V O L 13 N O 3 A N E S T H E S I A J U L Y 1958

Hypotensive response to carbon dioxide

The influence of carbon dioxide on the blood pressure response of cats to hypotensive drugs.

Department of Anzsthesia, Postgraduate Medical School Ducane Road, London, W 12

The physiological functions of carbon dioxide have long been recog- nized, but it is only within recent years that its influence in modifying the action of certain drugs has been appreciated. In experiments undertaken to study the neuromuscular blocking action of mecamyla- mine as modified by the administration of carbon dioxide it was ob- served that the normal hypertensive response of cats to this gas was reversed in those animals given mecamylaminel. Based on this ob- servation the experiments to be described were designed specifically to study the influence of carbon dioxide on the blood pressure response of cats to drugs commonly used to lower the blood pressure clinically.

METHOD

Healthy but otherwise unselected cats were used. After induction of ansesthesia with ethyl chloride and ether the right external jugular vein was exposed and cannulated. Thereafter chloralose 80mg/kg was given intravenously to maintain anasthesia. A tracheal cannula was inserted and artificial respiration established. The use of artificial respiration facilitated the administration of carbon dioxide and at the s9me time prevented the possible onset of hypoxia after the intrathecal injection of procaine. The blood pressure was recorded with a mercury manometer on a smoked drum from a cannula inserted in the left carotid artery.

Four drugs were used in this assessment. Three, hexamethonium, mecamylamine and trimetaphan were given intravenously through the Resd at Silver Jubilee Meeting, Association of Anaesthetists 5 December 1957. Work done in the Department of Pharmacology, Royal College of Surgeons of England, London.

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cannula in the external jugular vein. The fourth, procaine, was given intrathecally in the lumbar region.

Ideally, it would have been most suitable if the influence of carbon dioxide on each of these drugs could have been studied in turn in the same animal, but it had already been shown, not only that the effects of mecamylamine were prolonged, but also that this drug was capable of modifying the action of other ganglion blocking agents2. For this reason mecamylamine was studied separately from the other three drugs. Hexamethonium, procaine and trimetaphan were studied in the same animals but the order of administration was altered in successive experiments to ensure that any interaction between drugs would be observed. The change of sequence did not alter the type of response obtained.

In each cat the blood pressure response to carbon dioxide was elicited before the injection of any drug. When the blood pressure had returned to normal the hypotensive agent was injected. After each in- jection the blood pressure was allowed to stabilize before the animal was again exposed to carbon dioxide. Usually the exposure was limited to periods of five to ten minutes. Three different concentrations of carbon dioxide were used 5, lO and 20 per cent.

R E S U L T S

As soon as ventilation with carbon dioxide (5, 10 or 20 per cent) was started the blood pressure began to rise ( F I G 1) and remained high

A R

01 INFLUENCE OF CARBON DIOXIDE ON A NORMAL BLOOD PRESSURE B 35 MINS AFTER 40mg/Kg MECAMYL-

AMINE HCL 1.V

F I G . 1 Record of blood pressure in a cat anzsthetised with chloralose (80mg/kg), and exposed to 10 % carbon dioxide before and after the intravenous injection of mecamylamine.

until the administration ceased, thereupon it fell sharply, sometimes to very low levels, before gradually returning to normal.

A N E S T H E S I A 281

When cats previously given mecamylamine were ventilated with carbon dioxide there was an abrupt fall in blood pressure (FIG 1) which recovered rapidly when the carbon dioxide was discontinued. The quantitative relationships in a group of four cats given mecamylamine and exposed to 10 per cent carbon dioxide are demonstrated in T A B L E 1 .

MECAMYLAMINE HCL

TABLE 1 shows the dose of mecamylamine employed and the blood pressure responses involved in four cats ventilated with 10% carbon dioxide.

The immediate effect of carbon dioxide on the blood pressure of cats previously given either hexamethonium or trimetaphan was a slight and transient fall, (FIGS 2, 3 and 4, 5). This was rapidly

A A B

OL . .

MiNS. A. Img/Kg HEXAMETHONIUM. 6. 20 o/o CARBON DlOX ID-E

F I G . 2 Record of blood pressure in a cat anasthetised with chloralose (8Omg/kg). Exposure to 20 % carbon dioxide after intravenous hexamethonium produced initially further hypotension followed by a marked hypertensive response.

