Hydergine effect on cerebral circulation in cerebrovascular disease

Journal of the neurolooical Sciences Elsevier Publishing Company, Amsterdam - Printed in The Netherlands

475

Hydergine Effect on Cerebral Circulation in Cerebrovascular Disease L. C. M c H E N R Y , JR., M. E. JAFFE, J. K A W A M U R A AND H. I. G O L D B E R G Stroke Research Center, Philadelphia General Hospital, Philadelphia, Pa. (U.S.A.) (Received 4 November, 1970)

INTRODUCTION

Mixed hydrogenated ergot alkaloids have been shown to cause vasodilatation in the peripheral circulation with a fall in vascular resistance. In a recent report of the action of one such preparation (Hydergine) on the cerebral circulation, Szewczykowski et al. (1970) found that when given intravenously to baboons, Hydergine would produce a transient 8 - 1 4 ~ increase in cerebral blood flow (CBF) and a 13~o fall in cerebrovascular resistance (CVR). In other studies in man, varying effects on cerebral circulation in patients with cerebrovascular disease have been described. Using the nitrous oxide method, Hafkenschiel et al. (1950) were unable to demonstrate a change in CBF or CVR following the intramuscular administration of Hydergine. Heyck (1961), on the other hand, found that intravenous Hydergine increased CBF by 61 ~ and decreased the CVR by 39~. In view of these conflicting results, this investigation was undertaken to determine whether or not Hydergine would cause a change in CBF or CVR in patients with cerebrovascular disease. Also, the effects of Hydergine on regional cerebral blood flow were assessed to evaluate the action of the drug on areas of focal abnormality of the cerebral circulation. METHODS

Ten indi v iduals with stabilized neurological abnormalities resulting from cerebrovascular disease, as confirmed by clinical examination and cerebral angiography, were examined. These patients had each developed a neurological deficit from 5 days to 6 weeks prior to the performance of these measurements. The cerebrovascular diagnosis was confirmed by cerebral angiography. The criteria for abnormality of the cerebral angiogram are described elsewhere (McHenry et al. 1970). The diagnoses were as The study was supported by grants from the U.S. Public Health Service (NS-06520) and Sandoz, Inc.

J. neurol. Sci., 1971, 13:475-481

476

L. C. MCHENRY, JR., M. E. JAFFE, J. KAWAMURA, H. I. GOLDBERG

follows : 5 patients had moderate to severe diffuse cerebrovascular disease, 3 had complete or branch middle cerebral artery occlusion, 1 had internal carotid artery stenosis and 1 had anterior cerebral artery occlusion. All patients showed a hemiparesis or hemiplegia, dementia, aphasia or visual field deficits. Although confusion was present in 3 patients, none were stuporous at the time of these studies. Seven patients had moderate to severe hypertension. Control measurements were carried out on 2 neurologically normal volunteers. Regional cerebral blood flow (rCBF) measurements were performed by the 133Xenon injection method (Lassen and Ingvar 1963; McHenry et al. 1969) in association with cerebral angiography. 133Xenon in saline was injected via indwelling catheter into the internal carotid artery. The clearance of the tracer was measured by 8 collimated probes containing 0.5 x 0.5 NaI crystals. The scintillation detectors were coupled via amplifiers and pulse height analyzers to 2,4-channel tape recorders. The data from each clearance curve was measured by hand and analyzed by computer using the Sveinsdottir program (Hoedt-Rasmussen et al. 1966). rCBF values were calculated by the "height over area" or stochastic method from the following equation : rCBF~o = ~ 0 ° 2 x 100 where: H10 is the difference between the maximum counting rate and the counting rate after 10 min expressed as counts per min ; A10 is the area between the clearance curve and the baseline and is the total number of counts accumulated for 10 rain ; 2 is the blood-brain partition coefficient for xenon assuming a 60/40 grey/white matter ratio ; and 100 is the factor for calculation of blood flow in ml/100 g brain/min. rCBF10, therefore, is the average regional blood flow over 10 min. The hemispheric mean CBF value (CBF) is the mean of all 8 rCBFlo values obtained from the hemisphere supplied by the internal carotid artery receiving the isotope. The blood flow data given in Table 1 are the hemispheric mean CBF's. The present study was carried out as follows : First a baseline rCBF measurement was performed. In 6 of the 10 patients and in the 2 normal persons, 5 % CO2 in air was administered via a face mask for 2 min before and during a second rCBF measurement. Thirty min afterwards from 0.6 to 1.2 mg of Hydergine was given intramuscularly. The dosage given was gradually increased in consecutive patients to determine whether a greater dose was needed to produce a change in CBF. Two patients received 0.6 mg, 4 had 0.9 mg and the remaining 4 received 1.2 mg. Fifteen min after the parenteral Hydergine the third rCBF study was carried out. Blood pressure was monitored throughout the entire study and arterial pCO2 samples were obtained before, after and during each rCBF measurement. Cerebral angiography was done after the final blood flow study. On the basis of previous experimental studies (McHenry et al. 1969, 1970)any rCBF 10 value that differed 20 % or more from the hemispheric mean CBF is considered focally increased or decreased. When repeated rCBF measurements are performed in the same person a 20% change in rCBFlo and a 7% change in the hemispheric mean CBF are considered significant in our laboratory. J. neurol. Sci., 1971, 13:475-481

