EFFECTS OF ALTHESIN ON CEREBROSPINAL FLUID PRESSURE

Brit. J. Anaesth. (1973), 45, 179

EFFECTS OF ALTHESIN ON CEREBROSPINAL FLUID PRESSURE T. TAKAHASHI, M. TAKASAKI, A. NAMIKI AND S. DOHI SUMMARY

Changes in cerebrospinal fluid pressure after induction of anaesthesia with Althesin were recorded in 21 volunteer patients who had no abnormality of the central nervous or cardiorespiratory systems. In patients who breathed spontaneously, cerebrospinal fluid pressure fell by 45% at 1 min after intravenous injection of Althesin 0.1 ml/kg. It returned almost to preinduction levels by 12 min During this time, there was a slight increase in Pao03. When Paoo2 was controlled by mechanical ventilation, the cerebrospinal fluid pressure fell slightly more; by 53% when Paoo, was kept between 38-42 mm Hg and by 50% when Pac02 was maintained between 30-34 mm Hg. The significant fall of cerebrospinal fluid pressure produced by Althesin in conjunction with the rapid clear-headed recovery, may allow Althesin to be a valuable anaesthetic for neurosurgical procedures. The control of cerebrospinal fluid pressure during general anaesthesia for neurosurgical operation is one of the most important items among the factors to be managed by anaesthetists. Of the inhalation anaesthetics in use at present, only nitrous oxide Is known not to increase cerebrospinal fluid pressure, and of the intravenous anaesthetics, only barbiturates are known to decrease cerebrospinal fluid pressure. The new steroidal intravenous anaesthetic known as Althesin (CT1341) produces similar cardiorespiratory changes to the barbiturates (Campbell et al., 1971; Savege et al., 1972; Miller, Bradford and Campbell, 1972) whilst having a high therapeutic ratio, low local irritant effect and a rapid "clearheaded" recovery. In order to see whether this new agent could be considered for use in neurosurgery, we have studied its effects on cerebrospinal fluid pressure (c.s.f.p.). METHOD

Subjects. Twenty-one patients awaiting surgery, with no disorders of the central nervous system, respiratory or cardiovascular systems, served as volunteers for this experiment. They were divided into three groups of 7 as follows: Group 1, spontaneous respiration; Group 2, mechanically ventilated to maintain Paoo, between 38 and 42 mm Hg; Group 3, mechanically ventilated, Paco3 maintained between 30 and 34 mm Hg. The sex, age and weight of the volunteers in each group were as shown in table I.

TABLE I. Age, weight and the diagnosis of the volunteers receiving Althesin during anaesthesia. Cases Age Group 1

1 2 3 4 6 7 Mean

45 51 71 64 54 36 23 49

8 9 10 11 12 13 14 Mean

44 56 25 62 61 68 23 48

M F M M M M F

15 16 17 18 19 20 21 Mean

56 58 39 46 26 46

M M F F M M F

5

Group 2

Group 3

Sex M M F M M M M

56 48

Weight (kg) 66

55 53 58 63 58 57

Diagnosis gallstone gastric carcinoma gastric polyposis renal stone gallstone duodenal ulcer renal tuberculosis

59 62 43 67 46

84 50 42 56 49 47 53

44 74 65 67

gastric carcinoma gastric carcinoma gastric carcinoma gastric carcinoma rectal carcinoma gastric carcinoma mobile kidney gastric carcinoma gastric carcinoma gastric carcinoma gallstone duodenal ulcer rectal carcinoma gallstone

57

Anaesthesia. No premedication was given to any of the volunteers. In order to ensure the intravenous infusion route, 300-500 ml lactate-Ringer solution was adTAKEO TAKAHASHI, M.D.; MAYUMI TAXASAKI, M.D.; AJOYOSHI NAMIKI, MJX; SHUJI DOHI. MJ>.; Department of

Anaesthesiology, Sapporo Medical College and Hospital, Sapporo City, Japan.

