Friday, February 17, 2012

Hypoxic Drive Theory: A history of the myth

It's frustrating to watch a patient gasp for air.  Even worse, it's painful to watch a patient gasp for air because his doctor refuses to allow him much needed supplemental oxygen based on a 50-year-old medical myth:  the hypoxic drive theory.

The theory postulates that giving a patient with chronic (it's always there) carbon dioxide (CO2) retention, such as occurs in 50 percent of chronic obstructive pulmonary disease (COPD) patients who present with respiratory distress, will cause their CO2 to rise, breathing to slow down, and ultimately knock out their drive to breathe and cause respiratory acidosis and ultimately death.

The problem is the theory doesn't hold water with real world experience.  Of hundreds of thousands of patients we RTs take care of on a daily basis and place on supplemental oxygen (even as much as 100 percent oxygen), we see very few stop breathing. I give all my breathing treatments with oxygen, and no patient ever stopped breathing during a treatment.

If a patient suffering from an acute exacerbation of COPD is going to stop breathing, it's going to happen whether he receives oxygen or not due to exhaustion.  We've known this for years, but we lacked proof.

Now we have proof, because in 1987 the hypoxic drive theory was disproved. (1) The problem was that this proof came after the hypoxic drive theory had already become ingrained in the minds of prominent and well respected physicians around the world.  Despite evidence to the contrary, generation after generation of physicians have been educated about the hypoxic drive theory.  The theory, thus, has become a fact.

The result is needless suffering by many COPD patients and in some cases an untimely death.  The agony of watching patients suffer due to a myth, or hoax as some call it, has driven many RTs to an early retirement.

So, what is the hypoxic drive theory anyway?

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, such as greater than 50), and lowered oxygen level (PO2), such as 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 and a PaO2 of 50 and a Bicarb of 30.  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. They hypoxic drive theory, thus, states that many of them are hypoxic drive breathers. 

The hypoxic drive theory is taught in medical schools, and it's recommended that any COPD patient who is a CO2 retainer could be a hypoxic drive breather.  If you give them too much oxygen, enough to drive their PO2 above 70, you will be blunting their hypoxic drive to breathe, their respirations will slow, their CO2 will rise, acidosis will occur they will become lethargic, and ultimately they will stop breathing.  Yet evidence suggests "reduction in hypoxic ventilatory drive may not be the sole mechanism causing increasing hypercapnia in (COPD patients)." (3)

I polled over 60 nursing students over the past couple years and close to 100 percent of them believed that all COPD patients were hypoxic drive breathers who shouldn't be overly oxygenated.  Most doctors I work with believe a CO2 greater than 40 signifies a hypoxic drive breather. 

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

So how did this theory become so ingrained in the minds of physicians?

It must be noted here I have much admiration and respect for the medical community.  They do things I couldn't comprehend doing myself -- such as cutting people open and stitching.  Often I think it's better to be a respiratory therapist because, while we're a part of the critical thinking team, the final decision lies in the hands of the physician.

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 as an example.  In medical school an assistant would dissect a human corpse while the professor read from Galen.  Andreas Vesalius observed that what was being read was different from what he was seeing.

For example, Galen's writings described the sternum as having eight parts, yet the human sternum being dissected had only three parts.  Later, when Vesalius was dissecting an ape, he learned it was the ape that had an eight part sternum.  Galen had made his writings based on dissections of apes.  This made 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.

Yet Galen could nary be wrong, and Vesalius was laughed out of town.  Of course he is now considered the father of human anatomy.

In 1816 Rene Laennec invented the stethoscope, and instead of the medical community adapting his invention to improve their diagnostic skills, he was immediately mocked.  Doctors didn't think they should have to carry such frivolous equipment with them.

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.

Semmelweis proved the midwives were cleaner because the midwives washed their hands between patient procedures. Semmelweis made it mandatory for doctors to wash their hands in chlorinated lime solutions just like the midwives did.  In the months that followed moms dying of child bed fever plummeted.  Yet Semmelweis was hated and treated like a nut.

