Pattern of breathing during hypoxia or hypercapnia of the awake or anesthetized cat

Respiration Physiology (1976) 21, 193-206;

North-Holland Publishing Company, Amsterdam

PATTERN OF BREATHING DURING HYPOXIA OR HYPERCAPNIA OF THE AWAKE OR ANESTHETIZED CAT

HENRY

GAUTIER

Laboratoire de Physiologie, Faculte de Medecine

Saint-Antoine,

27 rue Chaligny, 75012 Paris, France

Abstract.

The breathing patterns during hypoxia and hypercapnia are similar in anesthetized cats but are qualitatively different in awake cats. The differences seen in the awake animals can be explained by either the central depressive effect of hypoxia or by a specific effect of hypercapnia on supra-pontine structures. The Breuer-Hering reflex sensitivity, i.h. the VT-T’] relationship, appears, in the awake cat, quite similar to that recently described in man. The inspiratory activity is shown to be controlled by mechanisms dependent on the nature of the respiratory stimulation. The recent model proposed for the control of inspiration during anesthesia must be modified to account for the results observed in awake animal. Anesthesia Breathing pattern Breuer-Hering reflex Central chemoreceptors

Control of breathing Hypercapnia Hypoxia lnspiratory duration

Several recent works have shown that the decrease in the duration of inspiration associated with increased tidal volume in the intact cat can be accounted f& by the Breuer-Hering reflex (Clark and von Euler, 1972; Grunstein et al., 1973 ; Widdicombe and Winning, 1974; Feldman and Gautier, 1976). Since the Breuer-Hering reflex is sensitive to anesthesia (Bouverot et al., 1970; Phillipson et al., 1971), it is thought that the pattern of breathing, analyzed in terms of VT and respiratory phases durations is likely to be different in the awake and the anesthetized animal. The dependence of TI on VT in the anesthetized cat has led Bradley et al. (1975) to an attractive hypothesis for the control of inspiratory duration by the brain stem respiratory centers. However, there is a question as to whether the hypothesis of Bradley et al. can account for the breathing pattern of the awake animal. According to several works mentioned above, the dependence of Tr on VT is independent of the nature of manoeuvers used to increase VT, such as inflation or breathing of hypoxic or hypocapnic mixtures. This is in agreement with other works in which the ventilatory activity, analyzed in terms of tidal volume and breathing rate, was independent of the nature of the respiratory stimuli used (Hey et al., 1966). Accepted for publication ! April 1976. 193

194

H. GAUTIER

The observations contrast, however, with the initial work of Haldane et al. (1919) which showed that, in awake man, hypercapnia predominantly affects VT, whereas hypoxia predominantly affects breathing rate. The difference between the effects of CO, and hypoxia on breathing patterns has been confirmed recently in animals (Cherniack et al., 1973; Fitzgerald, 1973) and man (Gautier, 1969; Doe11 et al., 1973). The present experiments were designed to study the ventilatory responses of awake or anesthetized cats to hypoxia or hypercapnia. The results show the classical depressive effect of anesthesia on the overall ventilatory response (VT x f) and on the inspiratory slope (VT x TI- ‘) or rate of increase of inspiratory activity considered as an index of respiratory drive (Barcroft and Margaria, 193 1; von Euler et al., 1970). In addition, it is shown that the pattern of breathing is dependent on the nature of the ventilatory stimulation and is also greatly affected by anesthesia.

Methods The experiments were performed on eleven healthy, adult, intact anesthetized awake cats with a mean body weight of 2.8 kg.

or

EXPERIMENTS ON ANESTHETIZED ANIMALS

Animals were anesthetized with sodium pentobarbital using an initial dose of Additional doses were given as required 30 mg . kg _ 1 injected intraperitoneally. to maintain surgical anesthesia. In order to record breathing, animals were intubated and connected to a heated Fleisch pneumotachograph which gave, by means of a transducer, the pneumotachogram and, after integration, the spirogram. Inspired and end-tidal concentrations of CO, and 0, were monitored throughout the experiments. At least 30 minutes after the beginning of anesthesia, the control ventilation of the cat breathing room air was recorded. Following this, the animal was given hypercapnic or hypoxic mixtures to breathe. The ventilatory response to COZ was studied with the animal breathing mixtures containing increasing concentrations of CO, up to 7 per cent with the oxygen concentration maintained at 21 per cent. The response to hypoxia was studied using mixtures containing decreasing concentrations of 0, down to 7 or 8 per cent. During hypoxia, the end-tidal concentration of CO, was either allowed to decrease because of the hyperventilation (hypocapnic hypoxia), or maintained constant at the control air breathing level by adding small amounts of CO, to the inspired gases (normocapnic hypoxia). When the recordings were completed in the anesthetized animal, a small teflon catheter was fixed in the trachea, allowing sampling of alveolar gases during the following awake state (Scotto and Naitove, 1970). Body temperature was kept constant at 38 “C by external heating throughout the experiments.