180 ministered by drip before commencing the study, and the flow rate was reduced to a minimum 10 min before and during the measurement of cerebrospinal fluid pressure. Oxygen 1-2 l./min was given via a facepiece to 5 of the 7 volunteers in group 1, the remaining 2 received none. In patients of groups 2 and 3, anaesthesia was induced with nitrous oxide 7 l./min and oxygen 2 l./min and endotrachel intubation was performed after intravenous injection of tubocurarine 30 mg. The tube was connected to a Bird Mark IV, 8 ventilator for controlled ventilation. Together with additional tubocurarine, anaesthesia was maintained with nitrous oxide 5-6 l./min and oxygen 2 l./min and cerebrospinal fluid pressure was monitored. Total tubocurarine administered before commencement of the study was 60-75 mg. Adjustment of arterial carbon dioxide tension. The ventilation volume was regulated to maintain arterial carbon dioxide tension (PaoOj) in groups 2 and 3 within the pre-set range. Arterial blood was drawn through an indwelling cannula in the radial artery, heparinized and excluded from air. Blood-gas was analysed by the Astrup method. Studies were carried out after the blood gas reading had remained constant for at least 15 min. In both group 2 and group 3, arterial oxygen tension (Pao3) was maintained between 90 and 130 mm Hg. Blood-gas values were monitored at the end of the study and several times when significant changes in cerebrospinal fluid pressure occurred. Only the data from patients in whom Pao2 and Pa<,oj were within the above mentioned limits have been included. Monitoring and recording. With the subject lying in the lateral position, arterial pressure, central venous pressure and cerebrospinal fluid pressure were recorded throughout the study. Arterial and central venous pressures were monitored using catheters introduced percutaneously into the radial artery, and superior caval vein via a cubital fossa vein, respectively. The position of the tip of the central venous catheter was confirmed by the length of the catheter inserted, and also by observation of the pressure curve on the monitoring recorder. For measurements of cerebrospinal fluid pressure, a no. 21 needle was introduced into the space between the third and fourth lumbar vertebrae. A tube was attached, and connected to a recorder (Nihon Koden RM150) together with the two other catheters via transducers (transducer MPU0.5 for

BRITISH JOURNAL OF ANAESTHESIA arterial pressure and LPU0.1 for central venous pressure). Continuous measurements were performed at least 20 min before and 12 min after the administration of Althesin. The top of the manubrium sterni was taken as zero level for central venous and arterial pressures. The cisterna magna and the point of the lumbar needle were placed at the same level and taken as zero level for cerebrospinal fluid pressure. With patients in group 1, arterial blood was drawn and measurements of Paoj, PaCoj and arterial blood pH were obtained at 1.5, 3, 5, 7, 10 and 12 min respectively after administration of Althesin. Dose and method of administration. Althesin 0.1 ml/kg was administered intravenously over an injection time of 30 sec in all three groups. RESULTS

The changes in cerebrospinal fluid, arterial and central venous pressures for each group are shown in table II. Examples thereof are given in figures 1 and 2. Cerebrospinal fluid pressure. This fell in all 21 patients. Mean maximum falls were 45% in group 1, 53% in group 2 and 50% in group 3, these being statistically significant. In group 1 the maximum fall occurred 1 min after injection, the pressure then rising gradually to approach the control value at 12 min. In groups 2 and 3, the pressure fell rapidly after administration of Althesin, and continued to fall gradually to reach the minimum value at 5-8 min after induction. It later rose slightly but was still significantly below the mean control level at 12 min. Arterial pressure. Mean arterial pressure fell in all cases. The mean maximum falls were 27% in group 1, 24% in group 2 and 18% in group 3 and these falls achieve statistical significance (P<0.01). The maximum falls of blood pressure were reached at 1 min after induction in many patients while in others, after a slight and temporary recovery, they were reached 10 min after administration. The mean level was still below preanaesthetic levels 12 min after induction in all but 2 patients (see table II). Central venous pressure. Central venous pressure fell T)y a mean of 54% in group 1, 57% in group 2 and 44% in group 3.

EFFECTS OF ALTHESIN ON CEREBROSPINAL FLUID PRESSURE

181

cmttoO

6

8

10

12

Mr-

CT-O4)

cv.p.

