blood circulation in the skin of the cat under halothane anaesthesia

Acta anaesth. Scandinav. 1965, 9, 191-201.

BLOOD CIRCULATION I N THE SKIN OF THE CAT UNDER HALOTHANE ANAESTHESIA

BY

P. LINDGREN, L. WESTERMARK and A. WAHLIN

During consciousness the control of the distribution of blood between different tissues is of great importance as considerable haemodynamic demands are made as a result of the individual's activity. Under anaesthesia, on the other hand, ' the regulative mechanisms are progressively inactivated as the depth of anaesthesia increases.

Concerning the effect of halothane on the circulatory system, it is mainly the changes in the cardiac functions and the arterial blood pressure that have hitherto attracted attention. During the last few years, however, the importance of the peripheral circulation for haemodynamics (review by COOPER ( 1962)3) has come into the foreground.

In conformity with the plan stated in an earlier study on the effect of halothane on the muscular blood flow (LINDGREN, WESTERMARK and WAHLIN (1964)12), viz. to investigate the effect of the substance on separate, homo- geneous tissues, we have chosen here to study the circulatory changes in the skin of the cat.

MATERIAL AND M E T H O D S

The experiments were performed on 21 heparinized cats weighing 3-5 kg under NembutalB as basal anaesthesia. The animals were tracheostomized and ventilated by means of a Palmer pump, usually with air, but in some cases with oxygen.

The reason for ventilating the animals artificially was stated by us in a previous article (LINDGREN, WESTERMARK and WAHLIN ( 1964)12). The main object is to eliminate the influence of a respiratory depression upon the blood flow, especially in deep anaesthesia.

From the Department of Anaesthesiology (Head: T. GORDH), the King Gustaf V Research Institute (Head: G. BIRKE), Karolinska Sjukhuset, and the Department of Pharmacology (Head: B. UVN&), Karolinska Institutet, Stockholm 60, Sweden. Received December 21, 1964.

192 P. LINDGREN, L. WESTERMARK AND A. WAHLIN

Blood pressure was in all experiments recorded in the brachial or in the femoral artery by means of a mercury manometer connected to the artery through a tube filled with saline.

Cutaneous bloodflow in a hind-leg paw was measured with the photo-electric drop-recording technique previously described by LINDCREN ( 1958)’l).

In eight of the experiments two recordiq units were used, one on the arterial side (A. tib. ant.), the other on the venous side ( V . saph. parva). The arterial and venous initial flows were of about the same size. In all calculations the initial flows were expressed as 100 per cent, as previously described by LINDCREN, WESTERMARK and WAHLIN ( 1964)12).

Perifheral resistance was calculated according to GREEN, LEWIS, NICKERSSON and HELLER ( 1944)8. The arterial :flow was used for the calculations.

Administration of halothane or ether.-After steady values of the blood pressure and of the flows had been established, halothane or ether was administered. For administration of halothane a Fluotec Mark I1 vaporizer (Cyprane Ltd., Buffalo, N.Y.) was connected to the inlet of the Palmer pump. The Fluotec vaporizer is graded from 0.5 to 4% valid for free flows of gas, according to the manufacturer. When the vaporizer was connected to the working Palmer pump, the concentrations of halothane obtained are about 20 per cent lower than the dial settings, as shown by H A L ~ N , WESTERMARK and WAHLIN (1964) 9. The Boyle vaporizer (B.O.C., London, England), graded in the units 1, 1.5, 2, 2.5, 3 and “full”, was used for administration of ether and connected to the ventilator in the same way as the Fluotec.

The compounds used were:- Fluothanem (I.C.I.). Ether AD Narcosin, Sv. Ph. Ed. XI. Heparin@ 5000 I.E./kg (AB Vitrum).