BREATHING EXPERIMENTS

IN AWAKE

PATTERN

OF THE AWAKE

OR ANESTHETIZED

195

CAT

ANIMALS

A week after the initial anesthesia, ventilation was measured in a plexiglass plethysmograph as initially described by Drorbaugh and Fenn (1955) and modified by Bartlett and Tenney (1970). In sessions lasting up to 3 hours, the ventilation of the cat was monitored with the plethysmograph flushed with hypoxic or with hypercapnic mixtures of the same composition which had been used in recording sessions under anesthesia. For each cat, there were at least 4 satisfactory sessions on separate days. Inspiratory and expiratory durations and tidal volume were computed from the pneumotachogram and its integration for the anesthetized animals and from changes of pressure in the plethysmograph for awake animals. All measurements were made during steady-states, when the animal breathed a given gas mixture for at least 6 minutes. TE,sec \il.ml.sec-’ 100

Tlsec 0. Hypercapnia . awake O anesth.

\j,l.min-’

1

40 PA

Fig.

1. Tidal

and

mean

volume

inspiratory

1

I

50

40

coz,torr

(VT), inspiratory flow (VI) during

I

Pa,$O~~

duration

(TI). expiratory

hypercapnia

duration

in a typical

animal

(TE), ventilatory

awake

(continuous

output

(V)

line) or

anesthetized (broken line). VI representing the rate of rise of inspiratory activity was computed from the ratio of VT over TI. In all figures, each point represents the mean of 5 consecutive breaths and lines connecting

values have been drawn

by eye.

196

H. GAUTIER

Results VENTILATORY RESPONSES TO co,

BREATHING

When the anesthetized animal breathed room air, as compared to the awake state, the ventilation was reduced and consequently, alveolar Pco2 was increased (fig. 1). During hypercapnia, the ventilatory output was increased proportionally to the alveolar Pco2 and the mean value of the ratio $‘/PA,,, was, in 10 animals, significantly higher in the awake (150_+ 11 ml . torr-‘) than in the anesthetized animals (72_+ 9 ml . torr- ‘). Similarly, the relationship between the slope of the inspiratory portion of the spirogram (VT/TI) and the alveolar PcoZ was approximately linear during hypercapnia and was greatly decreased during anesthesia (fig. 1).

PATTERN OF BREATHING DURING co,

BREATHING

Although the spirogram may present some day to day variations in the awake animal, the duration of the respiratory phases (TI and TE) remained always smaller, and the tidal volume greater, than in the anesthetized animal (fig. 1). .When the alveolar P co2 increased, a progressive increase in tidal volume and decrease in TE were observed in both the awake and the anesthetized animal. TI, however, decreased gradually during anesthesia, but showed only small changes in the awake state; it usually increased slightly with small concentrations of CO, and decreased thereafter, reaching values fairly similar to those during air breathing. The differences in the pattern of breathing observed in the awake and anesthetized VT,mt

I

I

I

I

Hypercapnia . awake o anesth.

100

50

0

I

I

I

I

I

1.0

1.5

1.0

1.5

2.0

TE,sec Tl,sec Fig. 2. Tidal volume plotted against inspiratory and expiratory durations in the same cat shown in fig. 1, awake (continuous line) or anesthetized (broken line) during hypercapnia.

BREATHING PATTERN OF THE AWAKE OR ANESTHETIZED CAT

7’1,sec

197

I

I

.

awake

o anesth. I

I

1.0

1.5

TE,

I I

set

Fig. 3. Expiratory duration plotted against inspiratory duration in the same cat shown in figs. 1 and 2, awake (continuous line) or anesthetized (broken line) during hypercapnia.

animals reported above were consistently observed in all cats studied ; they can be seen also very clearly on the classical VT-TI plot (fig. 2). Finally, because of the respective changes observed in Tr and TE, a linear relationship between these parameters was observed only during anesthesia (fig. 3).

VENTILATORY RESPONSES TO NORMOCAPNIC HYPOXIA

As is well established, the relationship between the ventilation and the alveolar PO, is not linear, however, an index of the responsiveness of the animal to hypoxia may be represented by the ventilatory output corresponding to a given alveolar Po,. Thus, for a Po, of 45 torr for example, the mean ventilator-y output of 3 animals studied in the same conditions was 1900 ml . min - ’ when awake and only 730 ml - min-’ during anesthesia. Similarly, the relationship between the inspiratory slope and alveolar Po, was depressed as indicated in fig. 4.

