British Journal of Neurosurgery (1992) 6 , 313-320

ORIGINAL ARTICLE

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Does thrombin prevent cerebral vasospasm following aneurysmal subarachnoid haemorrhage? PADRAIC O’NEILL,* STEVEN WALTON,t PATRICK M. FOYd & MALCOLM D. M. SHAWS

*Department of Neurosurgery, Mater Private Hospital, Eccles Street, Dublin, Ireland; tHaematology Department, Liverpool University, Liverpool, UK; $Mersey Regional Department of Surgical Neurology, Walton Hospital, Liverpool, UK

Abstract

Fibrinopeptide A (FPA) levels which have been shown to be a quantitative index of thrombin generation, were measured in blood and cerebrospinal fluid (CSF) samples from patients following subarachnoid haemorrhage (SAH) and from a control population. The levels found in samples obtained in patients following SAH are compared with those found in controls and also correlated with clinical grade on admission as assessed by the Glasgow Coma Score and the World Federation of Neurological Surgeons’ grading system, and with the amount of subarachnoid blood seen on CT, the Occurrence of ischaemic deterioration, the Occurrence of low-density change on CT,the presence of vasospasm on angiography, clinical outcome as assessed by the Glasgow Outcome Score 3 months following the ictus, and the incidence of ischaemia as a cause of death or disability as assessed 3 months following the ictus. The levels of FPA found in blood and CSF from patients following SAH were significantly raised when compared with those found in controls. There was significant correlation between blood FPA levels and the amount of subarachnoid blood seen on initial CT. CSF FPA levels had a statistically significant correlation with outcome as assessed at 3 months post-ictus. No statistically significant correlation was found between blood or CSF FPA levels and any of the other variables studied.

Key words: Delayed cerebral ischaemia,fibrinopepride A, subarachnoid haemowhage, thrombin, vasospasm.

Introduction Delayed cerebral ischaemia secondary to cerebrovascular spasm following aneurysmal subarachnoid haemorrhage (SAH) remains a major cause of mortality and morbidity.’ Increasing degrees of cerebrovascular spasm have been correlated with poor clinical grade;-S the occurrence of focal the occurrence of focal cerebral infarction,6-8 diminished cerebral blood f l o ~ ~ and - ’ ~poor final outcome.zJ3-15 The volume of blood at the site of haemorrhage is predictive of the occurrence of severe spasm.I6 One enigmatic characteristic of the

vasospasm, however, is that the median time of onset is 7 days. The reason for this delayed occurrence is unknown but one possible explanation is that blood contains substances that for a period of time protect against the development of spasm. Thrombin has recently been shown to be a vasodilator of human basilar arteries in vitro.” The present study was therefore designed to test the hypothesis that thrombin generation following SAH may have a protective effect against the occurrence of cerebral vasospasm and consequent delayed cerebral ischaemia.

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Padraic O’Neill et al.

Materials and methods

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General Fibrinogen is a plasma protein with three peptide chains A-alpha, B-beta and gamma, respectively. Thrombin acts on fibrinogen by cleaving the bond between arginine and glycine on the A-alpha and B-beta chains. This results in two molecules of fibrinopeptide A (FPA), two molecules of FPB and one of fibrin monomer. Plasma FPA is cleared rapidly by first-order kinetics and has a circulatory half-life of 3-5 min. The first-order rate constant for this process varies minimally between individuals and over a wide range of concentrations of FPA. Therefore the plasma concentration of FPA reflects the rate of its production and has been shown to be a specific and quantitative index of thrombin activity in v ~ v o . ~ * J ~

Patient population Only patients with proven aneurysmal SAH were included in the SAH group. The diagnosis of SAH was confirmed either by the presence of uniformly blood-stained and xanthochromic cerebrospinal fluid (CSF) at lumbar puncture or the presence of subarachnoid blood on C T of the brain or by both. An aneurysm was demonstrated by angiography in all cases. The control group included four patients admitted for craniotomy and anterior fossa floor repair who had a CSF fistula with rhinorrhoea. There was no history of recent trauma or infection in these cases. All other patients in the control group had suspected prolapsed lumbar intervertebral disc and had been admitted for radiculography.

Clinical details

recorded on patients in the SAH group: date of ictus, clinical grade on admission to the neurosurgical unit as assessed by both the Glasgow Coma ScoreZo and the originally proposed World Federation of Neurological Surgeons (WFNS) grading system,2’ whether ischaemic deterioration occurred, the clinical outcome as assessed at 3 months following the ictus and the clinical opinion as to the cause of death or disability as assessed at that time. For the purposes of the present study ischaemic deterioration is defined as deterioration in neurological status usually of relatively gradual onset where recurrent haemorrhage, hydrocephalus and metabolic disorders (e.g. hypoxia, hyponatraemia, etc.) have been excluded by repeat C T and biochemical laboratory investigations, respectively. The clinical outcome was assessed at 3 months using the Glasgow Outcome Score.ZZA functional assessment was also performed which included gross intellectual performance, memory, personality, speech and focal deficits. The assessor then formed a clinical judgement based on all available clinical and radiological information as to what was the chief cause of death or disability. The four factors considered were: initial SAH, recurrent SAH, delayed cerebral ischaemia or other causes.

