The core findings of the present study was that smokers more often presented in WFNS grade 5, but had less subarachnoid blood than nonsmokers. Despite WFNS grades 4 and 5 multiplying the odds for mortality and poor functional outcome, smokers had lower 30-day mortality and their functional outcome was not inferior to the outcome in nonsmokers. Smokers were younger when their aneurysm ruptured, their ruptured aneurysms were larger, and they more often had multiple aneurysms.
Patients and entry variables
Smokers presenting in a clinically poorer condition from aSAH than nonsmokers is a novel finding. The combination of higher WFNS grade and less subarachnoid blood in smokers is apparently self-contradictory. Yet, when an aneurysm ruptures, there is an instantaneous, immense increase in intracranial pressure (ICP) [
41]. The extend and duration of this ICP increase is decisive for both the arrest of hemorrhage [
41] and the level of consciousness at ictus. The risk of aSAH associated with smoking is greatest in the 3 h after nicotine intake [
34], and considering the rise in blood pressure and pulse caused by smoking [
13], this could translate into higher ICP levels upon aneurysm rupture in smokers. High ICP levels, in particular if maintained over a longer time period before declining, would cause coma and arrest subarachnoid bleeding more effectively. Such a scenario would also increase the number of sudden-death aSAH cases never reaching a hospital. In fact, Lindbohm et al. recently demonstrated that inclusion of sudden-death aSAH cases into mortality numbers reversed the paradox of higher survival in smokers [
31]. In other words, more smokers die from their aSAH when considering all cases and findings of better survival in hospital-admitted cohorts seems to be biased.
Fifty-eight percent of our patients were current smokers, more than three times the prevalence of daily smokers in the general population, which was 17% in 2011—and twice the national prevalence reported 10 years earlier. Smokers were therefore clearly over-represented among our patients with aSAH. This is in agreement with findings in aSAH patients from North America and Europe, where 40–75% of patients have been smokers—compared with 20–35% in the general population [
34,
58,
59]. Smoking rates have changed gradually in Norway during the last 50 years—from a maximum of three quarters of the male population smoking daily in the fifties, to about 12% of both genders today. Women in Norway have been fully emancipated as smokers for the last 20 years, corresponding to no difference in the fraction of females between our groups of smokers and nonsmokers. Given the association between smoking duration and multiple aneurysm formation [
52], the Norwegian smoking emancipation may have contributed to our finding of multiple aneurysms being more common in smokers with a female preponderance. Schatlo et al. [
52] found a clearly higher risk for multiplicity in males; however, their material included 44.3% patients with unruptured aneurysms. Other studies including only aSAH cases also found a link between multiple aneurysm formation and female sex [
10,
19]. The incidence of aSAH is decreasing in the Nordic countries, possibly due to reduced smoking rates and due to improved treatment of high blood pressure [
24,
30,
33].
Presently, smokers were younger than nonsmokers. The difference was though less than in earlier studies reporting smokers to be 5–10 years younger than nonsmokers at the onset of their hemorrhage [
7,
44,
59]. Aneurysm location was very similar in smokers and nonsmokers, and overall, our material shows the same distribution as that found in recent series [
11,
50], but ruptured aneurysm in the vertebrobasilar circulation was more common in our cohort than in that reported by Hammer at al. [
14]
The ruptured aneurysms were presently larger in smokers than in nonsmokers. Two other studies reported similar findings [
45,
61], whereas others did not find any difference in aneurysm diameter or rather increased odds for smaller aneurysms linked to smoking status [
11,
16]. Given that many aneurysms show growth before eventually rupturing [
53], and that smokers were younger when rupture occurred, one could speculate if there are biological factors in smokers leading to accelerated aneurysm growth. Such a mechanism could contribute to the increased risk of aneurysm rupture in smokers [
50]. Inactivation of α-1-antitrypsin may also be a possible mechanism [
56].
Hypertension is an established risk factor for aneurysm growth and for aSAH [
2,
50]. We found hypertension to be equally frequent in our smokers and nonsmokers. Possibly similar factors leading to aneurysm growth could facilitate the formation of multiple aneurysms [
10].
