Plasma catecholamine concentrations associated with cerebral vasospasm

Journal of the Neurological Sciences, 1980, 45 : 261-271 © Elsevier/North-Holland Biomedical Press

261

PLASMA CATECHOLAMINE CONCENTRATIONS ASSOCIATED WITH C E R E B R A L VASOSPASM

A. B. LOACH 1 and C. R. BENEDICTz,* 1Nuffield Department of Anaesthetics and 2MRC and University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford (Great Britain)

(Received 20 August, 1979) (Accepted 9 October, 1979)

SUMMARY Plasma concentrations of adrenaline and no, adrenaline were measured sequentially over the immediate post-operative period tbllowing clipping of an intracranial aneurysm in 11 patients. Those patients who developed local cerebral vasospasm showed a sustained rise in plasma catecholamines, particularly noradrenaline, whilst those patients who developed generalised cerebral vasospasm showed early peaks of very high concentrations of adrenaline and noradrenaline which preceded radiological evidence of generalised vasospam.

1NTROD UCTION Previous workers have demonstrated increased excretion of catecholamine breakdown products in the urine of patients who had suffered a subarachnoid haemorrhage (Tomomatsu et al. 1964; Eisalo et al. 1972; Neil-Dwyer et al. 1974) whilst Meyer et al. (1973) repolted high plasma and cerebrospinal fluid (CSF) concentrations of adrenaline and noradrenaline in patients who had had a cerebral haemorrhage. These investigators suggested that the increased concentrations of catecholamines or their breakdown products were due to sympathetic nervous system overactivity in these patients. Intracranial vessels are innervated by sympathetic nerve fibres (Falck et al. 1956; Neilsen and O w m a n 1967) and increased sympathetic nervous system activity has been

* Rhodes Scholar. Correspondence to : C. R. Benedict. Present address : Cardiovascular Unit, U.C. I- 104, Toronto General Hospital, 101 College Street, Toronto, Ont. M5G 1L7, Canada.

262 shown to result in vasoconstriction of cerebral blood vessels (Harper et al. 1972; Mirzoyan 1975). It is possible, therefore, that increased activity of the sympathetic nervous system might play a part in the development of cerebral vasospasm (Wilkins 1975). It has been shown that plasma noradrenaline and adrenaline concentration measurements reflect sympathetic nervous system and adrenal medullary activity (Benedict et al. 1978). We have previously shown that plasma noradrenaline concentrations were significantly raised in patients recovering from subarachnoid haemorrhage (Benedict and Loach 1978). In this study, plasma adrenaline and noradrenaline concentrations were measured post-operatively in patients who underwent clipping of an intracranial aneurysm following subarachnoid haemorrhage in order to investigate the relationship between the development of cerebral vasospasm and changes in plasma adrenaline and noradrenaline concentrations. METHODS Eleven patients, who underwent craniotomy and clipping of a ruptured intracranial aneurysm 4-10 days after subarachnoid haemorrhage were investigated. Informed consent was obtained from all the patients. Clinical details of the patients are shown in Table 1. Pre-operative and post-operative management were similar in each case. The anaesthetic sequence consisted of induction of anaesthesia using thiopentone and pancuronium, intubation of the trachea and automatic ventilation of the lungs with a mixture of 70 70 nitrous oxide and 30 7o oxygen. Anaesthesia was maintained with increments of pancuronium and supplements of fentanyl to provide analgesia. During surgical clipping of the aneurysm, systemic hypotension was induced by an infusion of a solution (0.01 ~) of sodium nitroprusside. There was no significant difference m duration of surgery in these patients. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine, automatic ventilation was stopped and spontaneous ventilation re-established before transfer to the intensive therapy unit for post-operative care. After a variable period in the intensive therapy unit (28-56 hr), the patients were transferred to the general neurosurgical ward when their clinical condition was considered suitable.

