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". This seems to be a popular topic. It has appeared multiple times in the CICM Part I exam, and is sure to appear again. Though fragments of the topic are discussed in other chapters (eg. response to CO2, control of ventilation, etc), occasionally the examiners are less interested in anything particularly granular, and so this chapter offers a handy list of factors and associated mechanisms to act as a reference to those answering CICM questions for exam practice.

The CICM SAQs which asked about this (Question 6 from the first paper of 2010 and Question 11 from the second paper of 2008) asked specifically for the factors which increase the respiratory rate,  but of course tidal volume is also usually affected by these. (the wording of these SAQs was changed in subsequent papers). Thus, factors which influence minute volume are going to be discussed here, as a catch-all term. 

In summary:

Physiological Factors which Influence the Respiratory Rate

Physiological factor Mechanism Physiological effect
PaCO2

Sensed by peripheral chemoreceptors:
- Carotid bodies (glossopharyngeal nerve)
- Aortic bodies (vagus nerve)

Increased PaCO2 increases the respiratory rate and tidal volume 

Decreased PaO2 increases the respiratory rate
(rapidly acting breath-to-breath control of respiration)
- this response to hypoxia is triphasic

PaO2
pH

Sensed by central chemoreceptors in the medulla

Decreased pH in the CSF increases the respiratory rate and tidal volume
(slow acting, steady state control; adjustments occur over minutes)
Temperature

Increased sensitivity of periphperal chemoreceptors to O2

Increased sensitivity of central chemoreceptors to changes in pH

A rise in temperature will increase the minute volume at any given PaCO2 and PaO2 level

Responses to hypoxia and hypercapnia are
amplified by hyperthermia

Exercise

Descending control of muscle activity simultaneously simulates the central respiratory control centres

The ventilatory response of exercise is increased ventilation, and because this is not a feedback mechanism the increase in ventilation is simultaneous with the beginning of exercise, or actually slightly preceeds it. 
Pregnancy

Progesterone acts directly on central integrative control of ventilation

During pregnancy, minute volume increases and the stable PaCO2  baseline progressively decreases, producing the respiratory alkalosis of pregnancy
Blood pressure

Sensed by aortic chemoreceptors and carotid sinus baroreceptors

Hypertension decreases the respiratory rate and hypotension increases it.

With a sufficient acute hypertensive event, respiration may briefly cease ("adrenaline apnea")

It is possible to approach this subject in one or two ways. Perhaps one might list all the possible physiological variables which affect ventilation, discuss how these variables are sensed, then how these sensor signals are integrated by the central respiratory control centres, and then how the response to their changes is passed on to effector organs. That appears to be what the college wanted in  Question 6 from the first paper of 2010, where successful candidates submitted answers which "took the form of key headings (eg, PaCO2, PaO2, pH, etc) with an accompanying explanation". An alternative approach would be to list the sensor organs, describe what they detect and how they sense it, then the controller, then the effectors. This is the approach favoured by the (presumably, different) group of examiners who were responsible for Question 13 from the second paper of 2015. To please both groups, this chapter will attempt both structures. Wherever possible, the "relative significance of the major factor(s)"  is discussed, and helpful graphs are offered, often stolen directly from the published works of pioneer authors.

Influence of PaCO2 on minute ventilation

So interesting was the topic of ventilatory response to CO2 that in the hands of this tangential author it had extended into a massive digression which ultimately budded into an entire additional chapter.  Because it has never been explored specifically by the college, here the exam candidate will be spared all such drivel, and it will suffice to say that:

  • Increasing PaCO2 causes an increase in minute ventilation.
  • This is mediated by peripheral chemoreceptors over the timescale of seconds, and by central chemoreceptors over minutes.
  • The relationship between PaCOis fairly linear in the range of 45-80 mmHg; the rate of minute volume increases by 2-5L/min per every 1mm Hg of CO2 increase.
    • The CO2/ventilation response curve is shifted to the left by metabolic acidosis and hypoxia
    • Sleep, sedation, anaesthesia and opiates shift the curve to the right and decrease the slope of the curve (i.e. the increase in minute ventilation is reduced per unit rise of CO2)
    • Age decreases the ventilatory response to CO2
    • A high level of physical fitness also diminishes the hypercapnic respiratory drive
  • The response to raised PaCO2 is rapid; about 75% of the maximum minute volume change is achieved over minutes
  • At a stable metabolic rate and with minimal inspired COthe relationship between minute volume and PaCO2 is described by a hyperbolic curve.