RESULTS

As the blood flow in the skin proved to be highly dependent of the depth of anaesthesia, it appeared necessary to study the influence of halothane at different stages of anaesthesia. Therefore the basal anaesthesia-necessary in order to perform the experiments-was kept so light as to preserve certain reflexes. The corneal and pinna reflexes and other easily tested reflexes were chosen as tests of the depth of anaesthesia. To study the effects of a successively increasing depth of anaesthesia the control level of anaesthesia had to be light. In this situation, however, it was difficult to create a sufficiently long control period of undisturbed flow, since under light basal anaesthesia even weak stimuli could temporarily almost stop the skin blood flow. Therefore-as a complement to the studies of the peripheral circulation during increasing anaesthesia-the reactions during decreasing anaesthesia after cessation of the halothane exposure were also recorded (fig. 2). In favourable experiments, the values of blood pressure and blood flow were remarkably similar during the disappearance and reappearance of the reflexes.

BLOOD CIRCULATION IN THE SKIN OF THE CAT 193

MWD PRESWRE

KO00 Nm Y PER CENT OF RESTING LEVEL

I.TIIM v Y R P

FIG. 1.-Changes of pulse rate, blood pressure, arterial and venous blood flow, and peripheral resistance during exposure to halothane.

The first phase shows a continuous exposure with increasing dial settings of halothane (1, 1.5, 2, 2.5, 3, 4%). The reflexes under observation disappeared during the first period of this phase. After a few minutes of recovery without return of reflexes the exposure of

4% was repeated. Signs of increasing depth of anaesthesia:- 1. Disappearance of the corneal reflex. 2. Reduction of the pinna reflex. 3. Disappearance of the pinna reflex.

Resting level ofpow :- a. arterial = 2.1 ml/min. = 100% b. venous = 1.7 ml/min. = lOOo/,

Cut: 3 kg. Basal anaesthesia: 33 mg Nembutal/kg body weight.

The animals were exposed either to increasing and decreasing concentrations of halothane during protracted periods, the disappearance and reappearance of the reflexes being carefully recorded, or, to relatively high concentrations of halothane during shorter periods.

Blood bressure.-In all experiments, the inhalation of halothane decreased the blood pressure to 80-50% of the resting level after only a few minutes of exposure. When the exposure was protracted, the blood pressure continued to fall, though more slowly, and after about 5 minutes it became stabilized. After the end of the exposure the pressure usually regained the original level. A more detailed account of the effect of halothane on the blood pressure is


FIG. 2.-After disappearance of reflexes under observation the changes of blood pressure, arterial and venous blood flow, and peripheral resistance during exposures to halothane are of the same type during ventilation with 100 per cent oxygen also. During recovery

the peripheral resistance increases. Dial settings of the Fluotec vaporizer:- A and C: 3 % B and D: 2% Signs of decreasing anaesthesia:- 1. Reappearing pinna reflex. 2. Spontaneous rhythmic variations of flow. 3. Slight corneal reflex. 4. Evident corneal reflex. 5. Strong corneal reflex.

Resting level ofJow :- a. arterial = 1.9 ml/min. = 100% b. venous = 2.3 ml/min. = 100%

Cat: 3.7 kg. Basal anaesthesia: 33 mg Nembutal/kg body weight.

given by us in an earlier publication (LINDGREN, WESTERMARK and WAHLIN ( 1964)12, in which the greater part of the present series was also involved.

Peripheral bloodflow.-Figure 1 shows an experiment in the first part of which the animal was exposed to halothane in increasing concentrations. I t is particularly noticeable that the skin blood flow at the beginning of the exposure increases in spite of the concomitant blood-pressure fall, in contrast to the previously described state in the muscle, when, roughly, the same experimental conditions exist. It was not until at the end of the exposure, when the higher concentrations were reached, that the flow started to decrease, though rather slowly in spite of a concomitant marked fall in blood pressure. When the halothane was withdrawn, the animal was not allowed to recover beyond a point just below the reappearance of the reflexes. If, thereafter, the exposure was repeated with the same high concentration at which the preceding exposure had ended, the values at the same concentrations as were obtained at the preceding exposure, as demonstrated in figure 1, were closely reproduced.


BLOOD PRESSURE

BLOOD FLOW IN PER CENT OF RESTING LEVEL

80 .

V. SAPH. PARVA- 40

6o 1 A. 118. ANT. - iI

% CHANGE OF PERIPHERAL RESIS- TANCE IN PER CENT OF RESTING LEVEL

80

TIME: 5 MH

EXPOSURES

FIG. 3.-Changes of blood pressure, arterial and venous blood flow, and peripheral resistance during exposures to ether.

