s a study was performed that ultimately lead Dr. EJM Campbell to give a lecture to pulmonologists in 1960 about the dangers of giving too much oxygen to COPD patients.  It was this lecture that forever linked hypoxic drive with COPD, and gave birth to the hypoxic drive theory.  (9)

Yet instead of a scientific theory being treated as a scientific theory it was treated as scientific fact, and this began the accepted practice of keeping patients in much need of supplemental oxygen hypoxic.

The medical profession decided the hypoxic drive theory sounded good so it must be good. The Hypoxic Drive Theory thus became the law of COPD land. Any evidence to the contrary would be rejected.

Of interest here is that the study Campbell referred to in his lecture consisted of only four COPD patients. Regardless, the theory quickly gained acceptance by the medical community, and became the gold standard when taking care of patients with COPD

Since then a few studies have confirmed the theory, although many have shed doubt on the theory.  Regardless, due to Campbell's presentation, the theory had already stuck in the minds of physicians and medical professors.  They had now become dogmatic to the theory, and closed minded to any evidence to the contrary.   (10)

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. Wilkins, Robert L, James K. Stoller, ed. "Egan's Fundamentals of Respiratory Care," 2009, pages 309-310
3. Caruana-Montaldo, Brendan, et al, "The Control of Breathing in Clinical Practice," Chest, 2000, 117, pages 205-225 (This article also provides a good review of the central and peripheral chemoreceptors and the drive to breathe)
4. Wojciechowski, William V., "Entry Level Exam Review for Respiratory Care:  Guidelines for success," 3rd edition, 2011, U.S., page 487?
5. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24
6. Tines, John Hudson, "Exploring the History of Medicine," 1999, great read for obtaining a pithy history of medicine
7. Glover, Dennis W. , "History of Respiratory therapy," 2010, page 94, great read for obtaining a pithy history of respiratory therapy
8. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24
9. Campbell, E.J.MRespiratory Failure,"  The British Medical Journal,  June 1965, 1451-1460 (article provided by link)

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Hypoxic drive myth, another exmaple of a dogmatic medical profession

A dogmatic doctor.

Despite convincing evidence that sheds doubt on the hypoxic drive theory, medical professors continue to teach it as fact, and physicians continue to worship it as the Holy Grail.  This is not, however, the first time the profession has been dogmatic, and it probably won't be the last, either.

There is actually convincing evidence suggests that a "reduction in hypoxic ventilatory drive may not be the sole mechanism causing increasing hypercapnia in (COPD patients)." (3)

Now, before I go on, it must be noted here I have much admiration and respect for the medical community.  The history, facts, and opinions shared in this post should in no way diminish my respect for the profession.

Yet while I respect and admire them, I also understand the medical profession is notorious for being proud, dogmatic, and slow to accept new ideas.

Take 1543, for example.  Back then it was normal for an assistant to dissect a human corpse while a professor read from one of Galen's books.  Andreas Vesalius observed that what was being read was different from what he was seeing.

For instance, Vesalius observed that Galen's writings described the sternum as having eight parts, yet the human sternum being dissected in front of him had only three parts.

Later, when Vesalius was dissecting an ape, he learned it was the ape that had an eight part sternum.  He learned that Galen had based his writings on dissections of apes.  This makes sense, considering in Galen's day it was illegal to dissect a human corpse.

In the 16th century, artists like Michelangelo knew more about the human anatomy than physicians, so Vesalius hired Johannes Oporinus to draw accurate pictures of human anatomy , and Vesalius published the first ever book on human anatomy De humani corpus in 1543.

Yet Galen could nary be wrong, and Vesalius was laughed out of town by a dogmatic profession.

In the end, however, Vesalius was proven right, and his wisdom gave birth to the science of human anatomy.

In 1816, Rene Laennec invented the stethoscope.  Instead of the medical community embracing and adapting the tool that would greatly improve their diagnostic skills, they mocked Laennec.  They were too proud to carry such a frivolous tool.

In the end, however, this tool became a required tool for all physicians.

In 1847, Ignaz Semmelweis observed that moms whose babies were delivered by medical students were far more likely to die of child bed fever compared to moms whose babies were delivered by midwives. He proved that this was because the medical students did not wash between patients, while the midwives did. He made it mandatory for the students to wash their hands as the midwives did, and this resulted in mom's dying from childbirth plummeting.

Back then, you see, medical students were proud to show how hard they worked by blood on their hands and aprons. So, since Semmelweis could offer no scientific proof why hand washing resulted in fewer deaths, he was mocked and forced to leave town.  (6)

In the end, however, semmelweis was proven right when, in 1864, Louis Pasteur proved the germ theory of disease.

So it is quite evident that physicians being dogmatic about the hypoxic drive theory, despite convincing proof that it's nothing more than a myth, are hesitant to give up on it.

