a review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage

A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage

Part II: Management

N. W. C. Dorsch FRCS FRACS

Department of Neurosurgery, Westmead Hospital, Sydney.

This review examines prevention and treatment of delayed cerebral vasospasm after aneurysm haemorrhage, with

emphasis on techniques for removal of cisternal blood, fhtid loading and induced hypertension, and calcium antagonists.

Most effective were fluids/hypertension and nimodipine, which reduced the incidence of DID by over half. Other

drugs that may be useful are tissue plasminogen activator and the aminosteroids. A number of others have also been

examined.

For the treatment of DID, calcium antagonists, and fluid loading and hypertensive treatment are the most effective.

TranslWal angioplasty is also proving to be useful. The combination of prophylaxis and treatment with fluids and

nimodipine should reduce poor outcome resulting from vasospasm by two-thirds, from 21% untreated to less than 7%.

In spite of the more or less proven efficacy of these measures, large numbers of cases are still being reported in whom

no specific management is being used.

Journal of Clinical Neuroscience 1994, l(2) :78 -92 0 Longman Group UK Ltd

Keywords: Aneurysm, Subarachnoid haemorrhage, Vasospasm

Introduction The first part of this review, in Volume l(l), detailed the magnitude of the problem of cerebral vasospasm. Probably few or none of the patients summarised there had received any drug or procedure likely to alter greatly the extent of the problem. Some received antifibrinolytic agents, and a number had unproven or disproved agents for the prevention or treatment of vasospasm, none making a real difference to the figures. Wilkins’ and Weir2 have summarised these treatments, which are not considered further.

In the last decade or more, newer forms of treatment have gained prominence. These include early operation with clearance of the basal cisterns, which experimentally helps to prevent vasospasm, clinical defects, and infarction.3 In some hands,4,5 removal of cisternal clot in humans has produced impressive results. However, the extensive dissection, with even bilateral craniotomies,4 may cause further damage to brain already traumatised by SAH.6~7 This problem may be lessened by the use of an irrigation-suction implement,‘but it is difficult to remove all clot mechanically.g Some have found a high incidence of DID despite clot removal.rO*”

Three other types of management do appear to influence the incidence and outcome of vasospasm. These are: induced hypervolaemia and/or hypertension; calcium antagonists, particularly nimodipine; and

ventricular or cisternal drainage or perfusion. They will be discussed in detail.

More recently still, other modes of management have arisen, again three in particular: removal of subarachnoid clot chemically with tissue plasminogen activator; the 21- aminosteroids, inhibitors of lipid peroxidation; and the (until recently) purely mechanical relief of vasospasm by transluminal angioplasty. These will be looked at in less detail, largely because there is little experience yet. Other recent forms of therapy will also be mentioned.

In this review similar problems to those noted previously were encountered in comparability of patient groups, proof of spasm, causes of outcomes, and so on. Again, actual numbers of patients have sometimes had to be calculated, when a percentage and a total number were all the data supplied. The problems were on the whole less severe, probably mainly because most relevant references were more recent, with more attention to vasospasm itself, especially where a trial of a new treatment was involved.

Fluids and pressors Kosnik and Hunt12 first reported the value of induced hypertension for reducing deficits due to vasospasm. Later, Pritz et all3 referred to the use ofvolume expansion alone,

78 J. Clin. Neuroscience Volume 1 Number 2 April 1994

Cerebral vasospasm in subarachnoid haemorrhage

and Maroon and NelsonI and others’” pointed out the decrease in all components of circulating blood that can occur after SAH, and the need for maintenance of at least a normal blood volume.

Prophylaxis of vasospasm

Interrst in blood volume expansion to reduce the incidence of delayed ischaemia is thus more recent, and the application varies widely. Some use fluid loading alone, some hypervolaemic haemodilution aiming at a specific haematocrit value;‘” others use fluid loading mainly postoperatively,” and others intensive monitoring, with the whole gamut of hypervolaemia, induced hypertension, and haemodilution (HHH).” Because the total numbers reported are not very large, and details of management were often not clear, the analysis below includes all these variations in one group. Note that, at the same time, many centres have introduced other management changes such as early operation. Changes in fluid management may thus not have been the only factor responsible for alterations in outcome.

In one study”’ there were 43 cases of DID in 133 historical controls (32%) and 37 in 212 treated cases (17%). In another series with ‘hemodilution’ in 309 cases compared with 312 historical controls,20 the proportion with good outcomes was 54% against 38%, and death rate 17% and 32% respectively. Although not placebo- controlled, these studies suggest that prophylactic fluid loading may help to reduce DID and improve outcome.

If all 31 reports specifying fluid loading, with the variations discussed above, are combined, 2516 patients are available, with 443 cases of DID, or 17.6%- considerably lower than the incidence without treatment (‘strictly defined’ as described in part I of this review) of 32.7% in 12 449 patien1.s. The large numbers help to confirm the probable usefulness of this type of prophylaxis. The distribution of the incidence of DID in these reports is compared with the natural history in Figure 1, and the apparent moderately lower incidence is evident there; the

lb 2b 3b 4b 5b 6b 7b 8b 9b 1 PERCENT INCIDENCE

Fig. 1 Histogram showing influence of HHH (all variations) prophylaxis on incidence of DID.

Percent of reports: percentage of the total number of reports in each category. For shaded bars, of ‘strictly defined’ reports of DID in natural history (N = 132); for solid bars, of reports of DID incidence with HHH prophylaxis (N = 31).

Percent incidence: bars within each 5% range of incidence represent the proportion of reports included in that range, eg about 15% of natural history reports and 6.5% of HHH prophylaxis reports fell between 35 and 40%.

i

cerebral arteries at the same time as a less than 10% fall in blood pressure.”

The rationale for the use of these agents in SAH is based

00 on the fact that the final pathway of action in arterial smooth muscle cells is the opening of calcium channels in their cell membranes, which increases intracellular calcium levels to activate muscle contraction. This presumably applies regardless of the mechanism of the arterial narrowing, ie depokdrisation or the action of agonists.