Dial settings of the ether vaporizer:- A = 3 units ''Full'' = Boyle vaporizer at maximum a. Disappearance of the corneal reflex. b. Disappearance of the pinna reflex. c. Reappearance of the pinna reflex. d. Reappearance of the tongue reflex.

Resting level offlow :- a. arterial = 7.3 ml/min. = lOOyo b. venous = 6.3 ml/min. = 100yo

Cut: 5.1 kg. Basal anaesthesia: 35 mg Nembutal/kg body weight.

In the analysis of the obtained recordings of the muscular blood flow under halothane anaesthesia in the cat ( LINDGREN, WESTERMARK and WAHLIN ( 1964) lP), it was noticed that the venous flow decreased more than did the arterial flow, and this phenomenon was tentatively explained as an accumulation of fluid in the muscular tissue. This circumstance was accentuated at high concentrations and was thought to be caused by a depressed cardiac function. A similar arteriovenous flow difference, although less marked, has also been found in the skin of the cat under the same experimental conditions. When these experiments were repeated in animals under deep anaesthesia and venti-

196 P. LINDCREN, L. WESTERMARK AND A. WRHLIN

lated with oxygen instead of air, which was the only change in experimental conditions, similar results were obtained (fig. 2).

Per$heral resistance.-The peripheral resistance in the tissue under test could decrease by 60% before the test reflexes had disappeared (fig. 1). The rapidity of the decrease in resistance depended upon the actual concentration during the exposure. This decrease of peripheral resistance in the skin region under test coincides with observations in man during the induction of light barbiturate anaesthesia ( GRAF, STROY and WAHLIN ( 1963)y. After the reflexes disappeared at a concentration of about 2%, the peripheral resistance remained fairly unchanged on the level attained at that moment-even if higher concentrations of halothane (311%) were given (cf. fig. 1)-until the exposure was withdrawn and the reflexes had returned, when the peripheral resistance increased again (cf. fig. 2). The last exposure in figure 1 demonstrates that the peripheral resistance remained unaffected after the disappearance of the reflexes in spite of the fact that the depth of anaesthesia was varied within relatively wide limits.

In conclusion, figure 1 illustrates an experiment in which the effect of the substance on the peripheral circulation is demonstrated. During the period before the disappearance of the reflexes, the flows in some experiments were only slightly affected, and sometimes they even decreased. Simultaneously the blood pressure, however, always decreased proportionally more than the flows. Thus, during this initial period, the peripheral resistance decreased in all experiments; the decrease ranged between about 20 and 60 per cent.

Simultaneously recorded venous and arterial blood .Rows of cutaneous region under test under the influence of ether.-Under the same experimental conditions as were used for the halothane exposures, the animals were also exposed to ether in various concentrations.

At lower concentrations blood pressure and flow were affected only to a slight extent. The peripheral resistance also showed a decrease in connection with ether, though to a considerably less extent than with halothane (fig. 3).

Not until the highest concentrations were used could an arteriovenous flow difference be demonstrated, and even then it was of a very moderate size.

DISCUSSION

Considerable attention was paid to the depth of anaesthesia in this investigation, as the skin blood flow is particularly sensitive to all kinds of stimuli during the first stages of anaesthesia. In man during consciousness, psychic stimulation can cause alterations in the peripheral circulation in the form of greatly reduced skin blood flow (GOLENHOFEN, BLAIR and SEIDEL (1961)a). Recently it has also been demonstrated by GRAF and WAHLIN (1963)' that


intubation in man, performed under light barbiturate anaesthesia and succinylcholine apnoep and after ventilation with oxygen, gives a higher increase of the peripheral resistance in the skin than in the muscle. The increased vascular resistance in the systemic circulation was considered to be caused by reflex activation of sympathetic vasoconstrictor activity. In man, GRAF, STROM and WAHLIN ( 1963)6 also demonstrated that spontaneous, rhythmic one-minute fluctuations of the blood flow in muscle and skin, characteristic of the unaffected peripheral circulation (GOLENHOFEN and HILDEBRANDT (1957)7, begin to disappear already during the induction of anaesthesia with barbiturates. Similar observations were also made by LINDGREN and WAHLIN in earlier investigations on the muscle blood flow in the cat during ether anaqthesia ( 1962)la. The demonstration of the disappearance of these rhythmic changes ‘in the peripheral circulation is of particular value, as the changes have been shown to be of central vasomotor origin (GOLENHOFEN and HILDE- BRANDT (1957)6). Thus, it seemed to us appropriate to observe the increasing anaesthetic I effect of halothane by means of the disappearance of certain reflexes and to try to correlate this effect with an increasing depression of the vasomotor system during the course of the anaesthesia.