*

""•

CVP 0 200

B.P.

•.V.'.'.W

wmtttO 200r

CSFP —s CS.F.P.

PBCOI

oL P*CO» M . I - 3 1 7

FIG. 1. An example of tracings from a patient in group 2 (mechanical ventilation; Paces 38-42 mm Hg).

It fell immediately after intravenous induction, and often remained at that level. In these three groups the mean falls below mean initial values reached significance. Arterial blood-gas analysis. Changes in Pao, and PaoOj in group 1, as obtained

TABLE II.

Group 2

Group 3

n*

300

,

from arterial blood-gas analysis, are shown in figure 3. With the exception of 1 case, Pao, tended to fall temporarily after injection of Althesin. In the most marked 2 cases breathing air, oxygen tension felTby 14 mm Hg and 22 mm Hg 1.5 min after administration. PaOo3 tended to rise 3 min after injection, and showed an average increase of 2.7 mm Hg 7 min after administration. pH was maintained within the normal range in all cases.

Effect of Althesin on mean cerebrosplnal fluid pressure, mean arterial blood pressure and mean central venous pressure. Mean cerebrospina 1 fluid pressure (mm H[3O)

Group 1

jai

FIG. 2. An example of tracings from a patient in group 3 (mechanical ventilation; Paooi 30-34 mm Hg).

Mean arterial 1jlood pressure (mm Hg)

Patient no.

Initial value

Lowest value

12 min.

Maximum change (.%)

Initial value

Lowest value

12 min.

I 2 3 4 5 6 7

150 123 110 165 190 120 188

92 83 65 97 98 24 122

138 135 75 170 107 79 172

-39 -34 —41 -41 -48 -80 -35

99 136 103 120 107 88 103

70 99 72 84 80 70 75

Mean SE P

150 12

83 11 <0.01

125 14

-43

108 3

79

IM.

8 9 10 11 12 13 14

185 140 250 175 140 87 130

65 72 85 33 103 58 60

75 86 123 34 109 64 65

Mean SE P

158 18

68 8 <0.01

80 11 <0.01

15 16 17 18 19 20 21

98 130 199 138 175 121 200

60 78 74 20 79 96 113

Mean SE P

152 14

74 10 <0.01

Maximum change

Mean central venous pressure (era H,O)

C/tf

InitialI value

71 99 73 100 85 74 82

-29 -27 -30 -30 -25 -20 -27

<0.01

83 4 <0.01

150 80 90 87 80 96 88

105 60 70 78 58 72 65

-53

96 9

69 82 78 35 83 97 115

-39 -40 -63 -86 -53 -21 -44

80 9 <0.01

-50

-65 -49

-66 -81 -26 -33 -54

Maximum change

Lowest value

12 min.