Several calcium antagonists have been used in the management of SAH to prevent or treat vasospasm. Most published experience has been with nimodipine, which will thus be dealt with in more detail than the others.

Review articles

wide scatter of incidence with this form of prophylaxis is contributed to by one report of zero incidence (in 19 patients) and one of 100% (ten patients).

Treatment of vasospasm

Many more reports specify the use of fluid loading and/ or hypertensive treatment for established DID, as it is more widely accepted for treatment of casospasm than prophylaxis. Possible reasons are that (a) it was first used as treatment: (b) active hypertensive treatment has a risk of complications, general and cerebral, as summarised by Piepgras, 21 including pulmonary oedema, haemothorax or pneumothorax from insertion of lines, or aggravation of cerebral oedema; and even fluid loading alone is not completely safe; (c) preoperative patients risk further SAH if blood pressure is raised.

The exact mode of treatment varies somewhat, with some units using increased fluids only, some hypertensive drugs only, and others often unspecified combinations. As with the natural history of DID, many reports had little detail of their results; some stated only death rate, some only ‘good’ outcomes, and some all possible outcomes. Again, the causes of the various outcomes were usually not denoted, and the time of outcome assessment was, if stated at all, very variable. The term ‘good outcome’ is again, as far as possible, applied only to those scoring GOS 1, i.e. able to ‘resume normal occupational and social activities’.‘?

There were 73 references with a complete breakdown of outcome; with 2111 patients, the figures add up to a

death rate of 17.5% (range O-48%). permanent deficit in 28..5% (range O-69%), and good outcome in 54.0% (range O-100%)). Ten other reports gave death rate only (range lo-38%. total 39 out of 145 patients, 27%). and in 15 only the good outcomes were given, with 257 doing well ow of

473 patients (54%, range 31-9000).

Calcium antagonists

These drugs have been used only in about the last decade for central nervous system disorders, more so since the development of nimodipine. This is a substituted dihvdropyridine, with much more effect on cerebral than peripheral arteries.?. ’ In one experiment using arterial rings contracted by a thromboxane derivative, it produced 84% relaxation in basilar and 22% in saphenous artery;‘” in cats intravenous nimodipine caused 25% dilatation of

1. Clin. Neuroscience Volume 1 Number 2 April 1994 79

Review articles Cerebral vasospasm in subarachnoid haemorrhage

Angiographic vasospasm

Not many reports on calcium antagonists specifically discussed this. In 28 references on their prophylactic use (21 involving nimodipine and seven nicardipine) , the incidence varied between 12% and 100%; the average in these 2306 patients was 39.5%. Although this is lower than without treatment, the difference is not large. This supports the view that calcium antagonists may not always work in this situation by preventing narrowing of arteries or relaxing them after ‘spasm’ develops, but through another mechanism such as neuronal protection (see part III of this review).

Seven controlled studies (including one3* that was for treatment of symptomatic or severe angiographic spasm rather than a true prophylactic study) were reviewed by Tettenborn and Dycka, with meta-analysis of the results,33 confirming a highly significant (x2 = 19.4, P < 0.0001) outcome difference, based on ‘good’ (GOS l-2) and poor outcomes. There was an odds ratio for poor outcome of 0.58 (95% confidence interval 0.45-0.74)) ie the risk of a poor outcome was 42% less for the nimodipine-treated patients than for those receiving placebo.

Prophylaxis of ischaemia with nimodipine

Controlled studies

Several double-blind placebo-controlled trials of nimodipine for the prevention of vasospasm have been reported. The earliest, by Allen et a1,26 was a multi-centre study involving 60 patients on placebo and 56 on oral nimodipine, 30 mg 4hourly. Symptomatic spasm was less (23%) with nimodipine than in controls (27%), but not significantly so; however, significantly (P = 0.03) fewer patients were dead or severely disabled at the end of the trial period.

Other studies used historical controls. Combining all those which include incidence figures (Table 1A) gives an incidence of DID in 11 ‘controlled’ studies of 30.8% in 1285 untreated patients (close to the 32.7% noted previously for natural history), and 19.5% with nimodipine pretreatment. The significance of this difference is reflected in the odds ratios (the ratio of the odds of developing DID without treatment to the odds with prophylactic nimodipine) . In only one report was this less than 1, and in more than half the studies, it exceeded 2. The results are summarised by a common odds ratio45 of 1.92 (95% Cl 1.56 to 2.37)) indicating a significant overall increased risk of DID in control patients.

A Canadian trial in poor grade patients*’ had 82 valid cases on placebo and 72 on oral nimodipine 90 mg 4 hourly. DID occurred in 56% and 36% of cases respectively, significantly different (x2 = 5.4, P = 0.02). At three months 10% of controls were at GOS 1, and 29% in the treated group (x2 = 8.2, P = 0.004).

A British study** included 50 valid cases, 25 each on placebo and nimodipine. The incidence of spasm was not stated, but there were fewer overall deaths at three months-6/25 control, and l/25 treated. Two placebo and no nimodipine cases had fatal DID, and there were respectively two and three poor outcomes due to DID. The total of poor outcomes was six in the nimodipine group, and 12 for controls.

Studies that provided information on the outcome of their patients are summarised in Table 1B. A considerable and highly significant improvement in outcome with nimodipine is seen, from the point of view of death alone, or of all bad outcomes combined, and regardless of the causes of poor outcomes. The common odds ratios, with lower confidence limits well above 1, are again significant. In Table 1B (part 2)) the seven randomised studies were analysed separately, and essentially no difference was found-the common odds ratio for these seven was 1.73, and for the others 1.63.

Overall incidence of DID

The largest trial was the British aneurysm nimodipine trial of Pickard and others published in 1989,2g comparing placebo with oral nimodipine 60 mg 4hourly. Sympto- matic vasospasm affected 33% of controls (92/276) and 22% treated (61/278, x2 = 8.4, P = 0.003). Death due to ischaemia (25 in controls and 17 in the treated group) was reduced by 32%, and severe disability (GOS 3-4) by 42%. Overall, 33% of the placebo group and 20% of those receiving nimodipine had poor outcomes at three months (x2 = 11.7, P < 0.001).