The circulatory changes demonstrated in the present investigation can be grouped into those occurring before and after the moment of disappearance of the reflexes. In contradistinction to what had previously been demonstrated to be valid for the peripheral blood flow in muscle under halothane anaesthesia with the same experimental technique (LINDCREN, WWTERMARK and WAHLIN (1964)12), a decreasing peripheral resistance could be shown in the skin until the moment of disappearance of the reflexes. After this initial reduction of resistance it was shown to be stationary in spite of increasing exposure to halothane. I t is true that this continued exposure involved a further fall in blood pressure and a further decrease in blood flow, but these occurred proportionally to each other.

As possible explanations of the decrease in the peripheral resistance in the skin caused by halothane, there are several alternatives: a peripheral action on the smooth muscles of the blood-vessel walls (BURN and EPSTEIN (1959)2); a central or reflex inhibition of the vasoconstrictor tone; or, possibly, an effect on the impulse transmission somewhere in the sympathetic chain of neurones. In skeletal muscles, such a vasodilatation cannot be seen at low concentrations of halothane and as there is no reason to presume that the smooth muscles of the skin vessels are more sensitive to the anaesthetic, the most probable explanation of the vasodilatation is to be found in a neuro- genic effect,

Concerning the possibility of action upon the transmission in the sympathetic system, it is true that it has been demonstrated that the transmission in the ganglia can be reduced (review by LOFSTROM (1964)14), but the reduction is too small to be of any physiological importance. Moreover, the above-

I


mentioned studies of the muscle blood flow argue against such an explanation -there are no special reasons for believing that halothane has a selectively depressing action on the ganglionic transmission in the neurones to the skin vessels.

Upon comparing the central regulation of the vasoconstrictor tone of the skin vessels with that of the muscle vessels, we find certain dissimilarities. That part of the skin blood flow which provides the control of temperature- and this is a considerable part-is controlled mainly from sympathetic, hypothalamic centres. On the other hand, the basal vasoconstrictor tone of the muscle vessels is regulated mainly from medullary centres. If we assume that the threshold concentrations for depression by halothane of the centres in the superior brain stem-causing a disappearance of the functions regulated from this part-are lower than those needed for depression of the activity of the medulla oblongata, the autonomic centres in the latter region will preserve an intact function, and we may have found a way to explain the vasodilatation in the skin. In other words, it would mean a reduced number of vasoconstrictor impulses induced from hypothalamus. The observations also agree with the regular finding of a warm skin during halothane anaesthesia in man ( PAYNE ( 1 963)16, BLACK ( 1964) l) .

If this explanation of the vasodilatation in the skin is correct, and if the reaction is only a question of the depth of anaesthesia, then other anaesthetics should also be able to cause the same reaction. Figure 3 illustrates that the effect of ether, for example, on the peripheral resistance is of the same kind as that of halothane, i.e. the resistance decreases until the moment when the reflexes disappear and thereafter it stabilizes-in this experiment at about 20 per cent below the resting level-despite a further increase in the depth of anaesthesia. For ether, as for halothane in the concentrations used, the difference between the reaction in muscle ( LINDGREN, WESTERMARK and WAHLIN (1964)12) and that in skin is an argument against a peripheral action on the smooth muscles of the vessel walls. I t is known that ether reduces the transmission in ganglia in too small a degree to cause any vasodilatation (NORMA" and LOFSTROM ( 1955)16). This, too, favours the view that the skin vasodilatation may be due to an effect of ether on the central nervous system, and probably a release of vasoconstrictor tone.