PATTERN OF BREATHING DURING NORMOCAPNIC HYPOXIA

For any Po,, the duration of the respiratory phases remained generally shorter and tidal volume larger in the awake as compared to the anesthetized animal (fig. 4). In both conditions, when PO, decreased and the alveolar Pco2 was maintained constant, there was a proportional decrease of phase durations and an increase of the tidal volume (fig. 4). Thus, the VT-TI and VT-TE relationships showed approx-

198

H. GAUTIER I

I

TE.sec

1

I

91, ml.sec-’

0.5 L Tt,sec 1.5 Hypoxia

\j.l.min-’

1.0 I VT,rnl

50

t

I

40

1

1

60

80

OLI

I

100

I

I

40

data (same symbols

as fig. 1) ofa typical animal awake (continuous

(broken

line) during

normocapnic

line) or anesthetized

hypoxia.

I

I

I

Hypoxia

VT,ml

.

J n

50

..

09 \ . . il.2

q

.

anesth.

..

\ f\$

n

UN__

%o [email protected]

-&

OI I 1.0 Fig. 5. Tidal volume

. awake

.

n

[7 X%

awake

100 PAo2::U

PA,,

Fig. 4. Ventilatory

I

1

60

1.5 TI ,sec plotted against

(continuous

O-O-O-

_ _o,o

I

I

1.0

1.5 TE,sec

inspiratory

line) or anesthetized

and expiratory (broken

durations

line) during

in the same cat shown in fig. 4. normocapnic

hypoxia.

BREATHING

PATTERN

OF THE AWAKE

OR ANESTHETIZED

199

CAT

imately the same trends in the awake and in the anesthetized animal (fig. 5). Similarly, there was a simultaneous decrease of TI and TE. The relationship between them appeared curvilinear in the cat represented in fig. 6; this, however, was not always the case as the relationship was often linear. I

I

1 Tl.sec

1.5

1.0

Hypoxia . awake q anesth. I

I

1.0

1.5

I

TE ,sec Fig. 6. Expiratory

duration

(continuous

plotted

against

inspiratory

line) or anesthetized

(broken

duration

in the same cat as in figs. 4 and 5, awake

line) during

normocapnic

I

I

hypoxia.

I

1

VT,ml

Hypoxia

. .

50

.

with

.

. hypocapnia

\

. normocapnia -\.

PA,+,torr \

.t

31

.

0 1.0

0.5 Fig. 7. Tidal volume

plotted

1.0

0.5 TE,sec

TI ,sec against

inspiratory

normocapnic

and expiratory or hypocapnic

durations hypoxia.

in a typical

awake

cat during

200

H. GAUTIER

PATTERN OF BREATHING IN HYPOCAPNIC

HYPOXIA

As expected, the ventilatory output was smaller in hypocapnic hypoxia than in normocapnic hypoxia in both the anesthetized and the awake animal. For an alveolar PO, of 45 torr, the mean ventilation was 900 ml . min- ’ in the awake cats and 415 ml . min- ’ m . the anesthetized cats during hypocapnia, as opposed to 1900 ml . min-’ and 730 ml . min- ’ during normocapnia. In the 6 cats studied during hypoxia, the pattern was consistently different between hypocapnic and normocapnic hypoxia (fig. 7). There was a small, nonsignificant, increase in tidal volume during hypocapnic hypoxia, and a large decrease in respiratory phase durations.

Discussion The results of the present experiments demonstrate the effects of anesthesia on the overall ventilatory response to respiratory stimuli and on the pattern of breathing. Moreover, they indicate that the precise changes in breathing pattern resulting from different respiratory stimulations are dependent on the nature of the stimulus.

ANESTHETIZED ANIMALS

The ventilatory response to CO, and to hypoxia is depressed during anesthesia. This observations confirms many reports of the effects of anesthesia on the CO, response (Wang and Nims, 1948; Richardson and Widdicombe, 1969) or on the response to hypoxia (Honda and Natsui, 1967; Weiskopf et al., 1974). In the anesthetized animal, the increase in ventilation observed during hypoxia and during hypercapnia is associated with similar changes of the spirogram, namely, simultaneous decreases in TI and TE with an increase in VT. Therefore, the Breuer-Hering reflex can, in this state, account for the dependence of TI on lung volume for different respiratory stimulations (Widdicombe and Winning, 1974) : stimulation of the chemoreceptors increases the rate of augmentation of inspiratory activity, as estimated by the change in the slope of the inspiration or the mean inspiratory flow and, because of the time course of the volume-threshold for the Breuer-Hering reflex termination of inspiration, the tidal volume will be increased and the duration of inspiration reduced (Clark and von Euler, 1972). In addition, the simultaneous decrease of TE, owing to mechanisms which have been studied recently (Gautier et al., 1973; Knox, 1973) will eontribute to an increase in the breathing rate. TE seems to be dependent on TI since a roughly linear relationship was found between Tr and TE especially during hypercapnia (Clark and von Euler, 1972 ; Widdicombe and Winning, 1974). Different results have been reported by Garcia and Cherniack (1967) and Cherniack et al. (1970/1971). These authors have