In addition to the above, some papers reported the use of prophylactic nimodipine in open series of patients. The incidence of DID with oral administration, from six references, was 276 in 1271 cases, or 21.7% (range 8 to 41%). With intravenous administration (52 references), it was lower at 653/4555 (14.30/o, range O-43%). The combined incidence was 929/5826 or 15.9%. With separate analysis the intravenous drug seems associated with considerably less DID. The large totals in each group suggest that the difference may be valid, but that cannot be stated with certainty. No comparative trial has been reported.

In a Finnish study with intravenous prophylaxis,30 there was angiographic vasospasm in 74% of controls (72/97) and 50% of those treated with nimodipine. There were fewer deaths from vasospasm (8/109 control, l/104 treated, x2 = 3.9, P = 0.049)) but no overall difference in outcome.

Treatment of vasospasm with nimodipine

Treatment continued from prophylaxis

A study of oral nimodipine plus Tranexamic acid31 showed more angiographic spasm in controls, but not significantly so. There was less DID with nimodipine, and poor outcomes due to vasospasm were reduced, with 39% for placebo, and 32% for nimodipine.

In most or all of the cases receiving nimodipine prophylactically, it was (presumably) continued as treatment if DID developed, supplemented no doubt in many cases with other measures such as induced hypertension or other drugs. The outcome of DID in 445 patients (36 references; results are given in overall percentages, followed by the range of percentages for reported groups of ten or more patients) was: death 18%


Cerebral vasospasm in subarachnoid haemorrhage Review articles

Table 1 Prophylactic nimodipine in ‘controlled’ trials

A. Incidence of DID

Reference Control No. DID

Treated No. DID

Odds

26

27

29

34

31

35

36

37

38

39

40

60

82

276

I

39 20

364

120

135

135

47

16 56 13 1.20

46 72 26 2.26

92 278 61 1.78

3 13 1 9.00

17 31 7 2.65

5 21 4 1.42

116 179 37 1.80

15 52 8 0.79

22 51 4 2.29

55 73 12 3.49

9 93 6 3.49

Oral, randomrsed

Oral, randomised. Gd 3-5

Oral, randomised

i.v., randomrsed, Gd 1-3

Oral, some + TXA. randomised, Gd l-3

Randomrsed

Historical controls

i.v. * oral, historrcal controls

I.V, historical controls, Gd l-4

i.v., historical controls

iv., historical controls

Total 1285 396 919 179

Percent 30.8 19.5

x2 = 35.1, P < 0.00001. Common odds ratio = 1.92, 95%CI 1.56-2.37 Gd: Hunt & Hess grade No: Number of patients in treatment qroup i v.: Intravenous admrnistration of druq DID, Delayed ischaemrc deficit Odds: odds ratro

B. Patient outcome

1. Death

Reference Control No.

28 25

29 276

30 109

34 7

41 114

38 135

42 91

43 24

39 135

36 230

44 135

TXA: Tranexamic acid

~___

Dead

6

60

15

2

16

0

18

0

31

63

37

Treated No.

25

278

104

13

39

51

113

45

73

196

408

Dead

1

43

10

1

3

2

11

3

12

26

92

Odds

.7.58

1.52

1.50

4.80

1.96

2.29

1.52

2.47

1.30

Comment

~~_ Oral, randomrsed

Oral, randomrsed

iv., randomised

i.v., randomised, grade l-3

i.v., matched historlcal controls, grade 1-2

i.v., historical controls, grade 1-4

Historical controls, grade l-3

Historical controls

i.v., historical controls

Historical controls, grade l-4

i.v., histoncal controls, all grades

Total 1281 248 1345 204 ___~~_ ~~ ~~~~~.

Percent 19.4 15.2 __--

x’= 7.8, P = 0 004. Common odds%0 = 1.71,95%CI 1.37-2.14

2. Poor outcomes (death and permanent deficit combined)

Reference Control Treated Odds Comment No. Poor No. Poor .~~______

28 25 12 25 5 3.69 Oral, randomised

29 276 91 278 55 1.99 Oral, randomised

30 109 23 104 17 1.37 i.v., randomised

34 7 3 13 1 9.00 i.v., randomrsed, grade l-3

26 60 18 56 12 1.57 Oral, randomised

27 82 54 72 44 1.23 Oral, randomrsed, grade 3-5

31 39 15 31 10 1.31 Oral, some + TXA, randomised, grade l-3

41 114 53 39 18 1.01 I.v., matched historical controls, grade 1-2

38 135 39 51 10 1.67 i.v., historical controls, grade l-4

42 91 34 113 19 2.95 Historical controls, grade l-3

43 24 2 45 7 0.49 Historical controls

39 135 50 73 15 2.27 iv., hrstorical controls

36 230 95 196 56 1.76 Historical controls, grade 1-4

44 36 18 249 134 0.86 i.v., hlstorical controls, early operation ______~_.

Total 1363 507 1345 403 _ ~._ Percent 37.2 30.0

x2 = 15 6, P= 0.00008.Common odds ratlo= 1.68,95%Cll.40-2.01



(O-29), permanent deficit 32% (O-60) and good outcome 50% (lo-91), similar to fluid loading and induced hypertension. Broadly similar figures were obtained in studies that mentioned only fatal (six reports, death rate 8/38) or good outcomes (nine studies, good outcome in 114/201).

De novo treatment of DID

In other reports nimodipine was used for the first time in patients who developed DID while not already receiving it, i.e. for treatment rather than prophylaxis. In a controlled trial of nimodipine used in this ways2 there were 73 valid cases on nimodipine and 54 placebo. All had severe angiographic vasospasm or DID. Outcome in controls was 14 dead, 17 poor, and 23 good, and with nimodipine treatment 7,22, and 44 respectively (x2 = 6.9, P = 0.03).

