MANIFESTACIONES CLÍNICAS DE LA AR

Brian J. Whipp{ and Susan A. Ward The ventilatory control system is highly complex, involving:

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transmission of primary humoral stimuli from their sites of generation to the sensing elements;

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integration of chemoreceptor afferent activity within brainstem ‘respiratory centres’;

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generation of respiratory motor-discharge patterns;

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neuromuscular transmission at the respiratory muscles; and

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generation of appropriate pulmonary pressure gradients to produce the required airflow and ventilation.

Consequently, while inhalation of

hypercapnic or hypoxic gas mixtures, either singly or in combination, is widely utilised to assess the normalcy of ventilatory

‘chemoreflex’ sensitivity, interpretation of responses should be made in the context of the entire ‘input–output’ relationship.

Individuals with increased airway resistance or impaired respiratory muscle function, for example, may have an abnormally low overall ventilatory carbon dioxide or hypoxic response despite normal chemoreflex responsiveness.

Ventilatory response to inhaled carbon dioxide

The relationship betweenV9Eand arterial (a) or alveolar (A; typically end-tidal (ET)) carbon dioxide tension (PCO2), with the subject sequentially inhaling a series of progressively greater hypercapnic inspirates (e.g. 3–6%), each for sufficiently long to establish a steady state, is used to estimate overall ventilatory carbon dioxide responsive-ness. The resultingV9E–PETCO2relationship is

typically linear in healthy, normoxic individuals, with a slope (DV9E/DPETCO2) averaging ,2–3 L?min^-1?mmHg^-1. This slope reflects the carbon dioxide responsiveness of

Key points

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Ventilatory carbon dioxide responsive-ness is determined as the slope of the linear iso-oxicV9E–PETCO2relationship (DV9E/DPETCO2), using steady-state, constant-concentration inspirates or hyperoxic rebreathing. DV9^E/DP^ETCO2

reflects central and, ifP^aO2is not excessive, also carotid chemoreceptor activity. Being appreciably shorter, the latter test is preferred, although DV9E/ DPETCO2reflects only central

chemoreflex activity.

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Ventilatory hypoxic responsiveness is determined from the curvilinear isocapnicV9^E–P^ETO2response, using steady-state, constant-concentration inspirates or rebreathing. It reflects solely carotid chemoreceptor activity.

ExpressingV9Eversus SaO2linearises the profile, with the slope (DV9E/ DSaO2) providing the hypoxic responsiveness index (however,PaO2, notSaO2, is the actual stimulus). This can also be estimated using the Dejours hypoxia-withdrawal test:

abrupt oxygen administration from a prior hypoxic background acutely suppresses carotid-body activity to cause a transient, rapidV9Edecline;

the maximum decrease as a fraction of the total hypoxicV9Eproviding the hypoxic index.

both the central ‘chemoreceptors’, located predominantly on the ventral medullary surfaces and also, ifPaO2is not excessive, the peripheral chemoreceptors (predominantly, if not exclusively, the carotid bodies in humans).

AtPaO2levels of ,90 mmHg, the central component accounts for 70–75% of the response, with the peripheral component accounting for the remainder. However, as the ‘peripheral’ component of carbon dioxide responsiveness increases with reductions ofPaO2below normal, DV9E/ DPETCO2increases with greater, constant degrees of hypoxaemia and decreases with greater, constant degrees of hyperoxia. This results in a ‘fan’ of hypoxia-dependent carbon dioxide response slopes reflecting altered response ‘sensitivity’ (also termed

‘potentiation’), with little or no change in the extrapolatedV9Eintercept on thePCO2axis (fig. 1). By contrast, sustained metabolic acidaemia or alkalaemia results in a parallel shift by the carbon dioxide response relationship (i.e. no change in carbon dioxide ‘sensitivity’) with a reduced or increasedV9Eintercept, respectively.

The increasing DV9E/DP^ETCO2with greater levels of simultaneous hypoxia reflects a

progressively greater carotid-body response component; it is crucial, therefore, to maintainPaO₂constant (iso-oxic) during the test. Above aPaO2of ,200 mmHg, the carotid-body component is effectively inactivated and hence the sufficiently hyperoxic carbon dioxide response entirely reflects that of the ‘central’ component.

Interpretation depends on the relationships between the typically measuredPETCO2(or, less typically,PaCO2) andPCO2(and hydrogen ion concentration [H⁺]) at each set of chemoreceptors; these relationships depend on factors such as the local-tissue perfusion, carbon dioxide production, carbon dioxide capacitance, H⁺buffering capacity and metabolic rate. The equilibrium process is rapid at the carotid body chemoreceptors, but is considerably delayed at the sites of central chemoreception.

It has been has proposed that three or more levels of inspired (I)PCO2should be used for DV9E/DPETCO2characterisation. Each level is maintained for ,8–10 min, with the average V9EandPETCO2over the final 2–3 min providing the steady-state values.

Consequently, the test is time-consuming, although transiently overshootingPICO2

beyond the required level can reduce the time required to attain the newV9Esteady state.