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. Wilkins, Robert L, James K. Stoller, ed. "Egan's Fundamentals of Respiratory Care," 2009, pages 309-310
3. Caruana-Montaldo, Brendan, et al, "The Control of Breathing in Clinical Practice," Chest, 2000, 117, pages 205-225 (This article also provides a good review of the central and peripheral chemoreceptors and the drive to breathe)
4. Wojciechowski, William V., "Entry Level Exam Review for Respiratory Care:  Guidelines for success," 3rd edition, 2011, U.S., page 487?
5. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24
6. Tines, John Hudson, "Exploring the History of Medicine," 1999, great read for obtaining a pithy history of medicine

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What is the hypoxic drive theory?

The hypoxic drive theory was born in the 1950s, was given credulity in 1960, and was first disproved in 1987.  (1)  Since then the theory, known to some as the myth or the hoax, has become one of the most hotly debated theories in all of medicine.

The crux of the theory is that the main drive to breath comes from neurons in the medulla oblongata at the base of the brain.  These neurons receive signals from central chemoreceptors on the medulla and peripheral chemoreceptors located in the bifurcations of the aortic arteries and the aortic arch.

Respiratory rate is adjusted to maintain a normal acid base balance (pH) throughout the body.  The majority of the times, the central chemo receptors send signals to the brain that control breathing. They monitor carbon dioxide (CO2) levels.  When CO2 levels are high a signal is sent to speed up the drive to breathe to blow off the excess CO2.  In this way, CO2 is our main drive to breathe.

The peripheral chemo receptors send a signal to breathe when the partial pressure of oxygen in the arteries (PaO2) is less than 60. This is referred to as the hypoxic drive.  This hypoxic response is far slower than signals sent by central chemoreceptors, and therefore the hypoxic drive has only a minor role in breathing.

In COPD patients, chronic airway obstruction due to bronchospasm and increased mucus secretion blocks air passages, and as a result many alveoli become ineffective at ventilating (CO2 cannot get out and oxygen cannot get in).  For these patients, this results in a chronically elevated CO2 (greater than 50), and lowered oxygen levels (SpO2 less than 90 and Po2 less than 60). (2)

As CO2 rises, bicarbonate (HCO3) falls in order to compensate and prevent acidosis (a drop in pH, or a pH less than 7.35).  The result here is that many of these patients normally live with something like a PaCO2 of 50, a PaO2 of 50, and a Bicarb of 30.  These patients are aptly referred to as CO2 retainers, or simply retainers.

In many instances students are incorrectly taught that all COPD patients are retainers who breathe under influence of the hypoxic drive.  The truth is that less than 25 percent of chronic CO2 retainers use the hypoxic drive to breathe, (4) and it's not as significant as once believed.

In fact, of patients who present to hospitals in respiratory distress, half will have reversible CO2 retention, and half will be chronic CO2 retainers.  (5)

The hypoxic drive theory has it that the high CO2 may make the chemoreceptors tolerant of the high CO2, and thus CO2 ceases to be that person's drive to breath.  These patients are your prototypical CO2 retainers. The hypoxic drive theory, thus, states that many of them are hypoxic drive breathers.

Those who believe in the theory believe if you give these patients too much oxygen, enough to drive their PO2 above 70, then you will blunt their hypoxic drive and knock out their drive to breathe.  Their respiratory rare will slow, their CO2 will therefore rise even more, acidosis will occur, the patient will become lethargic (very sleepy or somnolent), and ultimately they will stop breathing.

It is for this reason that most medical experts champion for never over-oxygenating patients who are CO2 retainers. The experts recommend using a nasal cannula set at 2-4lpm, and never higher.  Or, if their respiratory rate is sporadic, to use a venturi mask set no higher than 40% FiO2.

These experts say that if the CO2 rises, that the FiO2 should be lowered.  This has resulted in many physicians accepting PO2s in the lower 80s and even the upper 70s in certain patients.

Yet this often results in the ire of caregivers taking care of these patients, because they are the ones who have to watch them suffer from dyspnea, or air hunger, or the feeling they can't catch their breath.

It has also resulted in ire because many of these patients are placed on 100% oxygen with no ill effect.  Many of these patents have been given breathing treatments using oxygen, estimated to be about 60%, and have never seen any patient drop dead during a breathing treatment.

It was evidence like this that made clinicians second guess the hypoxic drive theory.  It was from here that various studies were done to show, once and for all, whether the hypoxic drive theory is a fact, or whether it's nothing more than a medical myth.

What in turn happened was that, even though most studies proved the theory was in fact a myth, the subject became even more controversial.

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. Wilkins, Robert L, James K. Stoller, ed. "Egan's Fundamentals of Respiratory Care," 2009, pages 309-310
3. Caruana-Montaldo, Brendan, et al, "The Control of Breathing in Clinical Practice," Chest, 2000, 117, pages 205-225 (This article also provides a good review of the central and peripheral chemoreceptors and the drive to breathe)
4. Wojciechowski, William V., "Entry Level Exam Review for Respiratory Care:  Guidelines for success," 3rd edition, 2011, U.S., page 487?
5. Cooper, Nicola, Kirsty Forrest, Paul Cramp, "Essential guide to acute care," 2nd edition, 2006, Massachusettes, page 24

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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.