This chapter is most relevant to Section F2(i) from the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the control of breathing". The concentration of arterial O2 is at least as important as the PaCO2, and equally likely to generate a painful CICM SAQ or cross-table viva station. Though, at the time of writing, it so far has not, at least insofar as we can make out from the minimal shreds of viva content left for us by the college. Again, the time-poor candidate is warned against wasting their time on revising this topic, and urged to limit their attention to the contents of the summary box below

So, in summary:

  • Decreasing PaO2 causes an increase in minute ventilation.
  • As for PaCO2, this is mediated by peripehral chemoreceptors over the timescale of seconds.
  • Unlike PaCO2, arterial oxygenation does not affect central chemoreceptors.
  • The receptors sense oxygen tension rather than content, and the responses to arterial hypoxemia are not triggered by anaemia.
  • The relationship between oxygen tension and minute volume can be described as a hyperbolic curve
  • The inflexion point for this relationship is approximately a PaO2 of 50-60 mmHg; beyond this threshold value the minute volume increases steeply
  • Ventilatory response to hypoxia is decreased by 
    • Hypocapnia
    • Carotid endarterectomy
    • CNS depression: sleep, anaesthesia, opiates
    • Starvation
    • Age
  • Ventilatory response to hypoxia is increased by
    • Hypercapnia
    • Exercise
  • The ventilatory response to hypoxia is triphasic:
    • The acute phase, where minute volume increases abruptly (5-10 minutes) 
    • The decline phase, where the minute volume decreases to a higher baseline plateau
    • If for whatever reason the patient remains isocapnic, there is a third phase where the minute volume rises again gradually over many hours.
       

Influence of PaO2 on minute ventilation

Hypoxia, being a life-threatening state, is one of the factors which affects the respiratory drive. This might seem weird, as the transfer of oxygen into the blood is somewhat less related to the minute ventilation, and given that only a very small amount of oxygen is physiologically necessary (200-250ml/minute),  theoretically only a litre of room air should be absolutely required under most circumstances.  However, it is known that dropping the arterial oxygen tension produces an abrupt and significant increase in minute volume, and this increase is proportional to the severity of the hypoxia.

Early exploration of the effects of hypoxia on the respiratory drive of man was marred by the experimenter's conflation of hypoxia and low barometric pressure, the latter being much easier to generate but having its own distinct physiological responses which are hardly trivial and which confused the test results.  It was also difficult to recruit volunteers. "Some men dreaded going into the low pressure chamber", complained Lutz & Schneider (1919) after exposing their volunteers to "abrupt and great changes in atmospheric pressure". To avoid the understandable anxiety and apprehension of their test subjects, Dripps & Comroe (1947) decided to pick people who trusted them ("subjects were chosen who were familiar with laboratory surroundings and with the experimenters") and for whom "an effort was made to afford a reassuring atmosphere". These gullible subjects were then gassed for 8 minutes at a time with a series of increasingly hypoxic gas mixtures, administered via a rubber face mask fixed to the mouth and nose with rubber cement. The graph below illustrates their results, lightly modified from the original.  The top axis was originally an unhelpful "calculated equivalent altitude" in thousands of feet, surely of more interest to the US Air Force who must have commissioned the research.

ventilaroty responses to hypoxia modified from Dripps & Conroe (1949).jpg

The upshot of this for the exam candidate is that, when called upon to "describe the ventilatory response to hypoxia", they may safely produce a graph which is flat until an alveolar O2 tension of around 50 mmHg, and which then increases at a linear rate.

Influence of arterial CO2 on hypoxic ventilatory drive

Something becomes immediately become apparent from the data presented above. When comparing the response to hypoxia with the response to hypercapnia, it would appear that hypoxia is a much weaker respiratory stimulant. With a 10 mmHg increase in PaCO2, one's minute volume increases by 20-50L, whereas a 10 mmHg drop in alveolar oxygen (say, from 50 to 40 mmHg) only increases the minute volume by 10L.