Other calcium antagonists are summarised in Table 2. A controlled study of Flunarizine5* had 11 cases of DID in 37 treated and 27 in 37 control patients (x2 = 12.1, P < 0.0001); the outcome of DID was also better. Another study of flunarizine (combined with vitamin E and trifluoperazine), by the same Japanese group, has an impressively low incidence of DID.54 Apart from that, numbers are small, and results varied considerably between series. Except possibly diltiazem, all of these drugs may protect against DID.

Table 2 Prophylaxis with other Ca antagonists-incidence of DID

From a total of 343 cases treated thus (six reports) the outcome (13% dead, 20% permanent deficit, and 67% good) seems better with this ‘de novo’ treatment than in patients who developed DID while already on nimodipine. A possible reason for this difference, if genuine, is that patients in whom treatment is continued from prophylaxis are highly selected, having already proven refractory to prophylactic treatment with the drug. On the other hand, where nimodipine is started only after DID develops, then these patients would presumably include many who, if they had been on it all the time since SAH, would not have developed DID at all. Such patients are likely to respond better and more quickly when it is introduced for the first time as treatment.

Ref. Drug Number DID Percent Comment

48 Dilt 105 32 30

49 Dilt 18 4 22

50 Dilt 30 12 40 Plus EAC

51 Dilt 13 5 38

52 Hun 37 11 30 Grade 2-5

53 Hun 48 2 4

54 Hun 173 2 1 Plus vit E, TFP

55 Verap 22 4 18

56 Verap 12 1 8 Plus dopamine

Total Dilt 166 53 32

Flun 258 15 6

Verap 34 5 15

All 458 73 16

Dilt: diltiazem Flun: flunanzine TFP: trifluoperazine Verap: verapamil EAC: epsilonaminocaproic acid

Other calcium antagonists

Apart from nimodipine, a number of other calcium channel blocking drugs have been used for the prophylaxis or treatment of vasospasm. Nicardipine has been the most reported.

A histogram showing the comparison of DID incidence between natural history and calcium antagonists (all combined, total reports = 83) is seen in Figure 2. It shows the very marked trend towards a lower incidence of DID when these drugs are used prophylactically.

Prophylaxis

Nicardipine was used in a controlled trial of the Co- operative Aneurysm Study group.46 The incidence of DID was lower with nicardipine prophylaxis, 32% in 449 patients, than with placebo, with 46% in 456 cases (x2 = 18.0, P < 0.001). However, the outcome at three months was not significantly different. Similarly, deaths and disabilities due to vasospasm, 8% in treated patients and 11% with placebo, were not different. In a second cooperative study, with two dose levels of nicardipine,47 the incidence of DID was 31% in each group and thus, for a total of 365 patients, much the same as in the first study.

18

r 16

8 k

14

c?z 12

& 10

!s 8

ti 6

g 4

2

0 0 10 20 30 40 50

PERCENT INCIDENCE

The high overall incidence of DID in those series may overshadow more impressive results from 14 other reports of prophylactic nicardipine, in which the incidence of DID was from zero to 28%. These series were smaller, and mostly uncontrolled; DID was often poorly defined, in contrast to the rigid definition in the co-operative studies. Combining all reports gives an incidence of DID with prophylactic nicardipine of 404/1643, or 24.6%. This is much higher than with intravenous nimodipine, but much lower than the expected natural incidence.

Fig. 2 Histogram of influence of calcium antagonist prophylaxis on incidence of DID.

Percent of reports: proportion of total reports in each categoty. Shaded bars: ‘strictly defined’ natural history (N = 132); solid bars: prophylaxis with a calcium antagonist (N = 89).

Treatment

Some of the series in Table 2 also gave the results of treatment. Continued use was often combined with hypervolaemic/hypertensive treatment. The information on outcome is most complete for nicardipine, with seven



reports totalling 191 cases, a death rate of 12%, and 17% permanent deficits. Results are less complete but similar for other series, three of flunarizine and three diltiazem, with 88 patients and 24 (27%) total bad outcomes.

Table 3 Prophylaxis of DID by ventriculo-cisternal perfusion

Risks of calcium antagonist treatment

These drugs have few side effects, which will not be dealt with in detail. A fall in blood pressure is quite common but not usually serious. Other significant effects include hyperglycaemia and changes in liver enzymes, and possibly intrapulmonary arteriovenous shunting.“’

A theoretical risk preoperatively is that of recurrent SAH. In the Finnish studyJo there were twice as many fatal rebleeds with nimodipine treatment (8/104) as in controls (4/109), but this was not significant (x2 = 1.0, P = 0.3). In the first cooperative trial of nicardipine”6 rebleeding causing death or disability affected 22 (4.8%) treated patients, and 20 (4.4%) controls, again not significant. The BRANT trial’” had 19 (7%) deaths and disabilities from rebleeding with nimodipine and 31 (12%) with placebo. Only in the trials mentioned above30,4” and one other” was there a higher incidence of rebleeding, or poor outcomes due to rebleeding, in treated patients. In four others there was less rebleeding in the treated group; from the four ‘controlled’ studies that mentioned the actual rebleeding rate, it was lrss with a calcium antagonist (54/ 448 or 12%) than in ‘controls’ (80/523 = 15%); again this was not significant. It thus appears likely that these drugs do not increase the risk of recurrent haemorrhage (possibly any increase in risk would be counteracted by their tendency to lower the blood pressure). Also, there was no suggestion in the above reports that if a rebleed occurs it is made worse by using calcium antagonists. Evidence from animal work suggests nimodipine may actually bc protective.‘”

with drugs.