Management and complications
Poor-grade aSAH was significantly more common in our smokers. Poor-grade patients are expected to have more complications and longer hospital stays [
23] as well as a higher mortality, but we could not find significant differences in smokers and nonsmokers. Smoking, regardless of aSAH severity, is expected to imply a higher frequency of complications, since at least 10% of smokers have a smoking-attributable chronic disease, such as bronchitis, emphysema, or heart disease. A very large multi-center study found an OR of 1.45 for respiratory events after major surgery in current smokers [
39].
Furthermore, the poorer admission status in smokers did not translate into more cerebral vasospasm or more new cerebral infarctions as compared with nonsmokers. On the contrary, severe vasospasm was found more frequently in nonsmokers than in smokers, whereas the frequency of new cerebral infarctions was similar. This may in part be caused by our inclusion of all new infarctions, also those that were procedure-related. The effect of smoking on the risk of cerebral infarction and vasospasm after aSAH is controversial; some have found an increased risk of cerebral infarction [
37], symptomatic vasospasm [
28,
59], or delayed clinical ischemia [
8,
17,
26], while others found no impact of smoking on the risk of cerebral infarction or delayed cerebral ischemia [
6]. Large amounts of SAH predispose for the development of vasospasm [
12,
17], which could explain why nonsmokers presently had more frequently severe multi-vessel spasm, but one would have expected that also moderate vasospasm would be more frequent in nonsmokers, which was not the case. This finding also contradicts in part the notion that stiffer, more atherosclerotic blood vessel renders smokers less prone to vasospasm. Since poor clinical grade is a major predictor of DCI, we could have expected more ischemic events in our smoker group. de Rooij et al. [
8] concluded in a meta-analysis that there was “strong evidence for an increased risk of DCI in smokers,” a finding that we could not corroborate. A possible explanation of this discrepancy is linked to the term DCI itself, since there was a large heterogeneity in what constitutes DCI in the studies analyzed by de Rooij et al. [
8], in part using DCI interchangeably for clinical symptoms and radiological ischemia and/or radiological vasospasm. DCI and symptomatic vasospasm is often used interchangeably and it is the association between symptomatic vasospasm and smoking that mainly has been studied in the literature, whereas no clear relation has been established between smoking and the risk of radiological vasospasm [
20]. Our study based vasospasm strictly on radiological and sonographic findings and the exclusive effect of smoking on severe multi-vessel spasm is novel. The lower frequency of this most dangerous form of vasospasm could have had an impact on our mortality numbers; however, there was a lower 30-day mortality in smokers in the paired analysis which was matched for vasospasm.
It may be possible that smoking, in addition to its harmful effects, has a beneficial effect in some acute vascular conditions. Several theories have been discussed. Smokers may have developed better collateral circulation or other compensatory mechanisms in response to chronic reduction in cerebral blood flow—mechanisms that may protect against secondary insults. Possible mechanisms for improved oxygen transport after acute smoking cessation are slightly higher hemoglobin values in smokers and the rapid reduction of hemoglobin-bound carbon monoxide [
38,
40]. It has even been reported about a direct neuroprotective effect of nicotine through attenuation of oxidative stress and proinflammatory responses in Parkinson’s disease, spinal cord trauma, and neurotoxic insults [
25,
47,
57]. Others have, however, shown that nicotine increases brain infarct size and worsens neurological deficits when ischemia is present [
4]. The long-term effect of smoking cessation on aneurysm formation and rupture is not completely clarified. The results of Schatlo et al. [
52] suggest that the risk of rupture is not reduced when quitting to smoke after the aneurysm has formed and that duration of smoking is important. The latter is in line with the findings of Can et al. [
5], but they and Qureshi et al. [
46] report a persistent increased risk of aneurysm rupture after smoking cessation. This contradicts Kim et al. [
22] who report that aSAH is reduced to 59% after 5 years of smoking cessation. With such long-lasting impact of smoking on the natural history of intracranial aneurysms, one cannot exclude that also the protective effects persist over some time. This is partly supported by former smokers faring slightly better on some measures than never-smokers in the study of Dasenbrock et al. [
7].