282 A N E S T H E S I A

A 6

loo’ mm.Hg

5 0 -

OL M INS.

A. 2mg/Kg HEXAMETHONIUM. B. 5% CARBON DIOXIDE.

F I G . 3 Record of blood pressure in a cat anresthetised with chloralose (80mglkg). The blood pressure fell markedly after the intrathecal injection of procaine and the hypotension was enhanced by exposure to 10% carbon dioxide. The blood pressure recovered rapidly when the carbon dioxide was discontinued.

MINS.

A. 0.5mg/Kg TRIMETAPHAN. 6. 209, CARBON DIOXIDE.

01

F I G . 4 Record of blood pressure in a cat anaesthetised with chloralose (bOmg/kg). The intravenous injection of trimetaphan produced a marked fall in blood pressure after a delay of approx. 30 sec. This was followed by tachycardia and a tendency for the blood pressure to recover which was not sustained. Exposure to 200,; carbon dioxide was followed by a slight initial hypotension succeeded by a marked hypertensive response.

ANESTHESIA 283

A B

OL MINS.

A. O.Srng/Kg TRIMETAPHAN. B. 5 % CARBON DIOXIDE.

FIG. 5 Record of blood pressure in a cat anaesthetised with chloralose (80mgFg). The nature of the response to 5 ,% carbon dioxide after the intravenous injection of trimetaphan was similar to that which followed 20% carbon dioxide;but was less marked.

followed by a hypertensive response which tended to be greater when the concentration of carbon dioxide was high but which was not sustained when carbon dioxide administration ceased. The results in a group of cats given hexamethonium are set out in TABLE 2 and those in a similar group given trimetaphan in TABLE 3.

HEXAMETHONIUM

TABLE 2 shows the dose of hexamethonium employed and the blood pressure responses involved in seven cats ventilated with different concentrations of carbon dioxide.

D

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TR I METAPH A N

TABLE 3 shows the dose of trimetaphan employed and the blood pressure responses involved in seven cats ventilated with different concentrations of carbon dioxide.

ine nypotension tnac touowea me inrracnecai injection or procame was enhanced when carbon dioxide was inhaled, and this effect was more marked with 20 per cent carbon dioxide than with lower con- centrations. This observation is well illustrated in F J G S 6 and 7. The results obtained in this group are listed in T A B L E 4.

OL MINS.

A. 20 mg PROCAINE HCL

8. CARBON DIOXIDE. INTRATHECALLY.

FIG. 6 Record of blood pressure in a cat anresthetised with chloralose (8Omg/kg). Exposure to 5 % carbon dioxide after intravenous hexamethonium produced hitially slight additional hypotension followed by a gradual increase in blood pressure, which however did not reach the original level.

ANESTHESIA 285

- MINS.

a EFFECT OF 20% CARBON DIOXIDE AFTER

A. NORMAL BLOOD PRESSURE. 8. 5 MINUTES LATER C 0 2 ON FOR 7 MINS. C. 2 0 MINUTES LATER C02 ON FOR 5 MINS. 0. 7 0 MINUTES LATER C 0 2 ON FOR 5 MINS.

20mg PROCAINE HCL INTRATHECALLY.

FIG. 7 Record of blood pressure in a cat anssthetised with chloralose (8hg/kg). The hypotensive effect of 20 % carbon dioxide is marked after intrathecal procaine and persists for some time after the blood pressure has returned to normal levels. The time relationship existing is shown.

PROCAINE HCL

T A B L E 4 shows the dose of procaine employed and the blood pressure responses involved in seven cats ventilated with different concentrations of carbon dioxide.

DISCUSSION

It is well known that carbon dioxide exerts both a central and a peripheral action3. Under normal circumstances the central effects predominate and arc due to direct stimulation of the vasomotor centres ; consequently, when carbon dioxide is inhaled vaso-constric- tion occurs in all sympathetically innervated peripheral vessels. The

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blood pressure rises, the heart rate is accelerated and the cardiac output is increased.