Influence of PaO2 on minute ventilation

Unlike CO2 which can also influence the CNS receptors, oxygen tension is only detected by peripheral chemoreceptors (discussed below).  As for CO2, the richness of information regarding ventilatory responses to O2 was so intoxicating that an entire extra chapter was generated by the process of "summarising" it. In brief: 

  • Decreasing PaO2 causes an increase in minute ventilation.
  • As for PaCO2, this is mediated by peripheral 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 pH on minute ventilation

In short, pH influences minute ventilation by acting on central chemoreceptors. Mitchell & Singer (1965), experimenting on an unnamed colleague ("the subject was a 40-year-old male physician") demonstrated that a raised minute volume is a sustained consequence of metabolic acidosis:

effects of sustained metabolic acidosis on ventilation

Obviously, the increased minute ventilation due to this effect will produce a drop in PaCO2, which in turn will ameliorate some of the acidosis (that's the point), and obscure the true relationship between pH and ventilation. On top of that, hypercapnia and hypocapnia will all do a variety of counterproductive confounding things in the periperal circulation and in general wreak havoc on your experiement. In order to isolate the effects  of pH on ventilation, one would need to find a way of abolishing all peripheral effects of acidaemia and CO2 changes. This was done by Schuitmaker et al (1987, who anaesthetised some cats and cannulated their vertebral arteries to exclusively perfuse their brainstems with a controlled PaO2 and PaCO2. The pH of the perfusion blood was controlled by adding small amounts of dilute hydrochloric acid. The authors graphed this in a somewhat peculiar way, choosing hydrogen ion concentration in nmol/L as their x-axis series, and so the graphs from their original publication had to be slightly altered:

isocapnic%20ventilatory%20response%20to%20metabolic%20acidosis.jpg

The bottom line is that pH, irrespective of CO2, will affect your respiratory drive, and the relationship is relatively linear over the survivable range of pH. Additionally, as mentioned above, acidosis will increase the ventilatory responses to hypercapnia and hypoxia.

Influence of pain on minute ventilation

It has generally always been assumed that pain is a respiratory stimulant, but this was not demonstrated scientifically until Borgbjerg et al (1996) tortured a group of healthy volunteers with ouchy calf tourniquets (pressurised up to a sadistic 450 mmHg). Without delving too deep into the gruesome detail, the investigators were able to determine that the slope of the PaCO2-ventilation response curve is unaffected, but the intercept shifts to the left (i.e. similar to what happens in metabolic acidosis). This appears to be a completely unconscious thing: decerebrate cats also seem to increase their minute volume in response to a nociceptive stimulus, a reflex mediated by some neurons scattered over the ventral surface of the medulla (Arita et al, 1988). In human volunteers, there is sufficient evidence to support the idea that this is almost completely without behavioural control, and is mediated by the chemoreceptor area of the medulla - which becomes quite obvious when one's anaesthetised patient increases their respiratory rate in response to an incision in spite of the fact that they are completely unconscious (Sarton et al, 1997).

Influence of body temperature on minute ventilation

Again, this is sensed by peripheral chemoreceptors. According to Nunn's, "ventilatory responses to both hypoxia and CO2 are enhanced by a modest (1.4°C) rise in body temperature". It's another assertion which Nunn's does not give a reference for, but a brief Googling of that statement yields several articles with similar findings. For example, Baker et al (1996) stewed some healthy volunteers in hot water baths (up to a core temperature of 38.5 °C) and found their minute volume almost doubled (from 6.3 L/min to 10.8 L/min) for any given PaCO2 level.  Increased sensitivity of the central chemoreceptors was determined as the most likely mechanism. Peripheral chemoreceptor sensitivity to hypoxia also increases with hyperthermia (Natalino et al, 1977).