However, thinking about this, one may come t the conclusion that these test subjects, huffing away at 400% of their normal minute volume, are surely blowing off a vast quantity of CO2. The resulting hypocapnia is therefore certainly affecting their ventilatory drive, decreasing the apparent response to hypoxia. This is usually referred to as hypoxia with "poikilocapnia" (literally, "variable CO2"), where the CO2 is left to wander and find its own value. When one tries to correct the experiment by adjusting the CO2 to keep it stable (isocapnia), the ventilatory response to hypoxia is markedly increased, as seen in the graphics below which were stolen from Howard & Robbins (1995) and severely mangled with vector graphics software.

ventilatory responses to isocapnic and poikilocapnic hypoxia from Howard and Robbins (1995)

Extending this concept further, one might expect that increasing CO2 beyond the stable baseline values might predictably increase the ventilatory response to hypoxia. One might even be able to plot some sort of graph to describe the relationship between alveolar PO2, minute volume and arterial CO2 concentration. If a CICM exam candidate is ever called upon to answer a question on this, they would probably be expected to reproduce something resembling this classic version from Cormack et al (1957). The original paper actually offered a separate graph for each of the seven test subjects ("healthy male medical students or members of the laboratory staff"); below the modified graph is traced from Subject 4 because their ventilatory responses were particularly vigorous.

ventilatory responses to hypoxia at different PaCO2 levels from Cormack (1957)

Logically, from this it follows that hypocapnia should flatten this hyperbolic relationship, i.e. with a very low PaCO2 one would "tolerate" a lower arterial oxygen tension before becoming tachypnoeic. This is more difficult to demonstrate experimentally, insofar as it is much easier for investigators to add CO2 rather than inconspicuously remove it. Weil et al (1970) produced the hypocapnic data below by forcing their subjects to hyperventilate (the subject was Edward Byrne-Quinn, one of the authors):

effect of hypocapnia on hypoxic respiratory drive from Weil et al (1970)

As one can see from these renderings, the curve is a hyperbola. At the higher values of PaO2, ever-increasing oxygenation has minimal effect on the minute volume, and the curve asymptotically approaches the resting minute volume value for whatever the CO2 currently is.   At lower values of PaO2, the minute volume rises so steeply that it also becomes asymptotic, mathematically pointing to infinity (but practically pointing at a minute volume of about 120-140 L/min, which is what a healthy adult is maximally able to attain).

Obviously, that last point makes little sense, as one never sees critically hypoxic patients hyperventilate maximally just before their cardiac arrest. In fact, their minute volume is observed to drop. This is the effect of severe hypoxia on central respiratory control centres. Bissonnette et al (2010) determined that the complete collapse of all respiratory function tends to occur around a PaO2 of 13 mmHg, at least as determined by diaphragm EMG in foetal sheep.

Triphasic ventilatory response to hypoxia

The response to a sudden drop in arterial oxygen follows three phases:

  • The acute phase, where minute volume increases abruptly (5-10 minutes) 
  • The decline phase, where the minute volume decreases to a plateau which is higher than the previous baseline (this represents an equilibrium, where the hypoxic person continues to breathe at a slightly higher rate, maintaining a lower baseline PaCO2)
  • If for whatever reason the patient remains isocapnic, there is a third phase where the minute volume rises again gradually over many hours

Easton et al (1986) described the first two phases of this process in an experiment where twenty young adults were subjected to isocapnic hypoxia for about 25 minutes (their SpO2 was maintained at 80%). They hyperventilated briefly, but then settled down to a lower minute volume. The authors illustrated their findings with a figure using data from one of their subjects, but its jagged rawness makes it unattractively real, and so a sanitised version is offered instead:

biphasic response to isocapnic hypoxia

The third phase is not seen unless one deliberately maintains a stable CO2 in the face of worsening hypoxia. There, a slow increase in minute volume occurs over hours, and apparently plateaus after about 24 hours. Nobody seems to know what this is caused by (the effect of angiotensin on carotid body receptors?)  Nunn's does not give a reference to describe the mechanism behind this, but refers to "species differences" which suggests some sort of cruel animal study is probably involved. For the CICM exam trainee, it will suffice to know that isocapnic hypoxia results in a gradually increasing minute volume which peaks after one day. The following is a cleaned-up version of Fig. 2 from Howard & Robbins (1995), elements of which have already appeared above; the subjects were subjected to the sort of hypoxia which generates an end-tidal PO2 of 55 mmHg.

Isocapnic and poikilocapnic hypoxia over hours

Factors which influence the effects of oxygen on respiratory drive

Apart from CO2, various other physiological factors and pathologies can influence the ventilatory response to hypoxia. 

