James Duffin

Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO(2) (Pa(CO(2))). This physiological response, termed cerebrovascular CO(2) reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO(2) from brain tissue, thereby attenuating the rise in central Pco(2), whereas hypocapnia causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of brain tissue Pco(2). Cerebrovascular reactivity and ventilatory response to Pa(CO(2)) are therefore tightly linked, so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO(2), primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupneic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, and exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO(2) that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude. In this review, we summarize the major factors that regulate CBF to emphasize the integrated mechanisms, in addition to Pa(CO(2)), that control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO(2). Next, we provide a detailed update on the integration of the role of cerebrovascular CO(2) reactivity and CBF in regulation of chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.

Prospective targeting and control of end-tidal CO2 and O2 concentrations

Current methods of forcing end‐tidal PCO2 (PETCO2) and PO2 (PETO2) rely on breath‐by‐breath adjustment of inspired gas concentrations using feedback loop algorithms. Such servo‐control mechanisms are complex because they have to anticipate and compensate for the respiratory response to a given inspiratory gas concentration on a breath‐by‐breath basis. In this paper, we introduce a low gas flow method to prospectively target and control PETCO2 and PETO2 independent of each other and of minute ventilation in spontaneously breathing humans. We used the method to change PETCO2 from control (40 mmHg for PETCO2 and 100 mmHg for PETO2) to two target PETCO2 values (45 and 50 mmHg) at iso‐oxia (100 mmHg), PETO2 to two target values (200 and 300 mmHg) at normocapnia (40 mmHg), and PETCO2 with PETO2 simultaneously to the same targets (45 with 200 mmHg and 50 with 300 mmHg). After each targeted value, PETCO2 and PETO2 were returned to control values. Each state was maintained for 30 s. The average difference between target and measured values for PETCO2 was ± 1 mmHg, and for PETO2 was ± 4 mmHg. PETCO2 varied by ± 1 mmHg and PETO2 by ± 5.6 mmHg (s.d.) over the 30 s stages. This degree of control was obtained despite considerable variability in minute ventilation between subjects (± 7.6 l min−1). We conclude that targeted end‐tidal gas concentrations can be attained in spontaneously breathing subjects using this prospective, feed‐forward, low gas flow system.

The entrainment of breathing frequency by exercise rhythm.

1. The incidence of entrainment of breathing frequency by the rhythm of exercise was detected by a cross‐correlation of the two frequencies. 2. During moderate, steady‐state exercise on a bicycle ergometer at 50 rev/min, eight of fifteen volunteers (53%) showed entrainment when pedalling speed was kept constant with a metronome, and three of fifteen volunteers (20%) showed entrainment when pedalling speed was kept constant with a speedometer. 3. At 70 rev/min, in a second group of fifteen volunteers, the results were nine of fifteen (60%) and five of fifteen (33%) respectively. 4. During moderate, steady state exercise on a treadmill, in a third group of fifteen volunteers, eight of 15 volunteers (53%) showed entrainment while walking, and twelve of fifteen volunteers (80%) showed entrainment while running. 5. It is concluded that the rhythm of exercise is likely to affect the rhythm of breathing and that this controlling factor must be considered during studies of breathing pattern in exercise.

The effect of hypoxia on the ventilatory response to carbon dioxide in man.

We used rebreathing with prior hyperventilation to measure ventilatory responses to CO2 at iso-oxic PO2s of 100, 80, 60 and 40 mmHg in seven subjects. The mean sub-threshold ventilation (S.E.) of 7.60 (1.31) L min-1 did not vary with iso-oxic PO2. The mean peripheral-chemoreflex threshold of 41 (0.6)) mmHg PCO2 at an iso-oxic PO2 of 100 was greater than 39 (1.2) and 39 (0.6) at 60 and 40, respectively. The mean peripheral-chemoreflex sensitivity of 11.5 (5.2) L min-1 mmHg-1 at an iso-oxic PO2 of 40 was significantly greater than 3.0 (1.3), 2.7 (1.2) and 2.4 (1.2) at 60, 80 and 100, respectively. The mean central-chemoreflex threshold of 45 (1.5) mmHg PCO2 at an iso-oxic PO2 of 40 was significantly less than 48 (0.4) and 48 (0.7) at 80 and 100, respectively. The mean central-chemoreflex sensitivity of 5.0 (1.1) L min-1 mmHg-1 did not vary with iso-oxic PO2. These findings provide insights into the control of breathing in humans, including the implication that CO2 must exceed its peripheral-chemoreflex threshold before hypoxia can effectively increase ventilation.