Influence of blood pressure on minute ventilation

Aortic body chemoreceptors and (to a lesser extent) carotid body chemoreceptors respond to hypotension and hypertension. This is generally investigated in terms of the ventilatory response to CO2, i.e. looking at how the subject ventilates under hypercapnic conditions before and after the change in blood pressure. In this fashion Heistad et al (1975) exsanguinated some dogs, and occluded the aortas of others, to generate hypotension and hypertension; the animals' responses to CO2 were markedly affected by this. At the same raised PaCO2, the hypotensive animals had a much higher minute volume; i.e. hypertension seemed to dampen the chemoreceptor response to hypercapnia, and hypotension seemed to exaggerate it.

ventilatory response to hypotension from Ohtake et al, 1993

Similarly, Ohtake et al (1993) infused their dogs with sodium nitroprusside and demonstrated some substantial increases in minute volume. Their slightly altered diagram is seen above. As one can see, of the total change in the ventilatory drive, much can be accounted for by the inefficiency of ventilating a poorly perfused lung, i.e. the size of the useless Zone 1 increases so much that the minute ventilation needs to rise substantially to produce the same rate of CO2 clearance. It therefore makes sense to conclude that the change in ventilation from hypotension may be in part a secondary phenomenon following from increasing PaCO2,  especially seeing as under isocapnic conditions the rate of carotid chemoreceptor neuron firing is fairly stable in a blood pressure range between about 60 mmHg and 160 mmHg (Biscoe et al, 1970). The aortic bodies may be more important in this reflex, as they increase their firing rate significantly in response to hypotension ( Lahiri et al, 1980).

Logically, it should follow that hypertension should cause a decrease in ventilation. This, for some reason, does not seem to be studied quite as vigorously, nor is it uniformly present in textbooks (Nunn's does not mention it at all). However, it appears to be a real phenomenon, to the extent that Hoff et al (1950) gave it the name "adrenaline apnea", as respiratory function can cease completely with a sufficiently large dose of catecholamine. In one recorded graphic, the authors gave their decerebrate subject about 400 mcg of adrenaline as a bolus. As one can see from their recording below, all respiratory activity essentially stopped for 90 seconds. 

ventilatory response to hyperension from Hoff et al, 1950

With not a whole lot written on this in the ensuing seventy years, apart from occasional studies in sleeping cats (Trelease et al, 1985), it is not clear what mechanism produces this effect, but it is almost certainly not an action of adrenaline directly on the medulla, as was originally supposed (for one, it does not penetrate the blood-brain barrier). Rather, it may be a caroid baroreceptor reflex; or, at least, cutting both carotid sinus nerves completely abolishes the response to hypertension (Grunstein et al, 1975). The grainy images from these authors' cat recordings (for some reason cats seem to be the favourite victim of carotid sinus researchers) is displayed below with minimal modification. 

ventilatory response to hypertension from Grunstein et al

So, it is clear from these early researchers' data that hypotension and hypertension increase and decrease the ventilatory drive and respiratory responses to hypercapnia. What remains unclear is what the point of this reflex might be, from a physiological perspective. "Could some evolutionary ancestor have derived some sort of survival benefit from becoming apnoeic during periods of extreme hypertension? How could that possibly be of use? There is nothing in the experiments reported here ...to indicate any possible or probable biological function of the phenomenon", Hoff et al shrugged in 1950. There is still a PhD in there for somebody, as far as is possible to tell from a few short minutes of lazy Googling.

Influence of pregnancy on minute ventilation

Pregnancy is probably the only scenario where one may develop a chronic respiratory alkalosis. Though authors disagree on the exact extent and timing (likely reflective of the differences in the populations of pregnant women each author managed to capture), most agree that their rate of increase in minute ventilation is linear, starts early in pregnancy (somewhere in the first trimester) and ends up around 40% above baseline (Milne, 1979). As this happens, PaCO2 falls exactly as it would be expected to.  This seems to be driven by progesterone, which exerts this effect directly on the central integrating controller of respiration (LoMauro et al, 2015)