How dare he tell the well established medical community what to do?  You see, back then medical status was determined by how much blood you had on your hands and apron.  Since Semmelweis could offer no scientific proof why hand washing did any good, Semmelweis was laughed out of town.  (6)

Oxygen was discovered in 1777 by Joseph Priestley.  In 1922 John Haldane wrote about his own research on oxygen in "The Therapeutic Administration of Oxygen."  Soon thereafter oxygen tanks became more and more common at the patient bedside, and ultimately oxygen was piped into the walls of hospitals.  Among the patients administered oxygen was COPD patients.  (7)

It was soon observed that oxygen made these patients CO2 rise, and some of these patients lost their drive to breathe.  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 done 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.  Because the hypoxic drive theory provided the first best example of why a COPD patient might stop breathing in the presence of oxygen, the theory has been taught from one generation to the next.  Despite scientific evidence, it has become the gold standard when treating COPD patients. (10)

So you can see how the medical profession has a long history of being relentless when it comes to holding on to antiquated ideas and adapting newer and better methods.  So it only makes sense that a theory concocted in 1960 and taught in medical schools would be a tough theory to let go of.

So where's the evidence the hypoxic drive theory is a myth?

Ironically, there has never been a real scientific study done to prove the hypoxic drive theory.  There have been several studies performed whereby researchers concluded the rise in CO2 in the presence of oxygen was caused by the hypoxic drive being knocked out, but this conclusion was not based on scientific evidence.

On the contrary, there are many studies that disprove the theory.

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 (1989, 8:52-53) questioning the popular hypoxic drive theory.  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.  (11)

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."

In another study, 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 not to be due to ventilation/ perfusion mismatching, "not just a failure of ventilatory response to the increase in PaCO2."  (12) 

Another study 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. (13)

Yet all these and other studies came too late.  The gold standard of COPD care had already been ingrained into the medical profession.  Disproving it, even with science, may be next to impossible.

So what is the true effect of oxygen on COPD patients?

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 ventilations 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." (14)

2.  VQ mismatching:  Consider that V = Ventilation and P = Perfusion.  So, generally this is Ventilation/ Perfusion mismatching.  To put it simply, this is caused by increased narrowing of the air passages in the lungs, and increased sputum that "obstructs" or prevents the ability of oxygen to get to alveoli, and prevents CO2 to enter the lungs.  COPD, thus, is a disease of V/Q mismatching; it's an obstructive airway disease. 

COPD, therefore, results in poorly ventilated alveoli due to bronchospasm and mucus plugs.  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. 

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," (15)

How should COPD patients be managed?

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

Based on this evidence, Schmidt and Hall recommended that these patients be maintained on as little oxygen as possible to maintain an adequate oxygen saturation which most physicians would agree should be about 88-92 percent.  Many modern textbooks, including Textbook of Canadian Medical-Surgical Nursing, support this view. (16)

Yet Schmidt and Hall also note that oxygen is essential to sustaining life, and preventing such patients from receiving adequate oxygenation due to an unproven theory may be detrimental to the patient, and may even result in death.  For this reason, they recommend these patients be monitored and treated based on clinical assessment and work of breathing "rather than by arbitrary laboratory values."

Most studies show that in the absence of respiratory distress a COPD patients CO2 may rise slightly in the presence of supplemental oxygen, yet will not cause the patient to stop breathing.  There have been many times I've had a CO2 retainer on 100% oxygen to maintain a hemoglobin saturation of 90 percent and I have rarely seen such a patient stop breathing.  In fact, in 17 years I've seen only one stop breathing.

The general idea in treating these patients is that if their ventilations decrease it's going to occur whether in the presence of oxygen or not.  If the patients drive to breath is tapped, and CO2 levels rise to critical levels, the best treatment is to support the patients ventilations with either non-invasive BiPAP or invasive ventilator.

What can we conclude here?


I personally think, as Schmidt and Hall suggest, that oxygen levels of COPD patients should be kept as low as possible in order to maintain adequate oxygenation, which should be an SpO2 of 88-92 percent and a PO2 of about 55-65 or somewhere in that area.  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)

 If a patients oxygen levels drop to critical levels, increasing supplemental oxygen should be an option.  This is common sense because without oxygen the body cannot function, the person may suffer an anoxic brain injury, and, if no oxygen is forthcoming, the person will die. 

If that patient's CO2 levels increase to critical levels while the oxygen saturation is acceptable and that patient shows signs of impending respiratory failure, the oxygen should be lowered first.  If this doesn't resolve the problem then ventilatory support (BiPAP or ventilator) would be the obvious next option.  

However, a trial on a higher oxygen level may sometimes be appropriate.  If the patient tolerates this higher oxygen level (say 100 percent) and the oxygen saturation remains in the 90 percent range, then the patient should remain on this oxygen level and weaned off it as his condition improves to maintain adequate oxygenation (SpO2 of 88-92 percent).

Yet if you have a chronic COPD retainer in the emergency room on 100% oxygen for over two hours to maintain an SpO2 of 86 percent, and as soon as that patient is admitted to a room the attending physician insists that you lower the oxygen immediately, you will have no choice but to comply.

