The Death of the Hypoxic Drive Theory

On March 15^th I gave a talk at the 22^nd Annual Tahoe “Odyssey” Conference, a conference for Respiratory Care Practitioners, Nurses, and Physicians. The topic was “The Death of the Hypoxic Drive Theory.

By “Hypoxic Drive Theory” I am referring to either the default assumption that any chronically compensated respiratory acidosis implies reliance on the hypoxic drive to maintain adequate gas exchange….or

…..that chronically compensated respiratory acidosis means the central chemoreceptors are defunct or deficient.

This is more than just a theory, it’s become a clinical mindset, almost a medical urban legend. “He’s a retainer”, “that’s where he lives”, “he’s in the 50/50 club”, etc., all are like so many clinical buzzwords.

There is the existence of a hypoxic drive. It normally accounts for about 10-15% of the total drive to breathe. We all have it, unless perhaps we’ve had bilateral carotid surgery. It becomes obliterated at a PaO2 above about 170, and becomes a greater stimulus as the PaO2 drops below 70, and especially below 50.

There is a hyperoxia associated hypercarbia, which can develop in certain patients while they are in crisis. But it has little, if anything, to do with respiratory drive.

When COPD patients are in acute respiratory failure they are usually breathing somewhere near their maximum limit. When 100% O2 is applied the CO2 can be driven up by 3 factors…

The Haldane Effect. Unsaturated hemoglobin carries CO2. A patient in crisis may arrive in the ER with an SpO2 on room air of 75%, the unmeasured mixed venous saturation may then in turn also be much lower than the 75% norm. All this unsaturated hemoglobin is then carrying an extra CO2 load. This is in the setting whereby the patient has an already elevated PaCO2, perhaps has an elevated Hgb after years of hypoxemia, and is “topped off” on their ability to ventilate. So for every rise in their SpO2 we are driving more CO2 into the plasma. If this were you or I, we would simply then ventilate this extra CO2 out via the lungs. But their lungs can’t and don’t, therefore the CO2 shows up in the “downstream” ABG.
The release of hypoxic pulmonary vasoconstriction. Imagine the worst ventilated alveoli. The local CO2 pressure there may be 100 or more. On room air the local O2 pressure will surely be less than 60 torr. At this level of local hypoxemia, the adjacent pulmonary vasculature will constrict. Blood will then be sent to the alveoli which is ventilating more effectively. Ventilation/perfusion matching is enhanced. But if 100% O2 is given the O2 pressure will not drop below 60, the pulmonary vasculature will not constrict, and V/Q matching will not be optimized. Just as giving Nipride may drop the PaO2 as hypoxic pulmonary vasoconstriction is released, so giving 100% O2 may also raise the PaCO2. This also can happen to patients in an asthmatic crisis given 100% O2. It’s not that we knock out a hypoxic drive, so much as we drive in a hypercarbic potential. Then further compromise ventilation through increased V/Q mismatching.
A small amount of the CO2 retainers whom are in acute failure, and whom have their PaCO2 increased further from the two mechanisms listed above, will then reduce their minute ventilation further by about 15-20%. Usually the PaO2 will have been about 40 on room air, the PaCO2 70. Given 100% O2 the PaO2 rises well above the 170 range whereby all hypoxic drive is obliterated, and the PaCO2 rises to 90 or more. But is this a result of a central drive deficiency? Or of central wisdom? When the PaO2 is 40 the patient can’t let their PaCO2 go up to 90. If they did the PaO2 would plummet to about 20 and rapid death would ensue (per the alveolar air equation). But when the hypoxic drive “gun to the head” is removed, the patient then titrates their respiratory effort such that the ventilatory effort and work is proportioned out for the long haul. It is not a drive deficiency. We may view this as patient permissive hypercapnea, may apply non-invasive ventilation, may simply realize that hypoxemia kills and hypercapnea does not, or may intubate them. Or hypoxemia may be used as a respiratory stimulant. But if this is the tactic chosen, it should be viewed as akin to giving epinephrine to an already compromised myocardium in order to maintain adequate perfusion pressure. Just as if we were to see this same patient arrive in stable condition for a clinic condition later we wouldn’t insist they needed an epi drip to maintain a sufficient cardiac output, so too should we not insist that a CO2 retainer not in crisis needs hypoxemia in order to stimulate adequate respiratory drive.

In the May 98 issue of Clinical Pulmonary Medicine is an article titled Acute Respiratory Failure in Chronic Obstructive Pulmonary
Disease” by Schiavi. In it the author concludes that…… “....The traditional idea that oxygen
induces hypoventilation by suppressing hypoxic ventilatory drive at the
level of peripheral chemoreceptors is no longer tenable.”