BREATHING

PATTERN

OF THE AWAKE OR ANESTHETSZED

201

CAT

shown that, in the anesthetized dogs paralyzed in order to avoid alteration of the breathing pattern due to the mechanical properties of lung and chest wall, hypercapnia tended to increase the amplitude of inspiratory discharge rather than the breathing rate, while hypoxia had the opposite effect on the phrenic nerve pattern. The reason for this difference in behavior between anesthetized, curarized dogs and anesthetized cats may be due to the differing measures of respiratory center output or, simply, a species difference. In fact, the behavior of anesthetized, paralyzed dogs is quite similar to that of our awake cats. Finally, it should be noted that in the anesthetized animal, the rate of increase of inspiratory activity (VT/TI) in always reduced for a given humoral drive when compared to that in an awake one. If the volume-threshold curve was the same in awake and anesthetized animal, there would have been a prolongation of TI and a reduction of VT in the latter.

AWAKE ANIMALS

The qualitative difference in the respiratory response observed in this study during hypoxia and hypercapnia in the awake cat is in contrast with the results of Phillipson et aI. (1970) and Jennings and Macklin (1972) in awake dogs and Hey et al. (1966) in awake men. These authors observed that the breathing pattern responses were similar for different respiratory stimulations. Although the divergence of the results may be explained by species differences only, it should be noted that in the above reports, the breathing patterns were analyzed in terms of tidal volume and breathing rate only. I

I

VT. ml

-I

I

. Hypercapnia

I

. Hypoxia

‘1.. :.. . :=y& \

l*

.‘$. *

I

I

0.5

1.0

.

.’ 1.5

1.0

TE set

TI ,set Fig. 8. Tidal volume plotted against inspiratory

and expiratory

capnia or normocapnic

durations

hypoxia.

in an awake cat during hyper-

202

H. GAUTIER

The differences observed in the respiratory pattern during hypoxia and hypercapnia, as indicated by the changes in the VT-TI relationship in the awake animal (fig. 8) may be due to indirect peripheral responses that can affect the respiratory system, or to direct effects of these stimuli on the respiratory centers. Peripheral responses might include the changes in respiratory mechanics resulting from changes in humoral factors. For example an increase in FRC is observed during hypoxia (Bouverot and Fitzgerald, 1969) but not during hypercapnia (Daubenspeck, 1972). This change in FRC or intra-pulmonary volume would alter the pulmonary stretch receptors discharge and modify the volume-threshold curve during hypoxia. It has also been shown that CO, can modify the stretch receptor discharge in the rabbit (Mustapha and Purves, 1972) and can also stimulate the frequency of breathing by an action somewhere in the lung (Bartoli et al., 1974). However, since the differences in the respiratory pattern persist after vagotomy in both the anesthetized dog (Cherniack et al., 1973) and the awake cat (Gautier, 1975), the receptors that mediate the response must be elsewhere. Moreover, in the latter report, the animals were tracheotomized, thus ruling out the possible role of the larynx in determining the pattern of breathing in these conditions. The different characteristic ventilatory responses to CO, and hypoxia observed in the awake animal might be caused by a specific central effect of these stimuli on the mechanisms responsible for the termination of the inspiration. a. Hypoxia

The effects of hypoxia on the neuronal activity of the respiratory centers have received very little attention (Batsel, 1965) and only few indications can be inferred from experiments where lesions were made in the central nervous system. Thus, Rosenstein et al. (1973) have shown that the pattern of breathing of decerebrated, non anesthetized cats, analyzed in terms of tidal volume and breathing rate is largely independent of the alveolar Po,. This suggests that the difference between hypoxic and hypercapnic responses may be mediated by supra-pontine structures. Furthermore, it has been suggested by Tenney et a/. (1971) that hypoxia has a cortical inhibitory effect and a diencephalic facilitatory effect on breathing. The role of these structures in the ventilatory response to hypercapnia has not been documented making the comparison between the two respiratory stimuli impossible. However, more recent works have re-evaluated the direct central depressive action of hypoxia that interacts with the facilitatory action known to originate in the arterial chemoreceptors (Miller and Tenney, 1975a, b). The depression caused by hypoxia was shown in awake cats with carotid sinus nerves cut which exhibited a reduction in tidal volume and an increase in breathing rate. Conversely, inhalation of pure oxygen by the same animals was followed by an increase in tidal volume. Thus, the ventilatory response to hypoxia in an intact animal reflects a balance between the tonic facilitatory carotid body chemoreceptor input and the direct central depression due to the low central P,,.