13.0 7.8 10.5 5.5 10.5 2.5 9.0

10.5 5.8 9.5 1.0 4.0 0.3 0.8

12.5 5.8 9.9 2.5 5.5 1.0 1.2

-19 -26 -10 -82 -62 -88 -91

-27

8.4 1.2

4.6 1.5 <0.01

5.5 1.5 <0.05

-54

105 71 80 80 68 76 74

-30 -25 -22 -10 -28 -25 -26

6.0 2.0 6.0 9.0 10.0 7.0 8.5

3.3 0 0 4.6 8.7 3.5 5.0

4.0 02 0.3 4.6 8.7 3.5 5.0

-45 -100 -100 -49 -13 -50

73 6 <0.01

79 4 <0.05

-24

6.9 0.9

3.6 I.I <0.01

3.8 1.0 <0.01

-37

70 104 112 103 85 90 92

56 68 110 83 73 75 75

63 80 115 86 73 98 77

-20 -35 -2 -19 -14 -17 -18

6.0 6.0 11.0 4.7 7.0 5.2 17.0

2.3 3.0 7.0 0.5 2.0 5.8 14.8

32 3.0 7.0 0.5 3.0 5.4 14.8

-62 -50 -36 -89 -71 + 12 -13

94 5

77 6 <0.0I

85 6

-18

8.1 1.5

3.1 1.7 <0.01

5.3 1.6 <0.01

-44

4

ox

C/0

-41

BRITISH JOURNAL OF ANAESTHESIA

182

these two factors on cerebral blood flow and cerebrospinal fluid pressure is but slight. Data from subjects 50 in group 2 (Paooj 38-42 mm Hg) in whom the Paoj was below 90 and above 130 mm Hg were discarded. This was done in order to exclude the S effects of changes of blood gases, especially of Paco^j I 40 on cerebrospinal fluid pressure. The fact that the conditions of this study laid down in group 2 do not affect cerebrospinal fluid pressure has been reported 30 previously by Takasaki (1972). After elimination of 2 200 the effects brought about by changes in blood-gas content cerebrospinal fluid pressure was observed 150 to diminish by a mean of 53%, an 8% larger fall than that observed in group 1. In group 1, the 100 minimum level was recorded 1 min after administration but in group 2, however, the fall continued and reached the minimum level at 5-8 min after ad50 ministration. The fall was still significant at 12 min after Althesin injection. 11 13 1 mm In neurosurgical anaesthesia, hyperventilation is FIG. 3. Paoos and Paoj values from often used in an attempt to decrease cerebral blood volunteers breathing spontaneously flow by reducing Paco2 and thus decreasing cerebro(group 1). spinal fluid pressures. Results in group 3 show that DISCUSSION the additional hyperventilation in this group did not produce falls significantly greater than those of group Discussion of study conditions. The factor which has the most marked effect on 2. The duration of the pressure fall was identical to cerebrospinal fluid pressure is the change in cerebral that of group 2. Thus, clearly, Althesin significantly blood flow caused by changes of Paoo,. The graph decreases cerebrospinal fluid pressure in both normoof the relation between Paoo3 and cerebral blood capnic and hypocapnic subjects and maintains this flow is a sigmoid curve; a slight rise in Paco3 causes low level for quite some time, at least until a significant increase in cerebral blood flow, and recovery from anaesthesia. similarly a fall in Paco3 causing a decrease. A change in cerebral blood flow is immediately reflected in Comparison with other anaesthetics. The only intravenous anaesthetics now in use changes of cerebrospinal fluid pressure. In the group breathing spontaneously, observation of Pao0j at which lower cerebrospinal fluid pressures are regular intervals showed slight increases and this barbiturates. It is known that, if respiratory deagrees with Campbell and associates (1971) and pression is prevented, barbiturates will significantly Savege and associates (1971) who have also reported decrease the pressure (Horsley, 1937; Stephen et aL, a rise in P a ^ of 2-3 mm Hg. The fall of cerebro- 1954; S0ndergard, 1961) and also the cerebral blood spinal fluid pressure in group 1 evidently overrides flow (Pierce, et al., 1962; McDowall, 1965) by reducing cerebral oxygen uptake. In view of these the tendency of an elevated Paooi to increase it. Reivich (1964) has stated that Pa
Paco2

Pao

EFFECTS OF ALTHESIN ON CEREBROSPINAL FLUID PRESSURE which is followed by an increase in respiratory rate, and the rise in Paooa is not substantial. Pao- is clearly observed to fall but this can be prevented by a small increment of oxygen in the inhaled air. Comparing our data concerning the effect of barbiturates on cerebrospinal fluid pressure, which are not yet complete, we believe that Althesin causes the pressure to decrease as much as, or more than, do barbiturates. Althesin appears likely to bring about the greatest fall in cerebrospinal fluid pressure among anaesthetic agents in common use. Discussion of a possible mechanism of fall in cerebrospinal fluid pressure. Both arterial pressure and Paoo, affect cerebrospinal fluid pressure but, generally speaking, when there is a gradual rise or fall in arterial pressure, there is no change in pressure because cerebral blood flow is kept constant by the homeostatic mechanism of the cerebral circulation. However, this compensatory mechanism is thought not to be proof against sudden changes (Harper, 1969). Furthermore, in our study central venous pressure fell concomitantly with the arterial pressure after administration of Althesin and this could have been sufficient to override the homeostatic mechanism and to reduce cerebrospinal fluid pressure. Under the experimental conditions described it was not possible for changes in blood-gases to modify cerebrospinal fluid pressure, or for cerebral mass volume or cerebrospinal fluid volume to change suddenly following administration of the drug (McDowall, 1969). Whether Althesin directly affects cerebral blood vessels or indirectly reduces brain circulation by changing the distribution of blood or diminishes cerebral oxygen requirements has yet to be clarified. Considering that Althesin causes peripheral vasodilatation (Du Cailar, 1972), and cerebral vasoconstrictive changes are known to be related mainly to blood-gas levels, it is rather unlikely that Althesin would directly impede the brain circulation. In view of the significant fall in cerebrospinal fluid pressure, it may be surmised that some additional factors other than fall in arterial pressure and central venous pressure may be acting here. REFERENCES