HYDERGINE EFFECT ON CEREBRAL CIRCULATION IN CEREBROVASCULAR DISEASE

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J. neurol. Sci., 1971, 13 : 475-481

478

L. C. MCHENRY, JR.~ M. E. JAFFE, J. KAWAMURA, H. I. GOLDBERG RESULTS

M e a n C B F results

In all 10 cases with cerebrovascular disease the baseline CBF was considerably decreased below the value for normal individuals (54+ 2.7 ml/100 g/min, McHenry et al. 1969). The CBF values, the mean arterial blood pressure (MAP), the CVR and pCO2 for each of the 3 measurements in each case are given in Table 1. The patients are grouped in Table 1 and Fig. 1 according to diagnostic categories rather than according to consecutive CBF studies with increasing dosages of Hydergine. Before Hydergine the average baseline values for the group were : CBF 31 + 3 ml/100 g/min; MAP 118_+7 mm Hg; CVR 3.8_+0.6 mm Hg/ml/100 g/min and pCO2 41 mm Hg. HYDERGJNEEFFECTON CEREBRALCIRCULATIONIN CtI~EM~CUI.AR '

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49

46 51

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MAP 107

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r,o 120

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~Mwl Fig. 1. Regional cerebral blood flow measurements before and after parenteral Hydergine. The control (cont.) rCBFIo values are on the left and the experimental (hyd) are on the right for each patient. The pCO2 and MAP are at the top and the hemispheric mean CBF at the bottom of each column. In the 5 patients with focal cerebral vascular disease, the probes over areas considered angiographically ischemic are designated by broken lines. In these 5 patients the solid lines are over regions considered angiographically normal. In the 5 patients with diffuse cerebrovascular disease on the left, angiographic clarification of probe localization could not be made. Open circles indicate control rCBFzo values 20% below the CBF, while an asterisk shows experimental values 20% below the mean. Inverted triangles indicate rCBFto values 20% greater than the CBF. Six of 72 rCBF measurements showed a significant increase after Hydergine.

After C O 2 inhalation the average CBF for 6 patients increased 26~o to 39+1.9 ml/100 g/rain; the MAP to 114___19 mm Hg; the CVR to 3.0+0.5 mm Hg/ml/100 g/min and the pCO2 to 53 mm Hg. Following parenteral Hydergine the average hemispheric mean CBF decreased 6 . 5 ~ to 2 9 + 4 ml/100 g/rain, the MAP to 93_+22 mm Hg; the CVR to 3.2+_0.9 mm Hg/ml/100 g/rain and the pCO2 to 40 mm Hg. Two patients (No. 2 and 5) had significant increases in CBF while 4 cases showed a decrease following Hydergine. In the remaining 4 cases there was no change in the CBF after Hydergine. The changes in CBF were not related to the dose of Hydergine given to each patient. J. neurol. Sci., 1971, 13:475-481

