In patients with aneurysmal subarachnoid hemorrhage (aSAH), the high mortality and morbidity are not only associated with the initial bleeding but also with intracerebral secondary complications, such as rebleeding, delayed cerebral ischemia (DCI), and hydrocephalus (1). Similar to intracerebral complications, extracerebral complications are frequent (with reviews finding cardiac injury in ~36%, arrhythmias in ~35%, and acute respiratory distress syndrome in ~4–18% of patients covering multiple studies) (2). Cardiovascular and pulmonary complications are the most frequent and are associated with a sudden and sustained increase in systemic catecholamines, which can lead to organ dysfunction, hypoxemia, hyperglycemia, and an inflammatory state with the release of cytokines (3). In particular, cardiac complications and markers of cardiac injury have been shown to be associated with unfavorable outcomes and the occurrence of DCI (4) with other studies proving the benefit of combined multi-organ dysfunction evaluation for the prediction of outcomes (5). Fever, anemia, and hyperglycemia have also been found to be associated with increased mortality and poor outcomes (6).

Sex-specific differences exist in almost every aspect of a disease. Women are more likely to be affected by aSAH (7–10) possibly due to the intrinsic weakness of the vessel walls, collagen, and elastin interference factors, as well as hormonal aspects (11, 12). Furthermore, aneurysm location itself also appears to be associated with sex (13, 14), with more aneurysms located along the internal carotid artery in female subjects and along the anterior cerebral artery in male subjects. However, so far, while complications after aSAH have been elucidated in various studies, the presence of sex-specific extracerebral complications during the stay at the neurocritical care unit (NCCU) is less investigated.

In this retrospective study, we focus on the extracerebral consequences of aSAH, particularly on sex-specific complications during the stay at the NCCU and their influence on outcomes. The identification of these might aid personalized management and treatment strategies.

We retrospectively reviewed the medical records of all consecutive patients with aSAH admitted to the NCCU of the University Hospital Zurich over a 6-year period (January 2016–December 2021). All adults (≥18 years old) admitted with aSAH (i.e., with imaging evidence of a ruptured aneurysm) were eligible for inclusion. Exclusion criteria were as follows: (1) patients with only unruptured, traumatic, fusiform, dissecting, or mycotic aneurysms and (2) patients' written or documented oral refusal to have their data analyzed for research projects. The study was performed in accordance with the ethical standards laid down in the 2013 Declaration of Helsinki. The local ethics committee approved the study. STROBE guidelines were used to draft the manuscript.

Overall, 343 patients fulfilled the inclusion criteria. Of these, 63.6% were women (N = 218). Women were older than men (p = 0.002, an average of 5 years). In addition, no differences by sex were found considering the presence of comorbidities, the severity of bleeding, radiographic findings on the first CT scan (presence of intracerebral hemorrhage, ventriculomegaly, and intraventricular hemorrhage), and treatment modality (coiling/ clipping), as shown in Table 1.

The extracerebral complications are listed in Table 2. More women than men suffered from cardiac complications (p = 0.013), particularly arrhythmic disorders (p = 0.019). Infectious diseases, overall, were more frequent in women than men (p = 0.048). More women suffered from urogenital tract infections (p = 0.002). Pulmonary complications were frequent, but no sex-related differences were found. Female sex also remained an independent predictor of cardiac complications after correction for age (p = 0.037, OR 1.837, 95% CI 1.036–3.257) but not for infectious complications when corrected for age (p = 0.054).

Considering outcomes, female sex, age, CCI, WFNS, and Fisher grading were associated with unfavorable outcomes in the univariate analysis. Considering the extracerebral complications, cardiac, pulmonary, hepatic/gastrointestinal, and hematologic complications were associated with unfavorable outcomes. In the multivariate analysis, increasing age, WFNS, and Fisher grading remained independent predictors of unfavorable outcomes irrespective of the addition of extracerebral complications. When these were added, aside from the above-mentioned known predictors, only pulmonary and cardiac complications remained independent predictors of unfavorable outcomes (Table 3). Sex was an independent predictor of unfavorable outcomes when considered univariately in the base model (excluding extracerebral complications) as well as in the multivariable analysis when adding pulmonary, hepatic/gastrointestinal, or hematologic complications. Interestingly, however, the female sex was not an independent predictor of unfavorable outcomes when including cardiac complications in the base model (Table 4) possibly due to the high association between sex and cardiac complications (p = 0.01, OR 2.040, 95% CI 1.163–3.579).