Outcome in smokers
Serious comorbidity, age, and foremost clinical grade are strong predictors of mortality after aSAH [
27,
51]. We also know that life expectancy in smokers is in general 10 years shorter than in never-smokers, premature deaths being caused by cardiovascular disease, cancer, or respiratory disease [
58]. We used the Charlson Comorbidity Index to describe comorbidity, which was similar in smokers and nonsmokers. Only 17% of all our patients had a high CCI (≥ 2) and there was no difference between smokers and nonsmokers. A CCI ≥ 2 or more has been shown to predict a relatively high risk of death within 6 months in stroke patients [
18], which concurs with our findings at 1 year. With poor-grade patients more often being smokers in the present study, one would anticipate mortality to be higher than in nonsmokers. Even though not being significant, lower mortality numbers were found 1 year after the ictus in smokers. This unexpected finding is in line with the study of Zheng et al. [
62] who found a borderline significant higher chance of good outcome in smokers in poor-grade aSAH (WFNS 4 and 5). The effect of worse clinical grades among smokers may have been outweighed by the positive effects of their younger age. One could, however, debate if our age difference of median 55 years in smokers versus 59 years in nonsmokers is clinically relevant. Moreover, in the paired analysis matched for age, the lower mortality in smokers persisted and even became significantly lower at 30 days. Several authors have found better outcomes in smokers compared with nonsmokers in different settings, including aSAH [
1,
7,
14,
35,
44] an effect that could not be explained by younger age alone. “Paradoxically superior outcomes” in smokers have also been reported after myocardial infarction and after acute ischemic stroke, but may be due to residual confounding or lower baseline risks [
1,
35]. Nevertheless, it seems that worse clinical grades in smokers had less impact on outcomes than in nonsmokers, since the outcomes in the two groups were similar. A contributing factor could be that the rate of rebleed presently was somewhat lower in smokers since a rebleed can triple 1-year mortality after aSAH [
42,
55]. On the other hand, rebleed was not an independent predictor of 1-year mortality in our study.
Cerebral vasospasm is one of the most feared complications to aSAH, potentially leading to poor outcome. The lower frequency of severe vasospasm in the present study may have contributed to similar functional outcomes in smokers and nonsmokers, compensating for worse clinical grade in the smokers. Grade of vasospasm or severe vasospasm was though not a predictor of mortality or functional outcome in the present study and poor functional outcome was numerically less frequent in smokers in the paired analysis matched for WFNS grade, age, and vasospasm. Hammer et al. [
14] found smoking (OR: 0.21;
p = 0.0031) and hypertension (OR: 0.18;
p = 0.0019) to reduce the risk of poor clinical outcome of aSAH after 1 year. Smoking was not a predictor of poor functional outcome in the present study.
Overall, smokers and nonsmokers have similar outcomes after aSAH, which is in agreement with recent findings and is also corroborated by the similar comorbidities, complications, and hemorrhage pattern in our two study groups [
6,
27,
36,
43]. Still, these results need to be interpreted in light of patient selection, merely comprising hospital-admitted aSAH cases.
Limitations and strengths
We registered merely current smoking status and not if nonsmokers have ever smoked and how long time it was since they abandoned smoking. There may be differences in former smokers and never-smokers. We also did not control for any nicotine replacement therapy during hospitalization. However, nicotine replacement therapy was very uncommon at our department during the study period so that any effect probably is negligible. A strength was that data were acquired from an observational prospective study, with robust follow-up data and little drop-out/missing data. We also have a well-established institutional treatment protocol ensuring standardized treatment of all patients and thereby similar treatment of both study groups. By including 31 variables, our study combines a larger amount of neurosurgical and medical variables than other studies and may thereby contribute with a more comprehensive approach. Furthermore, more detailed analysis of some variables such as radiological vasospasm disclosed a more nuanced pattern, thereby partly disentangling apparently conflicting literature on the matter.