Factors which increase the responsiveness to hypoxia include:

  • Exercise: at any given level of hypoxia, any sort of physical exercise will increase the ventilatory response. Practically, this means that the hypoxic patient working hard to breathe is experiencing more respiratory drive then the hypoxic patient who is at rest. Martin et al (1978) convinced a group of varsity-level athletes to run on treadmills under hypoxic conditions and established that with heavy exercise, ventilatory responses to hypoxia increase massively:
    ventilatory response to hypoxia during exercise from Martin et al (1978)

Factors which decrease the responsiveness to hypoxia include:

  • Carotid endarterectomy (because this tends to destroy the sensory glomus of the carotid body, and therefore removes the sensor apparatus). Where the procedure is bilateral, hypoxic ventilatory response is lost entirely (Wade et al, 1970). This is so effective and dependable that carotid endarterctomy has been proposed as a means of alleviating the chronic dyspnoea of severe COPD (Severinghaus, 1989)
  • Opiates: Weil et al (1975) established that morphine decrease the hypoxic ventilatory drive; a 7.5mg dose was enough to substantially depress the response of healthy volunteers.
  • Sleep: Douglas et al (1982) watched six sleeping men while titrating their inspired gas mixtures to an isocapnic hypoxia, and found that their minute volume increase was less than one-third of the waking value, per unit drop in saturation. For the record, one should increase one's minute volume by roughly 1L per every 1% drop in arterial saturation.
  • Anaesthesia: Predictably, being sedated makes you less responsive to hypoxia. Here's a graph demonstrating this in six mongrel doges, from Hirschman et al (1997)
    ventilatory responses to hypoxia with anaesthesia
  • Starvation: Doekel et al (1976) starved seven healthy subjects for ten days and found their ventilatory responses to hypoxia decreased by about 40%, in proportion to the decrease in their metabolic rate.
  • Age: Older people have a blunted hypoxic respiratory drive. When Kronenberg et al (1973) compared men in their 20s with men in their 70s, a 50% decrease in the ventilatory responses to moderate hypoxia was seen.

References

Dripps, Robert D., and Julius H. Comroe Jr. "The effect of the inhalation of high and low oxygen concentrations on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals." American Journal of Physiology-Legacy Content 149.2 (1947): 277-291.

Lutz, Brenton R., and Edward C. Schneider. "Circulatory responses to low oxygen tensions." American Journal of Physiology-Legacy Content 50.2 (1919): 228-251.

Cormack, R. S., D. J. C. Cunningham, and J. B. L. Gee. "The effect of carbon dioxide on the respiratory response to want of oxygen in man." Quarterly Journal of Experimental Physiology and Cognate Medical Sciences: Translation and Integration42.3 (1957): 303-319.

Howard, L. S., and P. A. Robbins. "Ventilatory response to 8 h of isocapnic and poikilocapnic hypoxia in humans." Journal of applied physiology 78.3 (1995): 1092-1097.

Easton, P. A., L. J. Slykerman, and N. R. Anthonisen. "Ventilatory response to sustained hypoxia in normal adults." Journal of Applied Physiology 61.3 (1986): 906-911.

Weil, John V., et al. "Hypoxic ventilatory drive in normal man." The Journal of clinical investigation 49.6 (1970): 1061-1072.

Bissonnette, John M., A. Roger Hohimer, and Sharon J. Knopp. "Effect of hypoxia on expiratory muscle activity in fetal sheep." Respiratory physiology & neurobiology 171.2 (2010): 110-114.

Powell, F. L., W. K. Milsom, and G. S. Mitchell. "Time domains of the hypoxic ventilatory response." Respiration physiology112.2 (1998): 123-134.

Weil, John V., et al. "Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man." New England Journal of Medicine 292.21 (1975): 1103-1106.

Doekel Jr, Robert C., et al. "Clinical semi-starvation: depression of hypoxic ventilatory response." New England Journal of Medicine 295.7 (1976): 358-361.

Douglas, Neil J., et al. "Hypoxic ventilatory response decreases during sleep in normal men." American Review of Respiratory Disease 125.3 (1982): 286-289.

Kronenberg, Richard S., and Charles W. Drage. "Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men." The Journal of clinical investigation 52.8 (1973): 1812-1819.

Wade, John G., et al. "Effect of carotid endarterectomy on carotid chemoreceptor and baroreceptor function in man." New England Journal of Medicine 282.15 (1970): 823-829.

Severinghaus, John W. "Carotid body resection for COPD?." Chest 95.5 (1989): 1128-1129.

Martin, BRUCE J., et al. "Exercise ventilation correlates positively with ventilatory chemoresponsiveness." Journal of Applied Physiology 45.4 (1978): 557-564.

Maskrey, Michael. "Influence of body temperature on responses to hypoxia and hypercapnia: implications for SIDS.Clinical and experimental Pharmacology and Physiology 22.8 (1995): 527-532.

Hirshman, C. A., et al. "Depression of hypoxic ventilatory response by halothane, enflurane and isoflurane in dogs.British journal of anaesthesia 49.10 (1977): 957-963.