This concern is obviated, to a considerable extent, by the rebreathing method of Readet al. (1967), which takes a small fraction of the time to perform while providing effectively the same DV9E/DPETCO2value as the steady-state method. The subject re-breathes from a 6–7-L bag initially containing ,7% carbon dioxide balance oxygen. The high initial PICO2is designed to raisePaCO2rapidly to, or close to, the mixed-venous level, such that the subsequent rebreathing provides an effectively linear increase inPaCO2; the high inspired oxygen tension (PIO2) maintains PaO2above levels for which variations in carotid chemosensitivity would influence the response slope.

The rebreathing relationship is shifted to the right of the steady-state relationship, reflecting both the transit delay between the lungs and sites of chemoreception and the 40

Figure 1. Steady-state ventilatory responses to inhaled PCO2at constant oxygen tension (PO2; solid lines). The dotted line depicts the response to progressively increasing P^CO2(hyperoxic rebreathing test).

V9Eresponse kinetics. Consequently, as the test is designed to provide a constant rate of change ofPCO2at the chemoreceptor sites, the rate of change ofV9Eis compared with the rate of change ofPETCO2(DV9E/DPETCO2).

This is currently the more common means of assessing carbon dioxide responsiveness, although it is important to recognise that the carbon dioxide responsiveness obtained by this hyperoxic method reflects only central chemoreflex activity.

One must be careful, however, to assume that hypoxia does not influence central chemoreceptor responsiveness; it does indirectly by increasing cerebral blood flow.

This tends to wash out CO₂from the region, narrowing the difference between the local tissuePCO2andPaCO2.

Beginning at a value below the spontaneous control condition, carbon dioxide

responsiveness is not characterised by the extrapolated dashed lines in figure 1. Rather, there is a region of virtual insensitivity to increasingPCO2, if previously lowered by, for example, acute hyperventilation or sufficient hypoxia. The transition from the insensitive to the sensitive region is considered to reflect a ventilatory recruitment threshold.

The difference between this threshold and the lowerPETCO2at which apnoea ensues is thought to be important in conditions such as sleep apnoea. Also, as this threshold is lower in hypoxia than in hyperoxia, it can be used to further understand the interaction between peripheral and central

chemoreceptor mediation. As a practical expedient, the difference inPETCO2between these conditions at resting ventilation can be used as an index of the threshold change;

Duffin (2011) has suggestedPETO2values of 150 and 50 mmHg for this assessment.

Estimation of ventilatory response to hypoxia

TheV9Eresponse to hypoxia, if defined under isocapnic conditions, is considered solely to reflect carotid chemoreceptor activity. Both constant-concentration inspirate and rebreathing techniques have been successfully utilised for the characterisation.

The pattern of theV9Eresponse to a step decrease ofPIO2is not monotonic, even with PETCO2being maintained as constant by controlling the inspired level (i.e. isocapnic hypoxia). There is an initial increase to a peak, usually well within 5 min, followed by a slow reduction (termed ‘hypoxic ventilatory decline’) to a final steady state (fig. 2a). The initial increase is considered to be the carotid body component and the subsequent decline is thought to result from the hypoxia-mediated increase in cerebral blood flow.

This reduces the degree of central chemoreceptor stimulation as a result of cerebral carbon dioxide wash-out, although an involvement of altered neurotransmission has also been proposed. If the hypoxic step is limited to the initial (or primary) response phase, then the resultingV9E–PaO2

relationship over a range of increasingly hypoxic inspirates is curvilinear, with theV9E rate of change approaching infinity at aPaO2

of ,30 mmHg. Naturally, at higher isocapnic PCO2levels, the curvature constant of the response is increased as a result of greater hypoxic–hypercapnic interaction at the carotid bodies. It is recommended that the subject be switched to air or even a mildly hyperoxic mixture between successive hypoxic steady states to avoid possible depression of brainstem respiratory neurones. If, instead of isocapnia being maintained in this test,PaCO2is allowed to decrease spontaneously asV9Eincreases (poikilocapnia), then both the peak initialV9E response and the final level achieved after the hypoxic ventilatory decline are reduced.

A rebreathing test, notionally similar to the Read–Leigh test of CO₂sensitivity, yields considerably greater data density in a significantly shorter period, although the requirement for isocapnia throughout the test does demand a degree of sophistication in avoiding, by means of a carbon dioxide-absorbing system, the otherwise progressive hypercapnia. The resulting curvilinear response to the progressive isocapnic hypoxia is shown in figure 2b for two subjects differing markedly in hypoxic sensitivity. There is little, from a

physiological standpoint, to choose between an exponential and a hyperbolic

characterisation of the response. The conflicting issues regarding the most appropriate index for hypoxic response characterisation appear to be obviated (on empirical grounds) by the demonstration that the curvilinearV9E–PaO2relationship can be transformed into a linear relationship by substitutingSaO2forPaO2(fig. 2c):

V9E5G?SaO2+ V9E(0)

whereV9E(0)is the controlV9Eand the slope parameter G is the hypoxic responsiveness quantifier. G has been shown to average ,1.5¡1.0 (average¡SD) L?min^-1?% decrease ofSaO₂in normal subjects. At higher isocapnic levels, G is increased as a result of the potentiating effect of carbon dioxide on carotid chemosensitivity, which sums with

the further central carbon dioxide–H⁺ stimulation.