Post-operative monitoring In the immediate post-operative period, the following variables were monitored continuously; systolic and diastolic blood pressures, heart rate and intracranial pressure. Blood pressure was measured through an indwelling catheter (Longdwe120 swg) inserted percutaneously into a radial artery and connected by saline-filled manometer tubing to a transducer (Statham P37) mounted at the level of the right atrium. The transducer signal was amplified and presented as a visual oscilloscopic display (Hewlett Packard, module 7803B). The signal was also fed to a 4-channel recorder

F F M

6. M.B.1 ~ 7. P.B. 8. H.P.

64 53 55

41 62 58

43

64

46 40 41

Age (yr)

Vertebral, ant. comm. Ant. comm. Ant. comm.

R post. comm. R middle cerebral Ant. comm.

Basilar

R middle cerebral

L pica L post. comm. L middle cerebral

Site ofaneurysm

130/80 120/60 110/60

120/80 140/70 200/110

115/45

130/70

120/90 110/70 110/60

Pre-op. BP

Local Local Generalised

Generalized None, haematoma None

None

None

None None None

Pre-op. spasm

a Multiple aneurysms treated at two operations following subarachnoid haemorrhage. b Died of myocardial infarct.

9. R.G. 10. I.G. 11. W.H.

M F F

M

5. D.W.

Group C

F

F M F

Sex

4. E.T.

Group B

1. B.W. 2. J.A. 3. M.B.2 a

Group A

Groups

CLINICAL DETAILS OF PATIENTS STUDIED

TABLE 1

11 11 111

1 111 11

11

1

1 11 1

Pre-op. Botterell grade

Severe generalised Severe generalised Severe generalised

Local and hydrocephalus Local and hydrocephalus Severe generalised Local Prob. sev. local

No No No

Post-op. spasm

Yes, mannitol Yes, mannitol Yes, mannitol

Yes, drainage and mannitol Yes No Yes, mannitol

Yes, drainage

No No No

Post-op. intracranial hypertension

Died Died Died

Good Fair Died b

Fair

Fair

Good Good Good

Outcome

264 (Devices M4). The zero, span and linearity of the transducer were calibrated using a mercury column for a range 0-300 mm Hg. lntracranial pressure was measured through a polythene catheter inserted into the lateral ventricle at operation and brought out through the wound. It was connected with saline-filled manometer tubing to art external transducer (Hewlett Packard, 1280C) mounted at the level of the external auditory meatus. The zero, span and linearity of this transducer were calibrated against a mercury column for a range of 0-50 mmHg. The signal was amplified (Hewlett Packard, module 780-19) and fed directly to the Devices M4 recorder.

Clinical management Patients were nursed head up to ensure that there was no obstruction to cerebral venous outflow and therapeutic intervention was minimal. All patients received diphenylhydantoin 100 mg 8-hourly by intramuscular injection as an anticonvulsant and ampicillin 500 mg 6-hourly intravenously prophylactically. Hydralazine was given in 10-mg doses intravenously whenever the systolic blood pressure exceeded 200 mm Hg. Rises in intracranial pressure above 20 mm Hg were controlled either by withdrawing cerebrospinal fluid through the ventricular catheter or by an intravenous infusion of 500 ml mannitol (20 ~o). The clinical state of the patients was assessed hourly by determining the response to verbal or painful stimuli and the presence of focal neurological signs. On the basis of their post-operative clinical course, patients were divided into 3 groups : (A) Those without post-operative complications (B) Those with post-operative complications who survived (C) Those who died. None of the patients developed post-operative infective complications or any intracranial collection of blood.