Ref. Number DID Percent ~~___ 63 13 1 8

61 30 11 37

64 66 6 9

65 25 8 32

66 7 6 86

24 4 17

8 0 0

59 28 3 11

67 89 20 22

-- Total 290 59

U-K. urokinase NaNO,: sodium nitnte sodium ozagrol, a thromboxane-A synthetase lnhtbltor NIC: nlcardlplne GTN glyceryl trlnltrate

Drug

U-K

U-K

U-K

U-K

U-K

U-K plus sodium Write

U-K + NaNO, + Na ozagrol

U-K plus ascorbic acid

NIC plus (13) iv. GTN

An obvious danger of such treatment is that of infection. This seemed ofvarying significance. One serie@’ had one (fatal) case of meningitis in 22 patients; another@ mentioned seven cases in 38 patients, while in a thirhsg it affected one patient in 28. From these few reports, the risk of infection appears reasonably low; obviously, minimising it would need careful management, with frequent testing of the CSF.

Newer techniques As mentioned above, several new forms of prevention OI treatment for vasospasm, using drugs or other techniques, have been recently introduced, or are still at the experimental or early trial stage. These will be discussed brieflv.

Recombinant tissue plasminogen activator (RTPA)

Cisternal drainage Some reports on the use of ventricular and/or cisternal drainage included washing through with saline solutions, or instillation of drugs possibly useful against vasospasm. In a study of cisternal irrigation with urokinase and ascorbic acids9 there were three cases of DID in 106 treated patients, and 37 out of 96 (39%) in controls. Sonobe et al@’ had 13 out of39 control cases develop DID, and two out of 23 treated with ventriculo-cisternal perfusion and drainage without drugs. Saito and Sano 61 found in early operation with cisternal drainage alone 34/98 (35%) DID; with irrigation 15/31 or 48%; and with urokinase as well 1 l/30 (37%).

The total incidence of delayed ischaemiawith cisternal drainage alone (16 reports) was 332/1169, or 28.4%, ranging from 9-47%. With irrigation or perfusion, in six reports, it was 61/359 (17%), including no DID in 22 consecuti\.e cases with added gentle mechanical ‘shaking’ of thr head in all three planes.“2 The addition of drugs appears little or no more effective, with (seven references) 59 developing DID in 290 cases, or 20% (Table 3). There were wide variations and considerable overlap of results, but it appears that irrigation may be more effective than drainage alone.

This was developed as a specific solvent of blood clot in vivo, and in theory should do this with little risk of haemorrhage. A study with a multi-haemorrhage dog model and intracisternal urokinase”” had in the treated group significantly less reduction (370/o, SD 6%) in basilal artery diameter than in controls (65%, SD 7%). Another group used plasmin itself’O successfully to minimise the vasculopathy seen in a two-haemorrhage model in pigs.

There is a risk of systemic fibrinolysis with agents such as urokinase and plasmin. ” TPA, on the other hand, has affinity for fibrin-bound plasminogen (i.e. that present in clot), and low affinity for the circulating form. In a two-injection dog model ?’ local TPA was successful in preventing basilar artery spasm. Weir’s group has used TPA in a monkey model. They noted that the prevention of spasm is more or less complete only if TPA is used before 48 hours.‘? Other studies used a subcutaneous reservoir’” or a slow-release gel,‘” while others were dosage” or timing” trials. They showed considerably less angiographic vasospasm, less residual subarachnoid blood, no inflammation or other abnormality, and no change in coagulation status, particularly no systemic fihrinolysis.

J. Clin. Neuroscience Volume 1 Number 2 April 1994 83


Clinical use Transluminal angioplasty (TLA)

There are still few reports of the use of TPA in patients. Because of the constraints of time noted above, it is always combined with early operation. Up to mid 1993 it had been reported in 268 patients (Table 4), with 43% angiographic spasm, and 26 cases (9.7%, range 3-50%) of symptomatic vasospasm. Of the 16 with DID whose outcome data were given, six died and four had residual deficits.

The use of local TPA at or soon after surgery raises the possibility of local bleeding, which has been the main problem noted. In the 268 cases reported (not all reports mentioned the problem) there were at least 60 episodes, including 10 extradural haematomas, of which four required evacuation, and four unspecified fatal bleeding episodes.

Until recently this treatment, initially purely mechanical, was little used. Basically it is an endovascular technique where, following angiography, a balloon is passed into the most narrowed areas and inflated to re-expand them. So far it has been used mainly as a ‘last resort’ treatment for DID, with some earlier use in more recent reports,s6 including some cases with angiographic spasm but not DID. In the last two or three years, ‘chemical angioplasty’, with injection of a vasodilator such as papaverine instead of using a balloon, has also been reported.

In the first report on this technique, by Zubkov et al,*’ there were seven deaths among 33 patients, who included 15 with DID. From 13 reports with a complete breakdown of outcome in 242 patients (Table 5)) there was immediate improvement in many, and final outcome was 20% dead,

Table 4 Prophylaxis of DID by intracisternal RTPA

Reference Number DID Angio

75 9 1 1

76 28 3 15f27

77 30 1 16

78 19 3

79 49 2 8

80 23 3 13

81 14 2 14

65 26 4

82 20 1 16TCD

83 44 3 10

84 6 3 10 mg.

Total 268 26 9312 16

Percent 9.7 43

Angio: angiographic (or TCD-transcranial Doppler) vasospasm Gd clinical grade Fisher: grading of severity on CT scan (85) EDH: extradural haematoma ICH: intracerebral haematoma op: operation for haematoma

Comments

2 bleeding problems

Gd 2-5. Fisher 2-3. 10 2 EDH (1 op), 1 SAH mg.

3, 10 or 13 1 ICH, 1 EDH (op), 21 severe bruising mg.

Fisher 3. Four doseslday for 3 days. 4 fatal bleeding

Gd 2-4. Fisher 3. Multiple doses. 2 EDH (no op)

Fisher 3-4. 3 subgaleal haemorrhage, 1 meningitis

Gd 3-5. Fisher 3. Dose 1.5-10 7 oozing, 1 EDH (op) mg.

Fisher 3-4. Dose 8 2 EDH mg.

Gd l-4. Fisher 3. Dose 10 Oozing during closure mg.