Campbell, D., Forrester, A. C . Miller, D. C , Hutton, I., Kennedy, T. A., Lawrie, T. D. V., Lorimer, A. R., and McCall, D. (1971). A preliminary clinical study of CT1341—a steroid anaesthetic agent. Brit. J. Anaesth., 43. 14.

183

Du Cailer, J. (1972). The effects in men of infusions of Althesin (CT1341) with particular regard to the cardiovascular system. Postgrad, med. J. (June suppl.), 72. Harper, A. M. (1969). General physiology of cerebral circulation (ed. D. G. McDowall), p. 473. International Anesthesiology Clinics. Boston: Little, Brown & Co. Horsley, J. S. (1937). The intracranial pressure during barbital narcosis. Lancet, 1, 141. McDowall, D. G. (1965). The effects of general anaesthetics on cerebral bloodflow and cerebral metabolism. Brit. J. Anaesth., 37, 236. (1969). Physiology of the cerebrospinal fluid; in Cerebral Circulation, p. 507. Boston: Little, Brown & Co. Miller, D. C , Bradford, E. M. W., and Campbell, D. (1972). Haemodynamic effects of Althesin in poor-risk patients. Postgrad, med. J. (June SuppL), 133. Pierce, E. C , Lambertsen, C. J., Deutsch, S., Chase, P. E., Linde H. W., Dripps, R. D., and Price, H. L. (1962). Cerebral circulation and hyperventilation in man. J. din. Invest., 41, 1664. Reivich, M. (1964). Arterial Pcoi and cerebral hemodynamics. Amer. J. Physiol., 206, 25. Savege, T. M,, Foley, E. I., Coultas, R. J., Walton, B., Strunin, L., Simpson, B. R., and Scott, D. F. (1971). CT1341: some effects in man; cardiorespiratory, electroencephalographic and biochemical measurements. Anaesthesia, 26, 402. Ross, L., and Maxwell, M. P. (1972). A comparison of the cardiorespiratory effects during induction of anaesthesia of Althesin with thiopentone and methohexitone. Postgrad, med. J. Qune Suppl.), 66. Sondergard, W. (1961). Intracranial pressure during general anaesthesia. Dan. med. Bull., 8, 18. Stephen, C R., Woodhall, B., Golden, J. B., Martin, R., and Nowill, W. K. (1954). The influence of anesthetic drugs and techniques on intra-cranial tension. Anesthesiology, 15, 365. Takasaki, M. (1972). Effect of droperidol and fentanyl on cerebrospinal fluid pressure. Masui (Japanese Journal of Anaesthesiology), 21, 211. EFFET D'ALTHESIN SUR LA PWESSION DU LIQUIDE CEPHALORACHIDIEN SOMMAIRE