The neuronal determinants of respiratory rhythm

Abbreviations

The cerebrovascular response to carbon dioxide in humans

Non‐technical summary  Two mechanisms control brain blood flow by changing blood vessel diameter: autoregulation maintains flow in the face of perfusion pressure changes, and brain metabolism adjusts flow to meet metabolic requirements. Brain blood vessel reactivity to CO2 and O2 is an important component of the latter. We used a specialised rebreathing technique to change CO2 over a wide range at constant O2, estimating brain blood flow responses from measurements of middle cerebral artery flow velocity. We found that below a threshold CO2, blood pressure was unchanged, but blood flow increased in response to CO2. This response had a sigmoidal shape, centred at a CO2 close to resting. Above the threshold, both blood flow and pressure increased with CO2. We concluded that this method measures the brain blood flow reactivity to CO2 without the confounding influence of blood pressure changes. The results obtained contribute to our understanding of brain blood flow regulation.

Non-invasive prospective targeting of arterial P(CO2) in subjects at rest.

Accurate measurements of arterial P  CO 2 (P  a,CO 2 ) currently require blood sampling because the end‐tidal P  CO 2 (P  ET,CO 2 ) of the expired gas often does not accurately reflect the mean alveolar P  CO 2 and P  a,CO 2. Differences between P  ET,CO 2 and P  a,CO 2 result from regional inhomogeneities in perfusion and gas exchange. We hypothesized that breathing via a sequential gas delivery circuit would reduce these inhomogeneities sufficiently to allow accurate prediction of P  a,CO 2 from P  ET,CO 2. We tested this hypothesis in five healthy middle‐aged men by comparing their P  ET,CO 2 values with P  a,CO 2 values at various combinations of P  ET,CO 2 (between 35 and 50 mmHg), P  O 2 (between 70 and 300 mmHg), and breathing frequencies (f; between 6 and 24 breaths min−1). Once each individual was in a steady state, P  a,CO 2 was collected in duplicate by consecutive blood samples to assess its repeatability. The difference between P  ET,CO 2 and average P  a,CO 2 was 0.5 ± 1.7 mmHg (P= 0.53; 95% CI −2.8, 3.8 mmHg) whereas the mean difference between the two measurements of P  a,CO 2 was −0.1 ± 1.6 mmHg (95% CI −3.7, 2.6 mmHg). Repeated measures ANOVAs revealed no significant differences between P  ET,CO 2 and P  a,CO 2 over the ranges of P  O 2, f and target P  ET,CO 2. We conclude that when breathing via a sequential gas delivery circuit, P  ET,CO 2 provides as accurate a measurement of P  a,CO 2 as the actual analysis of arterial blood.

A review of the control of breathing during exercise

During the past 100 years many experimental investigations have been carried out in an attempt to determine the control mechanisms responsible for generating the respiratory responses observed during incremental and constant-load exercise tests. As a result of these investigations a number of different and contradictory control mechanisms have been proposed to be the sole mediators of exercise hyperpnea. However, it is now becoming evident that none of the proposed mechanisms are solely responsible for eliciting the exercise respiratory response. The present-day challenge appears to be one of synthesizing the proposed mechanisms, in order to determine the role that each mechanism has in controlling ventilation during exercise. This review, which has been divided into three primary sections, has been designed to meet this challenge. The aim of the first section is to describe the changes in respiration that occur during constant-load and incremental exercise. The second section briefly introduces the reader to traditional and contemporary control mechanisms that might be responsible for eliciting at least a portion of the exercise ventilatory response during these types of exercise. The third section describes how the traditional and contemporary control mechanisms may interact in a complex fashion to produce the changes in breathing associated with constant-load exercise, and incorporates recent experimental evidence from our laboratory.

Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease

Although sleep apnoea is very common in patients with end-stage renal disease, the physiological mechanisms for this association have not yet been determined. The current authors hypothesised that altered respiratory chemo-responsiveness may play an important role. In total, 58 patients receiving treatment with chronic dialysis were recruited for overnight polysomnography. A modified Read rebreathing technique, which is used to assess basal ventilation, ventilatory sensitivity and threshold, was completed before and after overnight polysomnography. Patients were divided into apnoeic (n = 38; apnoea/hypopnoea index (AHI) 35±22 events·h-1) and nonapnoeic (n = 20; AHI 3±3 events·h-1) groups, with the presence of sleep apnoea defined as an AHI >10 events·h-1. While basal ventilation and the ventilatory recruitment threshold were similar between groups, ventilatory sensitivity during isoxic hypoxia (partial pressure of oxygen (PO2) 6.65 kPa) and hyperoxia (PO2 19.95 kPa) was significantly greater in apnoeic patients. Overnight changes in chemoreflex responsiveness were similar between groups. In conclusion, these data indicate that the responsiveness of both the central and peripheral chemoreflexes is augmented in patients with sleep apnoea and end-stage renal disease. Since increased ventilatory sensitivity to hypercapnia destabilises respiratory control, the current authors suggest this contributes to the pathogenesis of sleep apnoea in this patient population.

Measuring cerebrovascular reactivity: what stimulus to use?

Abstract  Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer‐controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.