During my talk I read a almost all of an editorial which appeared in the Sept. 97 issue of Critical Care Medicine, “Debunking Myths of Chronic Obstructive Lung Disease”, by Dr. John Hoyt.

““There are examples of mythology that float about in the atmosphere of medical information that desperately need to be debunked because they influence the care of patients. One sample of medical mythology is the commonly told story that the administration of oxygen to a patient with chronic obstructive lung disease will shut down the patient’s hypoxic respiratory drive and lead to apnea, cardiorespiratory arrest, and the subsequent death of the patient.

It is not clear where this fallacious information comes from, but it seems to enter the medical information database at an early age, almost like a computer virus corrupting the appropriate function of the equipment. In addition, this myth becomes very difficult to extinguish during the career of the physician, even with clear factual information of long standing. The danger here is that this medical mythology will inappropriately influence treatment decisions in patients.

The basic issue in this story is oxygen. The human body, particularly key organs such as the heart and brain, are not all that forgiving of insufficient supplies of oxygen. Thus, medical decision-making—based on the mythology that oxygen causes apnea and cardiorespiratory arrest in patients with chronic obstructive pulmonary disease by turning off the oxygen respiratory drive—might take the path of with-holding or delivering inadequate doses of oxygen to meet the metabolic needs of the patient in respiratory failure. This mistake is generally fatal for the patient, and a treatment tragedy for the misinformed physician.”….(the author goes on to describe the study…to be described later JW)

“Most mythological stories are based on some observation, which may be a correct observation, but an incorrect interpretation of the facts It is true that the administration of oxygen to a patient with an exacerbated chronic obstructive lung disease and acute respiratory failure may lead to an increased CO2. It is true that the hypercarbia may become severe and be associated with cardiorespiratory arrest. The problem is with interpreting the cause of the events…..

One should not fear apnea and cardiorespiratory arrest when giving oxygen to a patient with an exacerbated chronic obstructive lung disease and respiratory failure. Instead, one should be prepared to help the patient eliminate CO2 when deadspace increases. Providing assistance with the elimination of CO2 has been around since the beginning of critical care medicine. It is called mechanical ventilation..”

Focusing on one of the real causes of oxygen induced hypercarbia, enhanced V/Q mismatch, may also allow us to recognize that a rising CO2 level in a patient with status asthmaticus (on 100% O2) may not be so much an indication of advancing respiratory failure but, rather, of a worsening V/Q mismatch arising from the release of regional hypoxic pulmonary vasoconstriction.

Furthermore, it may not be so benign to have COPD, even real CO2 retainer, patients chronically hovering the boundary of an acceptable PaO2 or SpO2 value. There is growing evidence that the pathogenesis of Cor Pulmonale, nutritional status (lack of weight gain despite adequate nutritional consumption), cardiac modulation, post-operative wound healing, and recovery from acute respiratory distress, all are adversely affected by the default acceptance or goal of an SpO2 of 88-90% in these patients.

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To the tune of Bob Dylan's song “ Positively 4th Street”..

You had a lot of nerve

To turn up his O2

Just because he was dying

And really turning blue

I don't know the reason

why you won't accept the show

When it comes to the oxygen drug

You just have to "Say No"

You had a lot of nerve, to turn up his O2

Just because he was distressed and turning blue

I don't know the reason you worry about his hypoxic distress

If he were hiking Everest, it would be even less

Below is a list of references on this topic. I would most enthusiastically recommend in particlar reading the studies and discussion occurring in references #11 and # 17, both from the European Journal of Respiratory Disease.

Jeff Whitnack RRT/RPFT

References…

1. The Control of Breathing in Clinical Practice, Caruana-Montaldo, et al, Chest 117/1 Jan., 2000, pages 205-225

2. Debunking Myths of Chronic Obstructive Pulmonary Disease (Editorial) Hoyt, Crit Care Med 1997 Vol. 25, Number 9, pgs. 1450-51

3. Respiratory Failure, Campbell and Arnott, et al, Lancet 1960, ii 12, 1-7

4. The J. Burns Amberson Lecture---The Management of Acute Respiratory Failure in Chronic Bronchitis and Emphyzema by E.J.M. Campbell, Am Rev Resp Dis 1967, Oct. 96(4):626-639

5. (Hypothesis) Hypercapnea During Oxygen Therapy in Acute Exacerbation of Chronic Respiratory Failure, Rudolf, et al Lancet Sept. 3, 1977, pages 483-486