479

HYDERGINE EFFECT ON CEREBRAL CIRCULATION IN CEREBROVASCULAR DISEASE

The normal individuals gave the results shown in Table 2 for the 3 regional blood flow measurements (W.M. is shown in Fig. 2): TABLE 2 OBSERVATIONS IN 2 NORMAL CONTROL SUBJECTS

M.N. (0.6 mg Hydergine)

W.M. (0.6 rag Hyderoine)

Control CO 2 Hydergine

CBF

MAP

CVR

ApCO 2

CBF

MAP

CVR

ApC02

53 79 53

110 120 105

2.0 1.5 2.0

41 50 40

52 75 51

94 105 90

1.8 1.4 1.8

45 52 41

CBF pC02 MAP~ Control • 53 41 110 C02 Inhalation[] 79 50 120 Hydergine [] 53 40 105

/_.~" W.M.

Fig. 2. Results of rCBF measurements in 8 regions in a normal individual (W.M.) under baseline conditions (black bar), during 5 % CO2 inhalation (white bar), and 30 rain after 0.6 mg Of Hydergine intramuscularly (dotted bar). The individual rCBF~o value in ml/100 g/rain is shown in each bar. The mean CBF, pCO2 and MAP values during the 3 studies are at the lower left of the diagram.

Regional CBF results The individual rCBF10 values for the baseline and Hydergine rCBF measurements in each patient are shown in Fig. 1. A total of 72 regions were measured in these i0 patients. In 4 of the 5 patients with focal vascular disease there were 5 probes (open circles) over angiographically ischemic areas which showed baseline rCBFlo values significantly lower (i.e. > 20 ~o) than the CBF for that case. In the remaining cases there were no significant baseline regional blood flow abnormalities detected under resting conditions. J. neurol. Sci., 1971, 13:475-481

480

L . C . MCHENRY, JR., M. E. JAFFE, J. KAWAMURA, H. 1. GOLDBERG

DISCUSSION

The intramuscular injection of from 0.6-1.2 mg of Hydergine failed to produce at1 increase in CBF in 10 patients with cerebrovascular disease and in 2 normal individuals. The baseline CBF values in these patients are similar to those found previously in individuals with cerebrovascular disease (McHenry 1966). The mean CBF values for the control and drug measurements are similar to a control serial study (McHenry et al. 1969), that is, in 6 (Cases 1, 2, 4, 5, 8 and 10) of the 10 cases the CBF remained essentially the same after Hydergine. Of these 4 (Cases 1, 2, 5 and 8), who were tested with CO2 inhalation, demonstrated some preservation of the capacity for cerebral vasodilatation due to hypercapnia. All had over a 7 °/ooincrease in CBF during CO2 inhalation. The remaining 4 patients (Cases 3, 6, 7 and 9) had a significant (i.e. > 7 ~/o) fall in CBF after Hydergine. These patients also showed considerable falls in MAP after Hydergine. This would indicate that autoregulation was lost and that blood flow was passively following blood pressure. Two other patients (Cases 2 and 5) had decreases of 20 mm Hg or greater in MAP; however, the CBF did not fall, but actually increased --an indication of the preservation of autoregulation in these patients. If the data in this study are examined by evaluating the effects of Hydergine on CVR alone, somewhat different conclusions might be drawn. In 8 of the 10 cases, the CVR fell after Hydergine. This, at first sight, might imply that Hydergine produced cerebral vasodilatation and a fall in vascular resistance. The fall in CVR, however, could be related to a change in either the CBF or MAP, the CVR being actually a mathematic ratio between the MAP and CBF which, in this study, were measured quantitatively. An increase in CBF alone or a fall in MAP alone would lower the CVR. Various autonomic factors can affect the MAP while others (e.g. arterial pCO2 or PO2) may alter the CBF at the same time. Under normal circumstances, the blood pressure variations are compensated by changes in resistance to maintain a consistent cerebral perfusion, namely, autoregulation (Lassen 1964; Harper 1966). In some patients with cerebrovascular disease, however, this intrinsic ability to regulate CVR in response to a MAP change may be impaired. Drops in blood pressure cannot thereby be compensated by a fall in CVR, but actually a diminution in cerebral blood flow occurs. CBF can passively follow changes in MAP. The fact that there has been a fall in CVR does not always imply that blood flow has been improved. This is shown by Cases 3 and 9. The fall in MAP and CBF in Cases 6 and 7 was of similar proportion, so that the hemodynamic changes were not reflected in the CVR value. One cannot, therefore. imply that there are changes in cerebral hemodynamics by examining one factor alone. From this study one must conclude that parenteral Hydergine does not generally change the cerebral blood flow in stroke patients. The drug did not change the mean hemispheric blood flow in patients with cerebrovascular disease, nor did it alter flow in areas of focal abnormality except where this was reduced due to a reduction in systemic arterial pressure.