BREATHING

PATTERN

OF THE AWAKE OR ANESTHETSZED

CAT

203

During hypocapnic hypoxia, as compared to normocapnic hypoxia, the tidal volume was reduced; the breathing rate increased in both conditions. The reduction in the tidal volume results probably from the classical inhibitory effect of hypocapnia on breathing. However, another explanation was put forward by Cherniack et al. (1970/1971); these authors suggested that the CO,, by increasing cerebral blood flow, relieves cerebral hypoxia and increases brain oxygenation, thereby maintaining the respiratory neuronal activity. It is interesting to note that the difference in the pattern of breathing between hypocapnic and normocapnic hypoxia is not observed in man (Reynolds and Milhorn, 1973). b. Hypercapnia

An alternative explanation for the different respiratory pattern observed in hypoxia and hypercapnia can be proposed if we examine the VT-TI relationship in the awake animal breathing CO, mixtures. TI decreased consistently in all cats only when VT exceeded 65 to 70 ml, that is to say, 2 to 3 times the tidal volume during air breathing. This means that, in hypercapnia, the respiratory pattern ,of the awake cat was very similar to that of the awake man under the same conditions (Clark and von Euler, 1972; Cunningham and Gardner, 1972). Consequently, comparison of the breathing pattern of the anesthetized cat with that of the awake man (Clark and von Euler, 1972) may lead to an incorrect evaluation of the Breuer-Hering sensitivity of cat and man. In fact, it seems that the sensitivity of the Breuer-Hering reflex, as judged by the VT-TI relationship, is quite similar in awake cat or man. This sensitivity may be different in conscious dog, since Phillipson (1974) using a different approach, found that the Breuer-Hering reflex was operating at small lung volume. The relative independence of Tt and VT in the awake cat during hypercapnia, as compared with the anesthetized state, can be explained by the particular effect of anesthesia on the Breuer-Hering reflex (Bouverot et al., 1970; Phillipson et al., 1971). Since the respiratory response is qualitatively the same in the anesthetized cat and in the decerebrated, unanesthetized preparation (von Euler et al., 1970; Rosenstein et al., 1973) it is suggested that the CO, affects the breathing pattern via supra-pontine structures in the awake animal. For a given identical respiratory stimulation calculated form the rate of increase of inspiratory activity caused by CO, or hypoxia, TI is shorter during hypoxia than during hypercapnia (fig. 9). The same reasoning may be applied to the results concerning the tidal volume. Finally, the similar breathing pattern observed in awake or anesthetized animals may be caused by the similar depressing effect of hypoxia on the brain in both states. The difference in the pattern during hypercapnia, on the other hand, may be caused by the enhanced sensitivity of the Breuer-Hering reflex during anesthesia. Thus, the pattern of breathing during hypercapnia or hypoxia will be approximately the same during anesthesia but different in the awake state. The supra-pontine mechanisms sensitive to hypoxia or hypercapnia and responsible for the difference in the breathing pattern are likely to act at the level of the inspiratory off-switch mechanism in the model proposed by Bradley et al. (1975),

204

H. GAUTIER

Hypercapnia 1.0

l

_ *

’ sm . .

l

l

\

-0 .

. . \.

\

+ ‘.

l4

E

Hypoxia \i

0.5 L_ I

I

0

50

I 100

til, ml.sec-’ Fig. 9. Inspiratory duration plotted against the mean inspiratory flow (VT TI- ‘) in an awake cat (same animal as in fig. 8), during hypercapnia or normocapnic hypoxia.

but central recordings of respiratory activity during hypoxia are necessary to test this hypothesis. The pneumotaxic center does not seem to be a necessary structure for these responses since a qualitative difference in the respiratory response was seen after iesions of the pneumotaxic center (St. John, 1973). The duration of expiration decreases in all cases whatever the nature of the stimulation and the changes in TI. The relationship between TI and TE is different in hypoxia and hypercapnia in the awake animal suggesting that, at least in the awake animal, the control of TE is relatively independent of TI and is therefore mediated through a mechanism more complex than the one proposed by Clark and von Euler (1972).

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