The size of the reduction in the peripheral resistance, whether halothane or ether has been used, is not the same in different experiments. This may be due to different depths of basal anaesthesia. Starting the halothane or ether exposure during a very light stage should result in a more pronounced reduction in peripheral resistance than starting it during a deeper basal anaesthesia, since the latter itself probably reduces the peripheral resistance to some extent, leaving less resistance to be reduced by halothane or ether.

The original aim was to study the peripheral circulation to find out whether changes in the peripheral resistance could explain the fall in blood pressure


during halothane anaesthesia that has been described by so many authors (see, e.g., JOHNSTONE ( 1956)1°, RAVENT~S (1956)"). However, it is doubtful whether the decreased resistance in the skin can explain the blood-pressure fall. At the low concentrations of halothane during the initial stages of a fairly light anaesthesia, when this effect appears, favourable conditions may exist for enabling the vasodilatation in the skin to be compensated reflexly by a slight increase in the resistance in other regions controlled by medullary centres not affected in the light stage of anaesthesia. Investigations now in progress suggest that the increase in the peripheral resistance in the muscle is higher than the simultaneous decrease in the peripheral resistance in the skin, as the total peripheral resistance in the leg increases.

The increase in the resistance in the skeletal muscles, however, may be considered as an attempt to compensate for the falling blood pressure, for which cardiac factors are probably of greater importance than a vasodilatation in the skin. The hypothesis that the blood-pressure fall is to a noteworthy degree caused by a decrease in the peripheral resistance in the skin is also contradicted by the fact that the blood-pressure fall continues after the sta- bilization of the peripheral resistance.

SUMMARY

The effect of halothane on the peripheral circulation in the skin was studied in the hind paw in a series of heparinized cats under intraperitoneal light basal anaesthesia with Nembutal. The blood flow was recorded synchronously on both the arterial and venous side by means of a photo-electric drop-recording technique.

During the exposures to halothane special attention was paid to the depth of anaesthesia by noticing certain reflexes.

1. The peripheral resistance decreased during the initial phase of the exposure-until the disappearance of the reflexes under observation-and reached a value of about 80-40 per cent of the control level. This decrease appeared simultaneously with a blood-pressure fall of about 20-50 per cent.

2. During increasing depths of anaesthesia beyond the disappearance of the reflexes, a fairly stable level of peripheral resistance was seen, further falls in blood pressure being accompanied by a proportional decrease in blood flow.

3. An arteriovenous flow difference, possibly due to depressed cardiac function, was observed, but it was less marked than was found for the muscular flow under similar conditions (LINDGREN, WESTERMARK and WAHLIN ( 1964)12). When the animals were ventilated with oxygen instead of air, which was the only change of experimental conditions, similar results were obtained.


The vasodilator effect by halothane upon the skin vessels was thought to

The dilatation of theskm vessels is not considered to play any major part be caused mainly by a release from hypothalamic vasoconstrictor impulses.

in the blood-pressure fall during halothane anaesthesia.

Z U S A M M EN FA S S U NG

Die Wirkung von Halothan auf den peripheren Kreislauf in der Haut wurde an den Hinterpfoten einer Serie von heparinisierten Katzen unter oberflach- licher Basisnarkose rnit Nembutal, intraperitoneal verabreicht, untersucht. Der Blutstrom wurde synchron auf der arteriellen und veniisen Seite rnit Hilfe einer photoelektrischen Tropfenzahltechnik registriert.

Wahrend der Halothanzufuhr wurde besonderes Augenmerk auf die Nar- kosetiefe gelegt unter Beachtung gewisser Reflexe.

Der periphere Widerstand nahm wahrend der Initialphase der Halothan- zufuhr ab, und zwar bis zum Verschwinden der beobachteten Reflexe, wobei etwa 8 0 4 % der Kontrollwerte erreicht wurden. Diese Wider- standsabnahme trat gleichzeitig rnit einem Blutdruckabfall von etwa 20-50% auf. Wahrend der Vertiefung der Narkose uber das Verschwinden der Reflexe hinaus wurde ein ziemlich stabiler Grad des peripheren Widerstandes gesehen, wobei ein weiterer Abfall des Blutdrucks von einer proportionalen Abnahme der Durchblutung begleitet war. Es wurde eine arteriovenose Stromungsdifferenz beobachtet, die mog- licherweise auf verminderte Herzleistung zuruckgefuhrt werden kann, aber weniger ausgepragt war, als dies bei der Muskeldurchblutung unter ahn- lichen Bedingungen gefunden worden war (LINDGREN, WESTERMARK und WAHLIN (1964)12). Wenn die Tiere statt rnit Luft rnit Sauerstoff beatmet wurden, was die einzige Veranderung der Versuchsbedingungen darstellte, erhielt man ahnliche Resultate.