J. neurol. Sci., 1971, 13:475-481

HYDERGINE EFFECT ON CEREBRAL CIRCULATION IN CEREBROVASCULAR DISEASE

481

SUMMARY

Cerebral blood flow (CBF) was measured in 10 patients with cerebrovascular disease and in 2 normal individuals using the 133Xenon injection technique. After control measurements were performed, 0.6-1.2 mg of Hydergine was given intramuscularly. The mean CBF did not change significantly after Hydergine; mean figures before and after were 31 and 29 ml/100 g/min respectively. The fall in CVR, viz. 3.8-3.2 mm Hg/ ml/100 g/min was reflected by the mean fall in MAP, viz. 118 to 93 mm Hg, respectively, in the patients with cerebrovascular disease. It is concluded that parenteral Hydergine did not change cerebral blood flow significantly in this group of patients. REFERENCES HAFKENSCHIEL, J. H., C. W. CRUMPTONAND J. H. MOYER (1950) The effect of intramuscular dihydroergocornine on the cerebral circulation in normotensive patients, J. Pharmacol. exp. Ther., 98: 144-146. HARPER, A. M. (1966) Autoregulation of cerebral blood flow, J. Neurol. Neurosur#. Psychiat., 29: 398-403. HEYCK, H. (1961) Der Einfluss der Ausgangslage auf sympathicolytischer Effect am Hirnkreislauf bei zerebrovascularen Erkrankungen, Arztl. Forsch., 15: 243-251. HOEDT-RASMUSSEN,J., E. SVEINSDOTTIRAND N. A. LASSEN(1966) Regional cerebral blood flow determined by intra-arterial injection of radioactive inert gas, Circulat. Res., 18: 237-247. LASSEN, N. A. (1964) Autoregulation of cerebral blood flow, Circular. Res., Suppl. 15: 201-204. LASSEN, N. A. AND D. H. INGVAR(1963) Regional cerebral blood flow measurement in man, Arch. Neurol. (Chic.), 9: 615~22. MCHENRY, JR., L. C. (1966) Cerebral blood flow studies in cerebrovascular disease, Arch. intern. Med., 117: 546-556. MCHENRY, JR., L. C., M. E. JAFFEAND H. I. G-OLDBERG(1969) Regional cerebral blood flow measurements with small probes, Part 1 (Evaluation of the method), Neurology (Minneap.), 19:1198-1206. MCHENRY, JR., L. C., M. E. JAFFE, J. KAWAMURAAND H. I. GOLDBERG (1970) Effect of papaverine on regional blood flow in focal vascular disease of the brain, New Engl. J. &led., 282:1167-1170. SZEWCZYKOWSKI,J., J. S. MEYER, A. KONDO, F. NOMURAAND T. TERAURA0970) Effects of ergot alkaloids (Hydergine) on cerebral hemodynamics and oxygen consumption in monkeys, J. neurol. Sci., 10: 25-3 I.

J. neurol. Sci., 1971, 13 : 475~481