Les modifications de la pression du liquide cephalorachidien. survenant apres l'induction d'anesthisie avec Althesin, ont etc enregistrces chez vingt et un patientsvolontaires. qui ne presentaient aucune anomalie des systemes nerveux central et cardiorespiratoire. La pression du liquide cephalorachidien diminua chez les patients a respiration spontanee de 45 pourcent une minute apres Pinjection intraveineuse d'Althesin 0,1 ml/kg. Elle remonta presqu'au niveau de controle avant induction apres 12 minutes. II v cut durant cette periode une lefzere augmentation de la Paco,. La reduction de la pression du liquide cephalorachidien etait legercment plus orononcee. lorsque la Paco. fut contrdlee par respiration mecaiiaur; la reduction etait de 53 pourcent lorsque k Paco, se ma:ntint entre 38 et 42 mm Hg, et de 50 pourcent lors d'une Paco, entre 30 et 34 mm Hg. La diminution siipiificativ- <1e la pression du liquide cephalorachidien, Droduite par Althtsin, associee au fait pue le retablissement a esprit eveiU6 est rapide, peut faire de ce nrrfdicament up anesthesique valable pour les interventions neurochirurgicales.

BRITISH JOURNAL OF ANAESTHESIA

184 OBER DIE WIRKUNG VON ALTHESIN AUF DEN DRUCK DES LIQUORCEREBROSPINALIS

HFECTOS DE ALTHESIN SOBRE LA PRESION DEL LIQUIDO CEFALORRAQUIDEO

ZUSAMMENFASSUNG

RESUMEN

Veranderungen des Druckes des Liquor cerebrospinalis nach Einleitung der Anaesthcsie mit Althesin wurden bei 21 freiwilligen Patienten registriert, welche keine pathologischen Veranderungen des zentralen Nervensystems oder des cardiorespiratonschen Systems aufwiesen. Bei Patienten, welche spontan atmeten, fiel der Druck des Liquor cerebrospinalis eine Minute nach intravenoser Injektion von Althesin 0,1 ml/kg urn 45% ab. Er kehrte innerhalb von 12 Minuten auf den Ausgangswert zuriick. Wahrend dieser Zeit bestand ein geringer Anstieg des Paco,. Wenn Pacd bei mechanischer Beatmung kontrolliert wurde, fiel der Druck des Liquorcerebrospinalis noch geringgradig mehr ab, und zwar u n 53%, wenn Paco, zwischen 38 und 42 mm Hg gehalten wurde und 50% wenn Paco, zwischen 30 und 34 mm Hg gehalten wurde. Der durch Althesin hervogerufene eindeutige Abfall des Druckes des Liquor cerebrospinalis in Verbindung mit der raschen Riickkehr zur klarer Ansprechbarkeit konnte bedeuten, daB Althesin ein wertvolles Anaesthetikum fur neurochirurgische Mafinahmen darstellt.

Fueron registrados los cambios en la presi6n de Iiquido cefalorraquideo despues de la induction de anestesia con Althesin en veintiiin patiences voluntarios que presentaban anormalidad del sistema nervioso central o cardiorrespiratorio. En pacientes que respiraban espontaneamente la presi6n del Iiquido cefalorraqufdeo descendi6 en un 45 por ciento un minuto despues de la inyecci6n intravenosa de 0,1 ml/kg de Althesin. A los 12 minutos habia vuelto casi a los niveles anteriores a la inducci6n. Durante este itempo hubo un ligero incremento de la Paco,. Cuando fue controlada la Paco, mediante respiraci6n mecanica hubo un descenso ligeramente mayor de la presidn del Iiquido cefalorraqufdeo: Un 53 por ciento cuando la Paco, fue mantenida entre 38—42 mm Hg y un 50 por ciento cuando la Paco, fue mantenida entre 30-34 mm Hg. El descenso significativo de la presi6n del lfquido cefalorraquideo producido por Althesin y la rapida recuperation con pensamiento daro pueden permitir que Ahhesin sea un anestisico valioso para las intervenciones neuroquinirgicas.

FACULTY OF ANAESTHETISTS OF THE ROYAL COLLEGE OF SURGEONS OF ENGLAND A one-day SCIENTIFIC MEETING will be held in the Stopford Building, Manchester University, Manchester 15, on Saturday, May 5, 1973. Subject: "Suxamethonium" Tickets £1.00 per head, exclusive of refreshments. Further details may be obtained from the Secretary, Faculty of Anaesthetists, Royal College of Surgeons of England, 35-43 Lincoln's Inn Fields, London WC2A 3PN.