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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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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