Effect of exercise on minute ventilation

Exercise increases minute volume under isocapnic conditions and increases the ventilatory sensitivity to hypoxia. This is something amenable to chronic adaptation. Those among us who live largely sedentary lives bathed in the sinister glow of monitors will ventilate much less vigorously and much less efficiently than a trained athlete.  Folinsbee et al (1983) found that conditioned elite cyclists were able to generate a much greater respiratory rate to facilitate the removal of more CO2, and their maximal minute volume was on average 34.6% higher. Weirdly, comparing a group of volunteer sloths to a group of first-division Brazilian soccer players, de Castro et al (2017)  ended up with fairly similar maximal minute volume values for both groups (around 130L/min) which perhaps means that in Brazil even individuals who self-describe as "sedentary" are reasonably fit.

How does this happen, from a mechanism perspective? If one had to invent an answer to the question, one might sensibly intuit that increased work by muscles leads to an increased rate of metabolism which then increases the production of CO2 and therefore increased minute ventilation, but in fact that is not at all what happens. The respiratory control centres do not wait for hypercapnia - respiratory rate and tidal volume increase in tandem with exercise, and sometimes even slightly earlier. There is a central nervous system mechanism which drives both voluntary exertion and ventilation, and there is also a similar mechanism which responds to exertion involuntarily.  To arrive at this conclusion, Eldridge et al (1981) performed a series of macabre experiments on decorticate cats, which are detailed here for no specific educational reason (see stolen images below).

ventilatory response to exercise in the decorticate cat

In short, they removed most of their brains and then stimulated their diencephalon locomotor regions to make these cat-zombies walk on treadmills. The animals' phrenic nerve activity increased with this stimulation, whether they were actually walking on the treadmill or paralysed by some sort of curare toxin (what the authors called "fictive" locomotion). Clearly, the initiation of actual exercise is not essential to produce the ventilatory response to exercise. 

Effect of hyperglycaemia on ventilatory responses

This is a weird area. There is some evidence for direct glucose sensing by Type I cells of the peripheral chemoreceptor complex, and Nunn's brings this up at the end of the section on "things wot peripheral chemoreceptors respond at" (p. 61 of the 8th edition). Trying to track some support for this through the tangle of references, from Nunn's one finds their way to Conde & Peers (2013); the same authors (Conde et al, 2007) were able to demonstrate that hypoglycaemia has absolutely no effect on rat chemoreceptor firing rates, but in this 2013 editorial they were writing about a study by Ortega‐Sáenz et al (2013) which did find some relation in cadaveric human carotid bodies. To summarise, these glomus cells responded to hypoglycaemia which induces an increase in cytosolic calcium and thereby stimulates neurotransmitter release. To summarise even more, hypoglycaemia supposedly increases the respiratory rate. Logically, one might expect hyperglycaemia to dampen the activity peripheral chemoreceptors, but the literature is silent on this issue, as if nobody has ever pureed a rat glomus to test this hypothesis. Again, there's a PhD in there somewhere. 


 

References

Wolff, Christopher B. "The physiological control of respiration." Molecular aspects of medicine 13.6 (1992): 445-567.

Henderson, V. E., and E. Horne Craigie. "On the respiratory centre." American Journal of Physiology-Legacy Content115.3 (1936): 520-529.

Remmers, John E. "A century of control of breathing." American journal of respiratory and critical care medicine172.1 (2005): 6-11.

 Richter, D. W., F. Heyde, and M. Gabriel. "Intracellular recordings from different types of medullary respiratory neurons of the cat." Journal of neurophysiology 38.5 (1975): 1162-1171.

Milne, J. A. "The respiratory response to pregnancy." Postgraduate medical journal 55.643 (1979): 318-324.

López-Barneo, J., et al. "Carotid body oxygen sensing." European Respiratory Journal 32.5 (2008): 1386-1398.

Schuitmaker, J. J., et al. "Ventilatory responses to respiratory and metabolic acid-base disturbances in cats." Respiration physiology 67.1 (1987): 69-83.