Radiological details All neuroradiological studies were assessed independently by two neurosurgeons (P. 0”. and P. M. F.). The assessment was performed without knowledge of the patients identity or clinical course. The following information was recorded for each investigation.

CT. Number of days from ictus; whether subarachnoid blood was present and if present whether it was localized to one cistern, to two unilateral cisterns or was diffuse; the presence of low-density areas.

Following admission a clinical proforma was completed on each patient detailing age, sex, clinical diagnosis and drug history. Only pa- Angiography. Number of days from ictus; tients who had not received anti-inflammatory presence of aneurysm; presence or absence of agents in the previous 2 weeks were included. vasospasm. Only one diagnostic angiogram was The following additional information was performed.

Thrombin and cerebral vasospasm

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Collection of samples and assay procedure Blood samples. Blood samples were obtained from patients within 24 h of admission to the neurosurgical unit. The vein was punctured as atraumatically as possible, with a 21-gauge butterfly needle, without use of a tourniquet. The first 5 ml of blood were discarded following which the required volume of blood was collected into a second separate syringe and then transferred into the appropriate collection tube. CSF samples. CSF samples were obtained via lumbar spinal drains at the time of dural opening during surgery in patients following SAH and in the four control patients undergoing anterior fossa floor repair. Samples were obtained after the first 15 ml had been discarded. Other control samples were obtained at the time of radiculography after the first 5 ml of CSF had been discarded. Both blood and CSF samples were collected onto ice and centrifuged immediately in a cold centrifuge (4°C) at 1500 g for 20 min. The supernatant was then removed and stored at - 20°C until the time of assay. A commercially available radio-immunoassay (RIA) for FPA was used (IMCO Corporation Ltd.). Statistical methods The following tests of significance were used. (1) Chi-square (x2) testing (with Yate’s correction in the case of 2 x 2 tables) to test the association between two discontinuous variables. (2) Student’s (unpaired) t-test with the ‘effective degrees of freedom’ correction of unequal variances was used to test for equal means of a continuous variable over two groups. (3) If the data were grossly skewed and in the case of ordinal score-type variables, the Mann-Whitney (or unpaired Wilcoxon) test of mean ranks was used to compare two groups. The Kruskal-Wallis ‘analysis of variance of ranks’ was used for three or more groups.

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(4) T o measure the significance of association between two continuous variables, Spearman’s rank correlation coefficient (R,) was used.

Results General Blood samples were obtained from 50 patients following SAH and 15 controls. CSF samples were obtained from 29 patients following SAH and 23 controls. The initial C T was performed within 24 h of admission and subsequent ones as indicated clinically. Angiography and surgery were carried out as soon as logistically possible in good grade patients and in those with large space occupying haematomas. In poor grade patients without significant intracranial haematomas angiography and surgery were undertaken as soon as their neurological grade improved. In many cases referral to the neurosurgery unit was delayed. The mean time from ictus to angiography and surgery was 4.9 days (range 1-21 days) and 7.5 days (range 1-26 days), respectively.

Blood FPA levels Blood FPA levels were measured in 50 patients following SAH and in 15 controls (Table I). The individual values are documented in Table IIa. Levels of FPA found in blood from patients following SAH were significantly raised when compared with those found in controls (Table I,p=O.O24). There was also a significant correlation between blood FPA levels and the amount of subarachnoid blood visualized at initial C T (Table 111, p =0.046). No statistically significant correlation was found between blood FPA levels and any of the other clinical or radiological variables studied.

CSF PFA levels FPA levels were measured in 29 CSF samples from patients following SAH and 23 control samples. The individual values are shown in

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Padraic O’Neill et al. TABLE I. Blood and CSF levels of FPA in patients following SAH and in controls No. of patients

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SAH

Levels (pglml): mean (SE)

Controls

SAH

Controls

p-value SAH vs Controls

Blood

CSF

Blood

CSF

Blood

CSF

Blood

CSF

Blood

CSF

50

29

15

23

66.26 (8.46)

81.62 (13.9)

40.73 (7.05)

20.32 (4.3)

0.024

O.OOO1

TABLE111. Correlation between FPA in blood and CSF and various clinical and radiological variables

FPA blood FPA CSF

GCS

WFNS

Subarachnoid blood score

ID

Low density on CT

R,=0.56 R,=0.54

Rs=0.56 R,=0.91

p=0.046 p=0.80

p=O.7 p=0.14

p=0.25 p=0.82

VS

GOS

Isch DID

p=0.157 p=0.77 p=0.47 p=0.92 p=0.03 p=0.12

R,, Spearman’s rank correlation coefficient; p, probability. See Tables IIa and b for definition of abbreviations.

Table IIb. Levels of FPA found in CSF from patients following SAH were significantly raised compared with those found in controls (Table I,p

Does thrombin prevent cerebral vasospasm following aneurysmal subarachnoid haemorrhage?

Fibrinopeptide A (FPA) levels which have been shown to be a quantitative index of thrombin generation, were measured in blood and cerebrospinal fluid ...
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