Es wird angenommen, dass die vasodilatatorische Wirkung von Halothan auf die Hautgefasse hauptsachlich durch die Ausschaltung der hypothala- mischen Vasokonstriktorimpulse verursacht wird. Die Erweiterung der Haut- gefasse durfte jedoch keine grossere Rolle fur den Blutdruckabfall wahrend der Halothannarkose spielen.

Acknowledgement

This investigation was supported by a grant from the Swedish Medical Research Council (U 408).

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REFERENCES

BLACK, G. W.: Changes in the peripheral circulation of man during inhalational anesthesia. Pp. 278-284 in H. L. PRICE and P. J. COHEN: Effects of anesthetics on the circulation. Ch. C Thomas, Springfield, Ill., USA, 1964. BURN, J. H., and H. G. EPSTEIN: Hypotension due to halothane. Brit. 3. Anacsth. 1959, 31, 199. COOPER, K. E.: The peripheral circulation. Ann. Rev. Physwl. 1962, 24, 139-168. GOLENHOPEN, K., D. A. BLAIR and W. SEIDEL: Zur Natur affektiver Muskeldurch- blutungssteigerungen beim Menschen. PJiigcrs Arch. ges. Physwl. 1961, 272, 223-236. GOLENHOPEN, K., and G. HILDEBRANDT : Uber spontan-rhythmische Schwankungen der Muskeldurchblutung des Menschen. Ztschr. Krcislaufforsch. 1957, 46, 257-270. GRAP, K., G. STROM and A. WAHLIN: Circulatory effects of succinylcholine in man. Acta anacsth. Scandinav. 1963, Suppl. XIV. GAP, K., and A. WAHLIN: The effect of endotracheal manipulations in anaesthetized subjects with special reference to the behaviour of the vascular resistance in forearm and hand. Acta anaesth. Scandinnu. 1963, 7, 169-178. GREEN, H. D., R. N. LEWIS, N. D. NICKEMSON and A. L. HELLER: Blood flow, peripheral resistance and vascular tonus, with observations on the relationship between blood flow and cutaneous temperature. Am. 3. Physwl. 1944, 141, 518-536. HALL~N, B., L. WESTERMARK and A. WAHLIN: The concentration of halothane with the combined use of Fluotec vaporizer and Palmer ventilator for animal experimenta- tion. Acta anaesth. Scandinav. To be published 1965. IOHNSTONE, M. : Human cardiovascular response to Fluothane anaesthesia. Brit. 3. Anaesth. 1956, 28, 392-410. LINDGREN, P.: An improved method for drop recording of arterial or venous blood flow. A c h physiol. Scandinav. 1958, 42, 5-1 1. LINDGREN, P., L. WESTERMARK and A. WAHLIN: Blood circulation in skeletal muscles under halothane anaesthesia. Acta anaesth. Scandinav. 1964, in press. LINDGREN, P., and A. WAHLIN: Unpublished observations 1962. LOFSTROM, B. : Anaesthetic agents and ganglionic transmission. Proc. Eighth Congr. Scandinav. SOC. Anaesth. Acta anaesth. Scandiw. 1964, Suppl. XV, 36-37. NORMA", N., and B. LOFSTROM : Interaction of d-tubocurarine, ether, cyclopropane, thiopental on ganglionic transmission. 3. Pharmacol. d Expcr. Therap. 1955, 114, 231- 239. PAYNE, J. P.: The circulatory effects of halothane. Proc. Roy. SOC. Mcd. 1963, SS, 92-95. RAVENT~S, J. : The action of Fluothane-a new volatile anaesthetic. Brit. 3. Pharmacol. 1956, 11,394-409.

blood circulation in the skin of the cat under halothane anaesthesia

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