Fulop, M. "The ventilatory response in severe metabolic acidosis." Clinical Science 50.5 (1976): 367-373

Mitchell, R. A., and M. M. Singer. "Respiration and cerebrospinal fluid pH in metabolic acidosis and alkalosis." Journal of applied physiology 20.5 (1965): 905-911..

Borgbjerg, F. Molke, Kurt Nielsen, and Jan Franks. "Experimental pain stimulates respiration and attenuates morphine-induced respiratory depression: a controlled study in human volunteers." Pain 64.1 (1996): 123-128.

Arita, Hideho, Naoki Kogo, and Kiyoshi Ichikawa. "Locations of medullary neurons with non-phasic discharges excited by stimulation of central and/or peripheral chemoreceptors and by activation of nociceptors in cat.Brain research 442.1 (1988): 1-10.

Sarton, Elise, et al. "Influence of acute pain induced by activation of cutaneous nociceptors on ventilatory control." Anesthesiology: The Journal of the American Society of Anesthesiologists 87.2 (1997): 289-296.

Baker, Jason F., Robert C. Goode, and James Duffin. "The effect of a rise in body temperature on the central-chemoreflex ventilatory response to carbon dioxide." European journal of applied physiology and occupational physiology 72.5-6 (1996): 537-541.

Natalino, Michael R., Clifford W. Zwillich, and John V. Weil. "Effects of hyperthermia on hypoxic ventilatory response in normal man." The Journal of laboratory and clinical medicine89.3 (1977): 564-572.

Heistad, D., et al. "Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation." Journal of Applied Physiology 39.3 (1975): 411-416.

Biscoe, T. J., G. W. Bradley, and M. J. Purves. "The relation between carotid body chemoreceptor discharge, carotid sinus pressure and carotid body venous flow." The Journal of physiology 208.1 (1970): 99-120.

Ohtake, PATRICIA J., J. K. Walker, and DONALD B. Jennings. "Renin-angiotensin system stimulates respiration during acute hypotension but not during hypercapnia." Journal of Applied Physiology 74.3 (1993): 1220-1228.

Trelease, Robert B., et al. "Respiratory inhibition induced by transient hypertension during sleep in unrestrained cats." Experimental neurology 90.1 (1985): 173-186.

Hoff, Hebbel E., C. G. Breckenridge, and J. E. Cunningham. "Adrenaline apnea in the medullary animal." American Journal of Physiology-Legacy Content 160.3 (1950): 485-489.

Grunstein, M. M., J-Ph Derenne, and J. Milic-Emili. "Control of depth and frequency of breathing during baroreceptor stimulation in cats." Journal of applied physiology 39.3 (1975): 395-404.

LoMauro, Antonella, and Andrea Aliverti. "Respiratory physiology of pregnancy: Physiology masterclass." Breathe11.4 (2015): 297-301.

Castro, Renata Rodrigues Teixeira de, et al. "Minute-ventilation variability during cardiopulmonary exercise test is higher in sedentary men than in Athletes." Arquivos brasileiros de cardiologia 109.3 (2017): 185-190.

Folinsbee, LAWRENCE J., et al. "Exercise respiratory pattern in elite cyclists and sedentary subjects." Medicine and science in sports and exercise 15.6 (1983): 503-509.

Conde, Silvia Vilares, and Chris Peers. "Carotid body chemotransduction gets the human touch." The Journal of physiology 591.Pt 24 (2013): 6131.

Piskuric, Nikol A., and Colin A. Nurse. "Expanding role of ATP as a versatile messenger at carotid and aortic body chemoreceptors." The Journal of physiology 591.2 (2013): 415-422.

Conde, S. V., A. Obeso, and C. Gonzalez. "Low glucose effects on rat carotid body chemoreceptor cells' secretory responses and action potential frequency in the carotid sinus nerve." The Journal of physiology 585.3 (2007): 721-730.

Ortega‐Sáenz, Patricia, et al. "Cellular properties and chemosensory responses of the human carotid body." The Journal of physiology 591.24 (2013): 6157-6173.

Eldridge, Frederic L., David E. Millhorn, and Tony G. Waldrop. "Exercise hyperpnea and locomotion: parallel activation from the hypothalamus." Science 211.4484 (1981): 844-846.