In addition to the ease of measuringSaO2

noninvasively by pulse oximetry, and averting any assumption regarding the difference betweenPETO2andPaO2, the linearity of the V9Eresponse makes this rebreathing method a very practical means of assessing hypoxic ventilatory responsiveness. It is important to recognise, however, that the ventilatory stimulus isP^aO2;S^aO2is merely a practical expedient, with uncertainties regarding the influence of conditions altering haemoglobin affinity for oxygen.

The current degree of a subject’s hypoxic ventilatory drive may be estimated by the hypoxia-withdrawal test of Dejours (1962).

-5 0 5 10 15 20

Control Isocapnic hypoxic step Hypoxic ventilatory

decline

V'EL·min-1PETCO2 mmHg d) 65

Figure 2. a) V9^Etime-course to prolonged isocapnic step-decrease in end-tidal oxygen tension (P^O2). b and c) Ventilatory response to progressive isocapnic hypoxia (in two subjects) as a function, respectively, of end-tidal PO2and oxygen saturation (SO2). d) Ventilatory time-course to a hyperoxic step-increase in an exercising hypoxic subject with alveolar proteinosis. PETCO2: end-tidal carbon dioxide tension. b and c) Reproduced from Rebuck et al. (1981) with permission from the publisher. d) Reproduced from Wasserman et al. (1989) with permission from the publisher.

If a particular level ofPaO2is established by inhalation of a hypoxic gas mixture, or noting the spontaneousPaO2if the subject is already hypoxaemic (as in figure 2d for an exercising subject with alveolar proteinosis), then the abrupt administration of 100% oxygen will acutely suppress carotid-body hypoxic responsiveness and causeV9Eto fall transiently and rapidly. The maximum decrease inV9Eas a fraction of the total hypoxicV9Eprovides the hypoxic index. In addition to the assumption (probably justified in humans) that the consequently high level of oxygen tension (P^O2) actually silences the carotid bodies, the validity of the Dejours test (1962) depends upon theV9Edecrement reaching its nadir prior to the subsequently increasedPaCO2(caused by the reducedV9E) influencing central sites of carbon dioxide responsiveness. As the nadir of the response commonly occurs ,20–25 s after the hypoxic–hyperoxic transition, there is some uncertainty regarding this latter point.

Although this test is quite easy to perform and provides a useful qualitative estimate of hypoxic responsiveness, it remains to be precisely standardised and quantified.

The peripheral-chemosensory potentiation of the carbon dioxide response by hypoxia may also be used to provide an index of hypoxic ventilatory responsiveness, as follows:

1) from the linear difference between the hyperoxic and the hypoxic carbon dioxide response, and

2) the increase inV9Ebetween the hyperoxic (peripheral chemoreceptors silenced) and the hypoxic (40 mmHgPaO2) carbon dioxide response relationship, measured at a standard target level of 40 mmHgP^aCO2(DV⁴⁰).

Conclusions

While these approaches provide indices of acute ventilatory responsiveness,

laboratory-based tests of more chronic blood–gas and acid–base regulatory challenges are less well standardised.

Further reading

N Cunningham DJC, et al. Integration of respiratory responses to changes in alveolar partial pressures of CO2and O2

and in arterial pH. In: Widdicombe JG, et al., eds. Handbook of Physiology, Respiration. Vol II, Control of Breathing, Part 2. Washington DC, American Physiological Society, 1986; pp. 475–528.

N Dejours P (1962). Chemoreflexes in breathing.Physiol Rev; 42: 335–358.

N Dempsey JA,et al. (2004). The ventilatory responsiveness to CO2below eupnoea as a determinant of ventilatory stability in sleep.J Physiol; 560: 1–11.

N Duffin J (2011). Measuring the respiratory chemoreflexes in humans. Respir Physiol Neurobiol; 177: 71–79.

N Edelman NH, et al. Effects of CNS hypoxia on breathing. In: Crystal RG, et al., eds. The Lung: Scientific Founda-tions. 2nd Edn. New York, Raven Press, 1997; pp. 1757–1765.

N Read DJC, et al. (1967). Blood–brain tissue P^CO2relationships and ventilation during rebreathing. J Appl Physiol; 23:

53–70.

N Rebuck AS,et al. Measurement of venti-latory responses to hypercapnia and hypoxia. In: Hornbein T, ed. The Regulation of Breathing. New York, Dekker, 1981; pp. 745–772.

N Severinghaus JW (1976). Proposed stand-ard determination of ventilatory responses to hypoxia and hypercapnia in man.Chest;

70: Suppl. 1, 129–131.

N Wasserman K,et al. Respiratory control during exercise.In: Widdicombe JG, ed.

International Review of Physiology, Respiratory Physiology III. Baltimore, Univ Park Press, 1981; pp. 149–211.

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