The peripheral action of carbon dioxide tends to oppose these changes by dilating the peripheral vascular bed, particularly the veins and the capillaries. This dilatation was fkst demonstrated by von Anrep4 in 1912 when he perfused the isolated ears of rabbits with Ringer’s solution containing different concentrations of carbon dioxide. The immediate systemic effect of such generalized vaso- dilatation is a fall in blood pressure and it follows therefore that if for any reason the vasomotor impulses are inhibited hypotension will follow the accumulation of carbon dioxide. The importance of the vasomotor centres in this respect was first demonstrated by Dale and Evans5 in 1922 who showed that the rebreathing of expired air would raise the blood pressure in intact cats, but if the brain stem was then destroyed the rebreathing of expired air would be followed by hypo- tension. This work was confirmed by Pinkstone and his colleagues in 1936, who showed that the inhalation of carbon dioxide by sym- pathectomised cats and dogs resulted in a prompt and marked fall in blood pressure. The hypotension that follows ventilation with carbon dioxide during spinal anasthesia can now be explained. The intra- thecal injection of procaine in sufficient quantity will paralyse the total sympathetic outflow and will, therefore, inhibit all impulses from the vasomotor centre. In such circumstances the peripheral effects of carbon dioxide will predominate and hypotension will follow the inhalation of the gas.

The hypertensive response that followed the inhalation of carbon dioxide by cats given hexamethonium and trimetaphan suggests that not all vasomotor impulses are blocked by these drugs; to some extent this can be taken as a measure of their inefficiency as ganglion block- ing agents. Under normal circumstances neither hexamethonium nor trimetaphan readily enters the cerebro spinal fluid7 and therefore ganglia located within the nervous system are relatively unaffected by them. In recent years evidence has been produced notably by Skoogs and Boyd and Monro9 that sympathetic ganglia are not c o r h e d to the sympathetic chains. A certain number of ganglia are found elsewhere, either in the nerve trunks, nerve roots or within the sub-arachnoid space itself. The existence of such ganglia could ex- plain the persistence of vasomotor impulses in the presence of the above drugs and hence the hypertensive response.

The transient hypotension which preceded this rise in pressure was probably a direct effect of carbon dioxide on the heart muscle itself. Jerusalem and Starling l o have shown that concentrations between 12 and 20 per cent carbon dioxide are capable of producing cardiac dilatation and a fall in cardiac output. Later Itamill

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demonstrated that the fall in cardiac output was rapidly succeeded by hypertension and vasoconstriction. By weakening the vasoconstrictor response hexamethopium or trimetaphan would tend to prolong this pxiod of hypotension.

The success of mecamylamine as a ganglion blocking agent is probably related to its ability to diffuse freely through cell mem- braneslz and thus to penetrate the nervous system. The fact that hypo- tension follows the inhalation of carbon dioxide in cats previously given mecamylamine may well indicate the efficiency of that penetra- tion, although it is probable that the absence of a hypertensive re- sponse is proof of the inhibition of vasomotor impulses another ex- planation is possible. Previous work has shown that the plasma level of mecamylamine is raised when carbon dioxide is inhaled and lowered again when the inhalation is discontinued1, and it has further been demonstrated that mecamylamine has a direct depressant effect on the heart 13. The hypotension associated with carbon dioxide administra- tion could, therefore, be due to this direct action by virtue of the raised plasma level of the drug. Such an explanation is less likely how- ever because carbon dioxide is known to produce hypotension over a wide range of plasma mecamylamine levels 1, and there is no evidence that the degree of hypotension obtained is directly related to the con- centration of mecamylamine in the plasma.

SUMMARY

When carbon dioxide is inhaled by cats after the administration of a hypotensive drug, the blood pressure response is governed by the specific pharmacological properties of the drug used. If hexame- thonium or trimetaphan is given the blood pressure rises in response to carbon dioxide. If, on the other hand, procaine or mecamylamine is administered the hypotensive effect is enhanced. It is suggested that the type of response obtained is determined by the ability or otherwise of the drugs to block completely the sympathetic outflow. In the case of hexamethonium and trimetaphan this is limited by their in- ability to penetrate the sub-arachnoid space where some at least of the sympathetic ganglia are located. Mecamylamine is not handicapped in this respect and therefore might be expected to block all ganglia. Similarly procaine when injected into the sub-arachnoid space in sufficient quantity produces total sympathetic block by paralysing the sympathetic fibres as they leave the spinal cord. Acknowledgements I am indebted to Professor W. D. M. Paton, FRS, not only for advice and crit- icism but also for facilities to carry out this work. My thanks are also due to Mrs Dawn Gardiner and Mr Dennis Green for technical assistance and to the Dan Mason Research Foundation for generous financial support.

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