Could the patient's family then sue because the patient died of doctor induced hypoxemia?  While they could, the hypoxic drive theory is so well ingrained by the medical community that use of it would most certainly hold up in a court of law.  So even though you don't support it, you must comply with the physician's order.

Surely the medical profession is loved and respected by most of us, yet that's not to say the profession is flawless. Even in the absence of scientific evidence many doctors will continue to worship the hypoxic drive theory (or myth/ hoax if you will) and prevent patients from receiving adequate oxygen levels.

It's been over 50 years that the hypoxic drive theory has been taught, and it may take 50 more to phase out the myth of the hypoxic drive theory.  So the moments of frustration will continue.  As RTs, we will have no choice but to comply with physician orders.

Yet, most important, we must continue to educate ourselves, challenge physicians, and encourage science. We must learn and teach facts.  We must continue this discussion here in the arena of ideas.

Further reading:
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)
  10. Reference not yet published.   Yes, I have privelidge to esoteric wisdom.  Will post when available. 
  11. Schmidt, op cit, pages 52-53
  12. 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
  13. 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
  14. 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)
  15. 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)
  16. 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)
  17. Moulton, Chris, David W. Yates, "Lecture notes:  Emergency Medicine," 3rd ed., 2006, pages 215-16

I would like to give special thanks to Jeffrey Whitnack, RRT,  for his speech to the 22nd Annual Tahoe Odysey Conference, "The death of the hypoxic drive theory."  He provided me with most of the above references and covered much of the same material, although much better than I ever could.  I'd provide a link to his web page, but I see it's been taken down.  I would also like to thank my un-named reference of whom I cannot currently acknowledge knowing. Yes, there are physicians privy to knowledge of the hoax, and for that we can be very thankful. 

10 comments:

C Pacheco said...

I will pass this on to my instructor and also further investigate this myself. Thanks!

Rick Frea said...

Please do. And I will provide more sources in the coming weeks for anyone wishing to do further research on this subject.

Jared said...

Great article and as someone going through RT school at the moment, they harp on this theory every single day. I've had family members in the medical field that tell me they've never seen it.

Joanne Liu said...

Hi Rick,

I got a question on The Haldane effect, as you stated "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."

so I presume that applies to all people despite if they are CO2 retainers.

"Most people would simply increase their respiratory rate and blow off this CO2."

with this information may I conclude that O2 supplement cause people to breathe faster in order to get rid of the CO2 accumulated in the blood? But O2 therapy is known as to reduce the workload of breathing. This is quite confusing to me could you please explain?

Joanne Liu said...

Hi Rick,

I got a question on The Haldane effect, as you stated "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."

so I presume that applies to all people despite if they are CO2 retainers.

"Most people would simply increase their respiratory rate and blow off this CO2."

with this information may I conclude that O2 supplement cause people to breathe faster in order to get rid of the CO2 accumulated in the blood? But O2 therapy is known as to reduce the workload of breathing. This is quite confusing to me could you please explain?

Joanne Liu said...

Hi Rick,

I got a question on The Haldane effect, as you stated "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."

so I presume that applies to all people despite if they are CO2 retainers.

"Most people would simply increase their respiratory rate and blow off this CO2."

with this information may I conclude that O2 supplement cause people to breathe faster in order to get rid of the CO2 accumulated in the blood? But O2 therapy is known as to reduce the workload of breathing. This is quite confusing to me could you please explain?

Steve Wood, PhD said...

"As CO2 rises, bicarbonate (HCO3) falls in order to compensate and prevent acidosis (a drop in pH, or a pH less than 7.35)."

You should correct this to say that HCO3 rises in order to compensate, not falls. pH is proportional to the ratio of HCO3/PCO2.

Rick Frea said...

Thanks, Steve. Appreciate the correction

Anonymous said...

If a physician tells you to turn down the O2, and you know that hypoxia kills, how can you NOT refuse to follow orders if you are acting in the patient's best interest? Following physician orders, especially when you know that following said orders could result in a poor patient outcome, has NEVER been held up in a court of law. Is this a case of making sure your malpractice premiums are paid up to date?

TMB, BS, RRT

Katia said...

your should write textbooks.. I am a nursing student taking patho and your have just explained everything so well that I cant believe my final is tomorrow and I just found this. Thank you so much. I will pass this on to my instructors. In the medical surgical nursing text they do support the use of 2L/min oxygen for COPD patients presenting with respiratory distress. They also recommend encouraging pursed lip breathing, abdominal breathing, and incentive spirometry.