Fisher 3. Multiple doses. 1 EDH (op), 1 ICH, 2 SAH

1 EDH, 2 ICH, 1 haemorrhagic infarct

Table 5 Transluminal angioplasty in the treatment of DID

Reference Number Dead Def. Good Comments

88 13 4 0 9

89 22 3 4 15 14 improved, 4 worsened

90 10 3 3 4

91 4 0 3 1

92 8 1 2 5 No to HH response

93 8 2 2 4 No to HH response

94 50 8 10 32 No to HH, 33 immediate improvement response

95 11 4 2 5

86 60 15 18 27

96 13 6 1 6 No to HH, 4 immediate improvement response

97 13 1 8 4 nicardipine (several needed)

10 1 6 3 nicardipine plus papaverine (balloon later)

98 9 0 3 6 Papaverine

Morgan M* 8 0 1 7 Papaverine within 4 hours of onset

3 1 2 0 Papaverine after 4 hours from onset

Total 242 49 65 128

Percent 20 27 53

Def.: permanent deficit HH: hypervolaemidhypertensive treatment *. personal communication 1993, and since published in J. Clin. Neuroscience 1994, 1:42-46

84 1. Clin. Neuroscience Volume 1 Number 2 April 1994


27% deficits, 53% good. In general, impressive reversal of angiographic spasm, usually persisting, was seen. The final outcome of these patients is comparable with the results obtained with hypertensive treatment or calcium antagonists, and is impressive when one considers that most had already ‘failed’ conventional treatment. There were only occasional cases of rupture of an artery or an unsecured aneurysm in those undergoing balloon dilatation.86,“’

mentally relaxes postSAH vasospasm. ‘N In a double-blind study on patients with presumed DID treated with Alpha- CGRP,“’ nine out of 15 treated patients improved their GCS score, significantly more than in 15 controls. A formal multi-centre study, lz2 however, failed to show any effect.

A number of drugs have also been used to treat

Tirilazad mesylate (U74006F)

This is one of the recently developed group of 21- aminosteroids,gg~lOO which h ave a marked inhibitory effect on iron-dependent lipid peroxidation, and so act as potent free radical scavengers. Initial reports on its use in experimental cerebral ischaemia have been promising, suggesting that it is protective against ischaemic damage as well as vasospasm.lol~l’)‘L

established DID. They include trinitrotoluene,“” continued from prophylaxis, with no dead and one permanent deficit in 13 with DID, but eight and four respectively in 33 historical controls. In a trial of hydrocortisone”’ there were 23 dead. 31 poor and 17 good outcomes treated, and 15.33 and 21 respectively in controls (X’ = 2.1, P = 0.34).

The changes that develop in the arterial wall with the onset ofvasospasm are complex and poorly understood,lO” but it is likely that free radicals are involved; in the experimental situation at least, tirilazad appears effective in preventing spasm. Steinke et al,‘O4 in their monkey model of’ SAH and vasospasm, found a significant reduction in spasm when tirilazad was started 20 hours after the haemorrhage. Other studies with various modelslOO~‘O”~‘O~ have shown similar effects.

Barbiturate treatment has been used occasionally,12:i~‘2~ with fair outcomes for what was usually a last resort in ill patients. Other treatments included an anti-platelet agent sodium ozagrol,“” continued on from prophylactic use, with hypertensive therapy. Reduced glutathione was also continued as treatment in 20 who developed DID in a prophylactic study, lT6 four of them dying. Results using the oxygen transporter fluos01”~ were not impressive unless hypertensive treatment were used also.

Discussion

Significant clinical experience is limited to one phase II study, in which tirilazad in three dose levels was compared with placebo, on a background of oral nimodipine. lo6 Safety up to a dose of 6 mg/kg/day was not a problem, and there was a dosedependent reduction in DID, and improvement in outcome, up to 2 mg/kg/ day. Two large multi-centre trials, one with oral and one with i.\: nimodipine as background, are in progress.

The modern, partly effective methods of controlling cerebral vasospasm can be looked on as taking one of three main directions: removal of blood from subarachnoid cisterns, interruption of the processes leading to vasospasm, or minimising its effects if it does occur.

Other treatments

Many compounds with various theoretical effects have been used to prevent or treat vasospasm, with results often less than impressive. Earlier treatments have been summarised before. ‘Z Several treatments have since then undergone more or less controlled trials, among them the 5-lipoxygenase inhibitor AA861;‘07 high-dose methylprednisolone, a trial of which had impressive but not significant results in a small number of patients;‘O* thromboxane synthetase inhibitors;lOg,l10 a combination of anti-enzyme agents;“’ ticlopidine;“? and trinitrotoluene.“” The ‘intracellular’ calcium antagonist AT877 has been reported with a two-haemorrhage dog model to reduce the incidence of vasospasm,’ l4 and in a controlled trial”” there was significantly less angiographic spasm as well iis DID in treated patients.

Removal of subarachnoid blood, if done early and completely enough, will effectively prevent vasospasm; the degree of spasm correlates well with the amount of blood present.*” An obvious way to do this is by mechanical removal of the blood combined with early operation. It is limited by difficulties with access to all of the subarachnoid blood for removal, and the need for great expertise and patience to do it satisfactorily.

A mechanical counterpart which allows a wider clearance is to flush out cisternal blood with crystalloid solutions alone or with various drugs added. This seems to reduce the incidence of DID by about half. The ‘headshaking’ adaptation”? may make it even more effective. A risk with all such infusions is infection, but this has not so far appeared a great problem.

The other counterpart of physical removal of clot is chemical dissolution using TPA, which is probably safer and more effective than earlier similar drugs. It is promising in preliminary clinical trials, but still appears to carry a risk of bleeding.