6. Effects of the Administration of O2 on Ventilation and Blood Gases in Patients with Chronic Obstructive Pulmonary Disease During Acute Respiratory Failure, Aubier, et al, Am. Rev. Resp. Dis. Vol. 122 pages 747-754 1980

7. (Editorial) Hypercapnea during oxygen therapy in airways obstruction: a reappraisal. Stradling, Thorax 1986 41:897-902

8. Correspondence (Aubier and Stradling regarding study cited in # 6 above, Am Rev Resp Dis. Oct. 16^th, 1986

9. Central Respiratory Drive in Acute Respiratory Failure of Patients with Chronic Obstructive Pulmonary Disease, Aubier, et al, Am Rev Resp Dis Volume 122, pages 191-199, 1980

10. Hyperoxic-induced Hypercapnea in Stable Chronic Obstructive Pulmonary Disease, Sassoon, et al, Am Rev. Resp. Dis. 1987 135:pgs. 907-911

11. Inter-individual Variability of the Response to Oxygen Administration in Hypercapneic Patients, Gasparini, et al, Eur J of Resp Dis., 1986; 69(suppl 146) 427-443

12. Oxygen-induced Hypercarbia in Obstructive Pulmonary Disease, Dunn, et al, Am Rev Resp Dis 1991, 144:526-530

13. Causes of Hypercapnia with Oxygen Therapy in Patients with Chronic Obstructive Pulmonary Disease by Hanson, et al, Crit. Care Med 1996 Vol. 24 pgs. 23-28

14. Influence of Inspired oxygen concentration on deadspace, respiratory drive, and PaCO2 in intubated patients with chronic obstructive pulmonary disease, Crossley, et al, Crit Care Med 1997 Vol. 25, Number 9, pages 1522-1526

15. O2-induced changes in Ventilation and Ventilatory Drive in COPD. Dick, et all, Am J Resp Crit Care Med vol 115, pages 609-614, 1997

16. The Role of Hypoventilation and Ventilation-Perfusion Redistribution in Oxygen-induced Hypercapnea during Acute Excacerbation of Chronic Obstructive Pulmonary Disease, Robinson, et al, Am. J. Resp. Crit. Care Med Vol. 161, pgs. 1524-1529 2000

17. Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia Scano, et al, Eur. Resp. J. 1995 8:78-85

18. May 98 issue of Clinical Pulmonary Medicine is an article titled Acute Respiratory Failure in Chronic Obstructive Pulmonary
Disease” by Schiavi

19.Supplemental Perioperative Oxygen to Reduce the Incidence of Surgical-Wound Infection, Robert Greif et al, The New England Journal of Medicine -- January 20, 2000 -- Vol. 342, No. 3

20.Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients by Jonsson K, et al, Ann Surg 1991 Nov;214(5):605-13

21. Oxygen and wound healing by LaVan FB; Hunt TK, Clin Plast Surg 1990 Jul;17(3):463-72

22.Oxygen Supplementation and Cardiac-Autonomic Modulation in COPD^* Matthew N. Bartels, MD, MPH; John M. Gonzalez, BS; Woojin Kim, BS and Ronald E. De Meersman, PhD Chest. 2000;118:691-696

23.The Relationsip between Chronic Hypoxemia and Activation of the Tumor Necrosis Factor-x system in Patients with Chronic Obstructive Pulmonary Disease, by Noriaki, et al, Am Jr. Resp Crit Care Med Volume 161 Number 4 April 2000, 1179-1184

24.Elevated O2 cost of ventilation contributes to tissue wasting in COPD. Mannix ET; Manfredi F; Farber MO, Chest 1999 Mar;115(3):708-13

25.November 97 issue of Clinical Pulmonary Medicine, MacNee and Skwarski article titled “The Pathogenesis of Peripheral Edema in Chronic Obstructive Pulmonary Disease”

26.Oxygen Pressue Field Theory for Perfusionists, Nov. 1999, by Gary Grist BS, RN, CCP, Chief Perfusionist The Childrens Mercy Hospital, Kansas City, MO

27.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):681-686

28.Incidence of Nocturnal Desaturation While Breathing Oxygen in COPD Patients Undergoing Long-term Oxygen Therapy by Robert Plywaczewski, MD, et al, Chest. 2000;117:679-683.)

29. Uncontrolled Oxygen Administration and Respiratory Failure in Acute Asthma, Chien, et al, Chest 117/3/March 2000 pgs. ;728-733

30.Respiratory Arrest in Near-Fatal Asthma, Molfino, et al, N. Eng. J. Med 1991 324:285-288…see also editorial same issue, page 409-411 by McFadden