Angiography Post-operative check angiograms were carried out on all but one of the patients. Seven of the eleven patients had repeated angiograms initially 6-hourly, then 12hourly, using an indwelling carotid artery cannula (Adams et al. 1978). There were no complications using this procedure for repeated angiography. In 3 patients in whom this technique could not be applied, 4-vessel angiography was carried out on the first or second post-operative day. For one patient there was no 61inical indication for angiography; her neurological state was normal, she had no intracranial hypertension and was normotensive. At each angiogram, a sample of arterial blood was collected for estimation of PO2 and PCO2 to ensure that any changes observed in cerebral arterial calibre were not due to hypel- or hypocarbia and that the patient was adequately oxygenated. Angiograms were assessed at the time by a member of the neurosurgical staff and by one of the authors (A.B.L.) before the results of catecholamine estimations were known. Cerebral vasospasm, if present, was classified crudely into: local vasospasm~

265 which affected only one major intracranial vessel and generalised vasospasm which affected more than one major intracranial vessel. Control group Five male and four female patients aged 42.7 -+- 2.4 years formed this group. These patients had the following types of surgery: (1) thoracotomy for oesophageal stricture (2) and (3) cholecystectomy, (4) thoracic approach for correction of scoliosis of the spine, (5) repair of abdominal aortic aneurysm, (6) removal of thymic tumor, (7) removal of ovarian cyst, (8) vagotomy and pyloroplasty, and (9) removal of renal calculus. All these patients were normotensive and anaesthetic procedure during surgery was the same. Five ml venous blood samples were collected from these patients 24 hr before surgery, just prior to surgery, immediately after surgery, every 6 hr for 48 hr and then daily for 3 days. These patients were discharged 12-18 days after surgery. Plasma catecholamine estimation Venous blood samples of 5 ml were taken 6-hourly from an indwelling catheter from all the patients for estimation of plasma adrenaline and noradrenaline concentrations by the radioenzymatic method of H6rtnagl et al. (1977). All values were stated as mean 4- 1 SD. The data were analysed using Student's paired or unpaired t-test. The normal values for this assay in this laboratory (mean ± SEM) are adrenaline 0.693 -q- 0.415 nmol/1, and noradrenaline 2.861 ~k 0.650 nmol/1. These were obtained by measuring plasma adrenaline and noradrenaline concentration in 18 healthy subjects (11 males, 7 females) aged 21-70 years from whom a peripheral venous blood sample was collected after 30 min supine bed rest. Conversion factors used for the calculation of SI units were: adrenaline, 183.2 ng -- nmol; noradrenaline, 169.18 n g = 1 nmol. Plasma catecholamine estimations were continued until the patients were transferred to the general neurosurgical ward. RESULTS Plasma concentrations of adrenaline and noradrenaline for patients in each group are set out in Table 2. Group A. Patients without complications Of the 3 patients comprising this group two had serial angiography which failed to demonstrate any vasospasm. The third (BW) did not undergo post-operative angiography because it could not be justified clinically: her neurological state was normal, her intracranial pressure was normal and she was normotensive. Because she had a posterior inferior cerebellar artery aneurysm a catheter had not been introduced at operation. In this group of patients the plasma adrenaline concentration on admission to the intensive care unit was 2.60 q- 2.05 nmol/1 and the plasma noradrenaline concentration was 3.35 :k 1.89 nmol/l. The concentration of both

E n d o f surgery

Time

2.60 5- 2.05 3.35 ± 1.89

B vs C

A vs C

A vs B

Significance (P)

E nmol/l N E nmol/1

NE

E

E NE E NE

C. Patients who died

E nmol/l N E nmol/l

NS NS <0.05 <0.01 <0.01 <0.05

9.28 ± 2.00 12.89 % 0.83

2.52 -- 1.67 6.70 ± 3.66

B. Patients with post-operative complications

E nmol/I N E nmol/l

A. Patients without complications

Groups

Values are m e a n ± S.D.