Apart from tirilazad and methylprednisolone, other steroids have been studied, including fludrocortisone”” and high-dose hydrocortisone.“’ Immunosuppressive therapy, as used in transplant surgery, with steroids and cyclosporin A combined, is also under investigation. Cyclosporin Awas effective in a dog model,“s but not in a later similar study. “’ Another compound of interest is calcitonin gene-related peptide (CGRP), which experi-

These techniques must usually be combined with surgery for the relevant aneurysm, and applied soon after the haemorrhage if they are to work at all-after 48-72 hours the effectiveness decreases progressively. They are thus of no use for patients who do not arrive for specialised care until days after their haemorrhage. By then the chemical processes that cause vasospasm are under way. For these patients treatment to prevent or reverse these processes, or to prevent or minimise their effects, may he necessary, including transluminal angioplasty.



Balloon TLA is of course purely mechanical, and only used in general for treatment rather than prophylaxis of DID. Considering the small experience so far, and the general concentration on patients in whom other forms of treatment have already failed, results are quite good. In units where it is feasible it should be a useful adjunct to other forms of treatment. There is some risk of vessel rupture, and possibly also of embolism. Both balloon and chemical angioplasty are likely to be used more in future as experience increases, and earlier in the course of vasospasm.

vasospasm is concerned, first for a theoretical group of patients with aneurysmal SAH receiving standard treatment of 15 years ago, i.e. bed rest, fluid restriction, and delayed operation. In such a group 32.7% would suffer DID, and 9.9% would die and 11.1% be left with a permanent deficit (calculated from figures in part I of this review). Thus, bad outcomes due to vasospasm would total 21.0%.

Fluids and calcium antagonists

Most effective drugs of today probably act partly by interrupting the chemical cascade towards vasospasm, and partly by minimising its bad effects. A mechanism like the latter is obviously more in action when the treatment is used for therapy rather than prophylaxis.

The apparent effectiveness of such a simple technique as i.v. fluid loading is of interest. Few data are available on its mechanism; presumably it does not greatly affect angiographic spasm as such, but minimises or corrects the other, systemic defects usually needed on top of vasospasm for ischaemic deficits to occur. Fluids and hypertensive therapy seem effective particularly in preventing DID, and less dramatically so in treatment. Careful monitoring is needed because of the risks outlined.

This outcome may be compared with that of a group receiving what should now be standard prophylaxis and treatment, i.e. active fluid loading or at least maintenance of normovolaemia, prophylactic intravenous nimodipine, and if DID develops, continuation of nimodipine with increased fluids, and pressors if necessary. Based on the average rates mentioned above in the section on nimodipine, in a putative group of SAH cases there would be 13.4% DID, which would be fatal in 2.4% and lead to permanent deficit in 4.3%, i.e. vasospasm would cause bad outcomes in 6.7%.

Calcium antagonists, particularly nimodipine, have attracted much interest. With many patients now reported, and several well-run trials, there is little doubt of its effectiveness in preventing and treating DID. The numbers suggest that i.v. nimodipine is more effective than oral. Possible reasons for this include the reaching of a better therapeutic level, or the maintenance of a more steady blood level. Perhaps also the i.v. drug has, or is felt to have, more effect on systemic blood pressure because of its peripheral vasodilator effect; if this is the case, these patients may well be receiving more fluids than those on oral treatment (the incidence of DID with i.v. nimodipine prophylaxis is not that much less than with fluid loading and/or induced hypertension). On the other hand, these apparent differences are possibly simply dose-related. Pickard has estimated that 60 mg 4-hourly of oral nimodipine is equivalent in effectiveness to intravenous treatment in the usual doses.‘ss

This management should thus reduce poor outcomes due to delayed vasospasm by about two-thirds over the natural history. That may be about the best outcome presently possible, since most reported patients on nimodipine were probably started within a few days of SAH. Patients in the clinical setting would include some admitted after 72 hours, and even some already with DID. The incidence of DID may thus be higher in the usual situation.

Patients admitted too late for this regimen to be fully effective can still be helped, but may need other methods such as TLA. Even with the best possible outcomes as noted, a 7% rate of poor outcomes due to vasospasm leaves obvious room for further improvement; the intention must be to reduce this to zero or close to it.

Other treatments

Several possible modes of action of nimodipine and other calcium antagonists have been described. Possibly they act differently when used at different times and circumstances, and they may also act in more than one way at a given time. This is discussed more thoroughly in part III of this review.

In many recent trials of newer drugs there were high rates of delayed ischaemia, often over SO%, in control and treated patients. The explanation is unclear-it may be not a genuine finding; it may be coincidental, or the result of broadening of the criteria for definition of DID. Patients may have been included with very minor symptoms; perhaps there is now greater expertise in and attention to neurological observations, with more attention to minor changes, so that minor degrees of deterioration are more readily detected. Apart from this, it appears that some of these measures may be of value. Further trial is needed in most cases.

Another advantage of calcium antagonists is that they are fairly simple to administer. Provided attention is paid to blood pressure and fluids, complications and side effects are few. There is no evidence of increased rebleeding.

Calculation of numbers

It is useful to extrapolate from the figures presented in these two studies and to estimate outcome, as far as

It is obvious from a number of experimental studies that the process of vasospasm is a cascade, starting with the presence then lysis of erythrocytes in the CSF, and proceeding through a number of chemical and physio- logical steps. Probably some of the treatments already available do, and others in the future will, attack this process at different points; it is likely that a combination of different therapies, or ‘polypharmacy’, rather than a single totally effective treatment, will ultimately provide the answer to the problem of vasospasm. Some drugs already being tested, such as a single molecule with both calcium antagonist and aminosteroid actions,izg may act


Cerebral vasospasm in subarachnoid haemorrhage

as a single treatment, but it may turn out in the end to be more useful to have separate drugs whose dosage can be individually varied.

Already available or under trial, for example, are a thrombolytic agent to dissolve clot, an aminosteroid to prevent the onset of vasospasm and secondarily to protect ischaemic neurons, a calcium antagonist to do the same at different points in the process, the maintenance or increase of fluids and blood pressure to assist these, and balloon and/or chemical angioplasty for those who still develop problematic vasospasm.