In this study, we investigated the frequency of extracerebral complications in patients suffering from aSAH with a particular focus on sex-related differences and their influence on outcomes. Extracerebral complications in patients with aSAH are frequent. Wartenberg et al. described at least one medical complication in 79% of patients with aSAH (6). Similarly, Solenski et al. reported that all the patients recruited had one or more medical complications (20). We found that both sexes frequently suffered from complications (female: 79.8%, male 73.6%). We found cardiac and pulmonary complications to be the most frequent complications in this study population. Similar to prior reports, they were independent predictors of unfavorable outcomes (21–24). No specific subtype of pulmonary complication was associated with significantly worse outcomes, confirming prior reports (22). A catecholamine storm following acute brain injury has been proposed to lead to extracerebral complications by means of hypoxemia, hyperglycemia, and inflammatory state due to the release of pro-inflammatory cytokines (25). A similar mechanism could also explain the complications found in aSAH.

Cardiac complications and the combination of multi-organ dysfunction after aSAH have been shown to be associated with unfavorable outcomes (4, 5). However, whether extracerebral complications occur in a sex-specific manner remains poorly investigated. In our cohort, women suffered more frequently from cardiac complications even after correction for their older age. This difference was mostly based on the higher frequency of arrhytmogenic complications in female subjects. Interestingly, both the absolute frequency, as well as the lack of sex-related difference in the frequency of Takotsubo syndrome, differs from current reviews most likely due to the need for a transthoracic echocardiogram for its diagnosis, which is only ordered in patients with clinical suspicion (26). As previously described, women presented a worse outcome after aSAH (10). Possibly the difference in cardiac complication frequency might explain this difference. In our cohort, cardiac complications occurred mostly in women and mostly within the first 4 days after the initial hemorrhage (Figure 1). aSAH leads to an acute increased sympathetic nervous system activity with an increased release of catecholamines (27). This increased activity is also associated with cardiac complications and in particular Takotsubo syndrome (26). Some studies even report the beneficial effects of beta-blockers in patients with aSAH (28, 29). Standardized use of beta-blockers in aSAH, however, has not been established yet. Patients at risk for symptomatic vasospasm and DCI receive controlled arterial hypertension to improve cerebral perfusion. Induced hypertension may lead to serious adverse events, such as cardiac arrhythmia, myocardial infarction, pulmonary edema, brain edema, hemorrhagic infarction, and rebleeding (30). These adverse effects of induced hypertension might be potentiated in patients who already suffered cardiac complications/injury prior to its induction.

In the study population, women were more likely to suffer from infections, particularly urogenital infections, during their stay at the NCCU. This finding is in line with previous reports (31, 32). Anatomical differences and the use of bladder catheters might increase the risk of infections in women. This finding suggests that the use of bladder catheters should be carefully evaluated, and removal—in female patients, should be reconsidered on a daily basis in order to prevent the development of urogenital infections.

Extracerebral complications during the stay at the NCCU after aSAH are frequent. Cardiac and pulmonary complications are predictors of unfavorable outcomes. There are sex-specific extracerebral complications. Women more commonly suffer from cardiac and infectious complications. Patients with prior cardiac injury might benefit from personalized management when at risk of symptomatic vasospasm/DCI with either closer evaluation for further cardiac injury or possibly lower blood pressure target values. Due to the increased risk of urogenital infections in women, the use of bladder catheters should be carefully evaluated, and early removal should be advised.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Kantonale Ethik-Kommission Zürich. The patients/participants provided their written informed consent to participate in this study.

SBö: conceptualization, statistical analysis, critical revision, and data interpretation. SBe: data acquisition, writing—original draft, and data interpretation. LH: writing—original draft and data acquisition. FN and FC: critical revision and data acquisition. GB: supervision, writing—review and editing, project administration, and conceptualization. EK: supervision, writing—review and editing, and data interpretation. All authors contributed to the article and approved the submitted version.