NS <0.05 <0.01 <0.05 <0.001 <0.05

11.57 ± 3.94 20.63 5- 6.62

2.10 5- 0.59 9.07 -k 4.40

2.14 5-4-0.63 3.25 ± 0.57

6 hr

NS <0.001 <0.02 <0.005 <0.005 <0.05

8.30 5- 2.65 15.78 5- 3.32

2.04 5- 0.78 7.05 ± 0.64

NS <0.01 <0.02 <0.01 <0.01 NS

7.82 ± 3.21 14.25 5- 4.08

1.91 -+- 0.75 6.58 5- 1.18

1.54 5- 0.21 3.01 5- 1.02

18 hr

(NE) C O N C E N T R A T I O N S

1.57 5_ 0.44 3.12 5- 0.51

12 hr

C H A N G E S I N P L A S M A A D R E N A L I N E (E) A N D N O R A D R E N A L 1 N E NEUROSURGERY

TABLE 2

NS <0.05 NS <0.05 <0.05 NS

5.38 -k 3.08 10.82 ± 4.37

1.88 ± 0.73 5.75 ± 1.63

1.82 5- 0.98 3.31 5- 0.92

24 h r

NS NS NS NS NS NS

3 hr prior to death 3.73 5- 1.98 5.44 ~: 3.26

1.17 ± 1.38 4.15 5- 2.92

1.51 ± 0.44 3.31 5- 0.33

At transfer

1N E A C H G R O U P O F P A T I E N T S A F T E R

C~

to

267 catecholamines declined gradually and were within normal limits for this laboratory (Hortnagl et al. 1977) by the time the patients were transferred out of the intensive therapy unit.

Group B. Patients who developed complications Each of the 5 patients in this group developed cerebral vasospasm of either local or generalised type. The vasospasm was associated with slow deterioration in the clinical state, the patients becoming more drowsy and difficult to arouse and developing neurological signs. One patient (M.B.) developed severe generalised vasospasm associated initially with marked confusion and then drowsiness; one other patient (D.W.) developed a communicating hydrocephalus which later required the insertion of a shunt. One patient (H.P.) became mildly confused and over the first 24 hr developed a left hemiparesis which was thought to be due to spasm of the right middle cerebral artery. During carotid angiography at the end of this time he developed a myocardial infarct from which he died one day later. At post-mortem examination a fresh myocardial infarct and mural thrombus were demonstrated, all the intracranial vessels were patent and there was slight softening at the region supplied by the right middle cerebral artery. The remaining 4 patients, after the initial phase of clinical deterioration, showed symptomatic improvement within 4 days of surgery and eventually made an acceptable recovery. In this group plasma adrenaline concentrations were similar to those of Group A and were declining to normal values by the time of transfer to the neurosurgical ward. However, plasma noradrenaline concentrations rose, reaching a peak at 6 hr postoperatively, and were sustained for a further 12 hr. These concentrations differed significantly from the corresponding concentrations in patients of Group A. Group C. Patients who died All 3 patients in this group developed severe generalised vasospasm postoperatively and died within 60 hr. Each patient had initially made a good recovery from anaesthesia before becoming progressively more drowsy and unresponsive over the next 12 hr. By the end of this time they responded only to painful stimuli. Plasma adrenaline concentrations measured in these patients were significantly higher than those recorded in the other two groups as shown in Table 2. Plasma noradrenaline concentrations, however, were significantly increased only when compared with those of the patients in Group A. In each of these patients plasma concentrations of adrenaline and noradrenaline reached a peak within 8 hr of the end of surgery and then steadily declined. In all 3 cases serial angiograms were performed beginning at the conclusion of surgery; the severity of cerebral vasospasm seen on the angiograms increased slowly to reach a maximum at 24--36 hr after surgery and then regressed slightly. In contrast to the changes in plasma catecholamines the earliest time at which an angiogram was considered to show severe generalised vasospasm was at 16 hr postoperatively in two patients : the other developed severe generalised vasospasm at 28 hr. The one other patient (M.B.) in this study who developed severe generalised

268 vasospasm also had a high peak plasma concentration of noradrenaline during surgery 10 hr before the radiographic appearance of generalised vasospasm. The mean peak plasma concentration of noradrenaline was 23.53 nmol/l for all 4 patients who developed generalised cerebral vasospasm.