Cost-effectiveness

Recently there has been interest in the cost-effectiveness of treatment,1”0 with the conclusion among others that, on the whole, it was worth treating aneurysms after they rupture. Such an analysis of prophylaxis and treatment of cerebral vasospasm is beyond the scope of this review, but factors needing to be considered include: with no treatment available, prolonged hospitalisation for those who develop DID, and more community loss and cost in the incrrased numbers of dead and disabled. With increased fluids, the treatment itself would cost little, but the intensive monitoring needed for maximum effectiveness is very costly. Many calcium antagonists are expensive, and one would need to analyse whether it was justified to treat all patients prophylactically, or ‘cheaper’ to reserve treatment for only those who develop DID. Resulting as it does in a two-thirds reduction in the numbers of dead and disabled, it is likely that, in spite of drug prices, this treatment is very cost-effective.

From this point of view, the calculation of patient outcomes, extrapolated to large numbers, becomes significant. As seen above, if patients are treated with intravenous nimodipine prophylaxis continued as treatment when necessary, one would expect 2.4% deaths and 4.3% permanent deficits due to vasospasm. On the other hand, in patients treated with fluid/hypertensive prophylaxis one would expect 17.6% of DID; with nimodipine treatment for only these patients there would be 2.3% deaths and 3.5% deficits. These calculated outcome figures are somewhat better than using nimodipine from the start: this is a strong indication for looking at the relative costs of intensive fluid treatment and monitoring followed in some by the need for nimodipine, and of nimodipine alone for all cases (bearing in mind that the above calculations refer to vasospasm onl!; and the possibility that nimodipine may have other actions in addition to those relevant to vasospasm, which may help to improve the outcome of SAH patients further than would be expected from the point of view of spasm alone”“).

For cisternal infusion the cost of equipment and monitoring would need to be analysed, along with the risk of infection. Recombinant TPA seems effective, but the drug is very expensive, and its use adds considerably to operation time. TLA is effective in treatment, but needs the availability of expensive equipment, and a highly- trained and skilled team, which on the other hand would also br available for other radiological purposes.

Review articles

Trends with time

Figure 3 shows changes with time in the incidence of DID, separately for the natural history (‘strictly defined’), patients receiving any of the above prophylactic therapies, and both those groups combined. Figure 4 shows changes in outcome, for untreated patients (natural history) alone, and for all cases combined. These suggest a trend towards both a lower incidence of DID, and improvements in proportions of deaths and good recoveries. There is a suggestion of more marked improvements with the introduction of fluids/hypertension in the late 1970s to early 198Os, and of calcium antagonists in the mid 1980s.

!i E w m 01040 675 2174 1147 2695 2347 1163 5 S .1198 864 2974 2446 5721 6906 2850

EL--- ’ -_~-.~_J__P_ I 79-81 82-3 84-5 86-7 88-9 90-l 92.3]

YEAR OF LAST PUBLICATION

Fig. 3 Change with time in reported incidence of DID.

Patient Number: number of patients reported in each time period.

Percent Incidence: incidence of DID per time period.

Open squares-natural history, strictly defined.

Closed squares-natural history plus those receiving prophylaxis.

Asterisks-patients receiving any form of vasospasm prevention: fluids/ hypertension, calcium antagonists, TPA or other measures described above. The number in this group in each time interval is the difference between the two numbers above, i.e. respectively 158, 189, 800, 1299, 3026,4559 and 1687.

!zF5 I% 0 415 416 546 850 777 633 894 430

22 . 443 460 764 1454 1028 1249 2338 1303

557-

20’ ~78 II _~ _L._ _1__.._2__1_

79-81 82-3 84-5 86-7 88-9 90-l 92-i

YEAR OF LAST PUBLICATION

Fig. 4 Change with time in reported outcome of DID.

Patient Number: number of patients reported in each time period.

Percent Outcome: percent of reported patients dying (lower section) or recovering to a good outcome (upper section).

Open squares-natural history, no specific treatment

Closed squares-natural history, plus patients receiving any form of vasospasm treatment, fluids/hypertension, calcium antagonists, TLA and other measures noted above.



It is noteworthy, and a cause of concern, that despite the more or less proven efficacy of several therapies in reducing the problem of vasospasm, large numbers of reported patients are still evidently not receiving such treatments. This is evident from the patient numbers at the top of Figures 3 and 4; in fact, if all cases under the ‘natural history’ heading are included in the incidence figures, there have been since the beginning of 1991 almost equal numbers reported-4770 patients with no prophylactic management and 32.7% incidence of DID, and 5142 with some form of prophylaxis and 18.8% DID. In the same period, 32.6% of 643 reported patients with DID died, compared with 20.2% of 978 who received some form of treatment.

9.

10.

11.

microirrigation-suction system in acute stage of ruptured aneurysm. Presented at the Second International Workshop on Intracranial Aneurysms, Nagoya, Japan, Apr 47,1989. Findlay J M, Weir B K A, Kanamaru K et al. Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature. Can J Neurol Sci 1989;16:2840. Ljunggren B, Brandt L, Kagstrdm E, Sundbarg G. Results of early operations for ruptured aneurysms. J Neurosurg 1981;54:473-9. Inagawa T, Yamamoto M, Kamiya K. Effect of clot removal on cerebral vasospasm. J Neurosurg 1990; 72:22430.

12.

13. Acknowledgments The help of many who have replied to requests for clarification is again acknowledged with thanks, as is that of Dr D Tettenborn, Bayer AG, Wuppertal, Germany, who provided useful data and references. Support was received several times from Bayer AG, Bayer Australia, or Upjohn Australia, for attendance at conferences at which many of the data presented here were obtained. The help of Ms M King, Department of Community Medicine, Westmead Hospital, with statistical advice and analysis, and critical review of the manuscript, is gratefully acknowledged.

14.

15.

16.

Received 17 July 1993

Accepted for publication 4 October 1993 17.

Correspondence and offprint requests: Ass. Professor N. Dorsch, Department of Neurosurgery, Westmead Hospital, Westmead, NSW 2145, Australia.

18.

Tel: 61 2 633 6022 Fax: 61 2 893 7440

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a review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage

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