Control group Plasma noradrenaline concentration prior to surgery was 2.14 4- 0.27 nmol/l, immediately after surgery 2.36 4- 0.34 nmol/1, 6 hr after surgery 3.62 4- 1.02 nmol/I, 12 hr after surgery 3.30 4- 0.51 nmol/l, 18 hr after surgery 2.63 4- 0.31 rtmol/l and 24 hr after surgery 2.32 4- 0.27 nmol/1 which was within normal range. Plasma adrenaline concentration prior to surgery was 0.32 4- 0.24 nmol/l, immediately after surgery 1.36 4- 0.86 nmol/1, 6 hr after surgery 1.84 4- 0.84 nmol/l, 12 hr after surgery 1.63 4- 0.72 nmol/l, 18 hr after surgery 1.41 4- 0.64 nmol/1, 24 hr after surgery 1.06 4- 0.39 nmol/1, 48 hr after surgery 0.74 4- 0.34 nmol/l and 72 hr after surgery 0.66 4- 0.41 nmol/I which was within normal range.

Evaluation of the effect of indwelling cannula and repeated carotid angiography on plasma catecholamines In 5 patients plasma adrenaline and noradrenaline concentrations were measured immediately prior to angiography and 15, 30 and 60 min after angiography to determine whether indwelling cannula in carotid artery and angiography altered plasma catecholamine concentrations. Resting plasma noradrenaline concentration was 4.59 i 0.96 nmol/l, 15 min after angiography 4.87 -+- 1.04 nmol/1, 30 min after angiography 4.78 4- 1.09 nmol/l and 60 min after angiography 4.67 4- 0.94 nmol/l. None of these values were significantly different from pre-angiography concentrations. Similarly resting plasma adrenaline concentration was 2.96 4- 1.87 nmol/l, 15 min after angiography 2.89 4- 1.92 nmol/1, 30 min after angiography 2.92 -+- 1.74 nmol/l and 60 min after angiography 2.88 4- 1.76 nmol/1. Again none of these values were significantly different from pre-angiography concentrations. DISCUSSION In this study elevated concentrations of noradrenaline and adrenaline were found in patients who had local cerebral vasospasm and very high concentrations in patients who had severe generalised cerebral vasospasm. Local vasospasm was associated with sustained rise particularly of noradrenaline whilst the onset of severe generalised vasospasm was associated with a marked increase in both noradrenaline and adrenaline secretion. All the patients observed were treated as far as possible in the same way so that those patients who did not develop vasospasm (Group A) may be considered as control for those who did. Thus many other factors which might have causedincreased plasma catecholamine concentrations can be eliminated: the slight head-up tilt at which patients were nursed was the same for all cases; none of the patients became

269 hypoxic or hypercapnic, and of the drugs administered none was amongst those known to alter plasma catecholamine concentrations. Furthermore, to determine whether the high concentrations of catecholamines noted in group B and C patients were due to post-operative stress, a similarly "very ill" group of post-operative patients not subjected to aneurysm surgery were studied. The catecholamine concentrations and their changes noted after surgery were similar to those changes in group A indicating that alteration in concentration of adrenaline and noradrenaline in group B and C were not due to stress per se post-operatively. A number of further observations can be made: (l) Severe generalised vasospasm occurred in every patient who had a plasma noradrenaline concentration greater than 17.5 nmol/l. (2) In all 4 patients who developed severe generalised vasospasm this was preceded 10-28 hr before by a peak in plasma noradrenaline concentration which exceeded 17.5 nmol/l. (3) Local vasospasm, confined to one major intracranial vessel, was associated with sustained plasma noradrenaline concentrations between 6.0 and 12.0 nmol/l. (4) Patients who did not develop vasospasm showed only small changes in plasma catecholamines, i.e. less than 6.0 nmol/1. Therefore, it is likely that the onset of cerebral vasospasm is associated with an increase in plasma catecholamine concentrations and the severity of the vasospasm present appears to be related to the concentrations in the plasma. Peerless and Griffiths (1972) found increased concentrations of catecholamines in plasma in patients with subarachnoid haemorrhage and correlated the high concentrations with elevated blood pressure, ECG evidence of myocardial ischaemia and angiographic evidence of cerebrovascular spasm. Although their work is not directly comparable, the association between high plasma catecholamine concentrations and cerebrovascular spasm was also seen in our patients in the post-operative period. Since circulating adrenaline and noradrenaline arise from the sympatho-adrenal medullary system, it appears that markedly increased activity of the sympatho-adrenal medullary system is present particularly in those patients who develop severe generalised vasospasm. The reason for sympatho-adrenal medullary overactivity following subarachnoid haemorrhage is not clear. Crompton (1963) described areas of infarction in the hypothalamus in 61 ~ of patients dying after rupture of an intracranial aneurysm and considered that they were due to damage or distortion of vulnerable fine perforating arteries supplying the hypothalamus. Nagai et al. (1976) found that experimentally induced cerebral vasospasm in dogs was accompanied by ischaemic changes in the hypothalamus. Sited in the hypothalamus are the rostral connections of the sympathetic nervous system and it is possible that interference in hypothalamic blood supply great enough to produce infarction might lead to sympathetic nervous system dysfunction. Melville et al. (1963) found that electrical stimulation of the hypothalamus of cats led to pressor response and electrocardiographic ST changes which they ascribed to activation of the sympathetic nervous system because they could be abolished by spinal cord section at the level of C2. Thus one possible sequence is that critical reduction in hypothalamic

270 blood supply brought about by mechanical distortion of hypothalamic vessels of supply following rupture of an intracranial aneurysm leads to increased sympathoadrenal medullary activity and increased plasma concentrations of noradrenaline and adrenaline. In 1936 Stavraky reported that electrical stimulation of the hypothalamus caused constriction of pial arteries in addition to sympathetic nervous stimulation whilst in 1961 Armstrong and Hayes reported a patient with a phaeochromocytoma in whom fortuitous cerebral angiography revealed segmental constriction of intracranial vessels. In this study peak plasma catecholamine concentrations were observed well in advance of the development of severe generalised vasospasm. This observation supports Wilkins' (1975) suggestion that a generalised sympathetic discharge following interference with a hypothalamic blood supply could be a causative factor in producing cerebral vasospasm. Alternatively there may be no direct relationship between cerebral vasospasm and catecholamine release by the sympatho-adrenal medullary system. Early cerebrovascular spasm which may not be demonstrated by the radiological techniques available could lead to neuronal hypoxia by reducing tissue blood flow which produces the small infarcts described by Crompton (1963). Cerebral anoxia has been shown to cause catecholamine release. Stupfel and Roffi (1961) and Toyoda and Meyer (1969) found that the most potent stimulus for the release of adrenaline from the adrenal medulla was a rapid decrease in cerebral blood flow. Thus the elevated plasma catecholamine concentrations reported in this study might simply be due to cerebral anoxia produced by cerebral vasospasm. While whether increased sympathetic nervous system activity causes cerebral vasospasm is debatable at least as far as the myocardium is concerned, the use of betablockers may prevent the occurrence of ischaemic changes due to enhanced sympathetic activity. Further the ganglionic blockade of the superior cervical ganglion which gives rise to the sympathetic fibres that innervate the cerebral blood vessels may possibly prevent the deleterious effect due to cerebral vasospasm associated with increased sympathetic nervous system activity. ACKNOWLEDGEMENTS The authors thank Mr. C. B. T. Adams and Mr. M. Briggs for permission to study patients in their care and Professors A. Crampton Smith and D: Grahame-Smith for their support.

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