The role of previous medical history and secondary complications for the outcome of aneurysmal subarachnoid hemorrhage in elderly patients

Annkika Lenkeit, Marvin Darkwah Oppong, Thiemo Florian Dinger, Meltem Gümüs, Jan Rodemerk, Mehdi Chihi, Yahya Ahmadipour, Anne-Kathrin Uerschels, Philipp Dammann, Cornelius Deuschl, Karsten H. Wrede, Ulrich Sure, Ramazan Jabbarli

ABSTRACT

Objective: Aneurysmal subarachnoid hemorrhage (SAH) presents a devastating diagnosis for elderly individuals, resulting in high morbidity and mortality rates. The aim of the study was to analyze the impact of previous medical history and concomitant complications during SAH on the outcome of elderly SAH patients.

Methods: Consecutive SAH cases aged ≥65 years old treated in our hospital between 01/2003 and 06/2016 were included (n=218). The data on comorbidities, previous medication, initial severity, secondary complications of and the outcome after SAH were collected. The study endpoints were the occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months after SAH (modified Rankin scale > 3).

Results: Cerebral infarcts were documented in 111 (51.2%) individuals. Multivariate analysis showed that angiographic vasospasm increased (adjusted odds ratio [aOR]=3.11, p=0.022), whereat aspirin treatment decreased (aOR=0.25, p=0.001) the infarct risk in elderly SAH patients. In turn, increasing age (aOR=1.11 per-age-increase, p=0.002), intracranial hypertension (>20 mmHg, aOR=3.32, p=0.006) and acute kidney failure (aOR=6.65, p=0.035) during SAH were independently related to the risk of in-hospital mortality (n=50; 22.9%). Finally, patients’ age (aOR=1.09, p=0.022), high initial SAH burden (WFNS≥4: aOR=7.5, p<0.0001; intraventricular hemorrhage: aOR=4.38, p=0.007), aneurysm clipping (aOR=4.07, p=0.018), and intracranial hypertension during SAH (aOR=4.08, p=0.006) were independent predictors of unfavorable outcome at 6 months (n=106/192; 55.5%). Previous medical history showed no negative impact on the severity, course and outcome of SAH in elderly patients.

Conclusions: About the half of elderly SAH patients face poor outcome after aneurysm securing. The initial severity of and complications during SAH are the major contributors to poor treatment results. Our findings might help to optimize the treatment strategies in elderly SAH patients.

Introduction:

Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysm is a life-threatening disease characterized with a number of outcome-relevant complications like aneurysm rebleeding, intractable intracranial hypertension, delayed cerebral ischemia, as well as cerebral and systemic infections.^1-3  Along with these complications, some pre-existing conditions, initial severity of SAH, less aggressive therapy management also contribute to a considerable morbidity and mortality of SAH.⁴ Particularly, an increasing age is the acknowledged predictor of poor outcome after SAH.⁵ This circumstance is of eminent relevance, as in the context of recent demographic changes, the age group of older individuals is becoming larger and more important in terms of public health organization.^6,7

To date, the data on the role of previous medical history on the course and outcome of SAH patients in advanced age is very sparse.^8,9 The majority of the previous studies focused on the value of clinical status on admission and found out an influence of cognition, Hunt and Hess and WFNS (World federation of Neurosurgical Societies) scales as outcome predictors in elderly SAH individuals.^10-12 At the same time, worse course and outcome of SAH might be related to different reasons, not limited to the initial severity of SAH.¹³ Especially in elderly patients with specific comorbidity patterns, the value of the previous medical history on SAH outcome requires further clarification. So far, occurrence of cardiac complications after SAH and their association with poor outcome have been described in the literature.¹¹ In this context, the knowledge on outcome-relevant preexisting conditions and secondary complications might be essential for proper SAH management and neuro-intensive care of elderly patients with ruptured aneurysms.

Our aim was to investigate the role of previous medical history including the comorbidities and previous medication, as well as different complications occurring during SAH on the treatment outcome in elderly SAH patients.

Materials and Methods:

Patient population

The study based on the institutional retrospective database including all consecutive cases with acute aneurysmal SAH aged 65 years and older, who were treated in our clinic between 01/2003 and 06/2016. SAH individuals without aneurysm treatment were excluded from the further analysis. The study was approved by the institutional ethics committee (Faculty of Medicine of the University Duisburg-Essen, Registration number: 15-6331-BO) and registered in the German clinical trial register (DRKS, Unique identifier: DRKS00008749).

SAH management

The initial clinical SAH management on the intensive care unit included neurological monitoring and blood pressure control. SAH was diagnosed by computed tomography (CT) scan, and, if needed, by additional lumbar puncture. The ruptured aneurysms were diagnosed with digital subtraction angiography (DSA), with subsequent treatment allocation for clipping or coiling. The anticoagulants were interrupted and, when applicable, antagonized at admission, unless their continuous use during SAH was deemed necessary due to cardiac, neurologic or neuroradiologic (after endovascular aneurysm treatment) indications, as described previously in details.¹⁴ Postoperative/post-interventional intensive care therapy included transcranial Doppler ultrasound sonography (TCD) at least once daily for 14 days and oral administration of nimodipine for 21 days after onset of SAH. Mean arterial pressure was raised at > 70 mmHg. In case of refractory symptomatic cerebral vasospasm, repeated DSA with intra-arterial spasmolysis was performed. Acute hydrocephalus was treated by placement of an external ventricular or lumbar drainage. An early post treatment CT scan of the head in the first 24 h was performed. Additional CT scans were performed, if clinically indicated.

Data management

All variables of interest were gathered from the institutional retrospective SAH database with additional screening of the electronic medical records. Along with demographic data, a number of pre-SAH variables regarding the pre-existing comorbidities and previous medication were collected. The history of previous anticoagulation (prior to SAH onset), and those continuously admitted during SAH was also recorded.

Initial clinical severity of SAH was evaluated by the WFSN scale.¹⁵  The admission CT scans were reviewed for the assessment of the radiographic SAH severity according to the original Fisher¹⁶, as well as the presence of intraventricular (IVH) and intracerebral (ICH) hemorrhage. Moreover, the follow-up CT scan(s) up to 6 weeks after SAH were also reviewed with regard to the occurrence of any new cerebral infarction(s).

The development of following complications during SAH was assessed: aneurysm re-bleeding, cerebral vasospasm requiring intra-arterial spasmolysis, sustained increase of intracranial pressure (ICP)>20 mmHg requiring conservative and/or surgical (decompressive craniectomy) treatment, epilepsy, systemic infection, pleural effusion, pneumothorax, new onset cardiac arrhythmia, acute kidney failure, thrombotic complications, Finally, the functional outcome at discharge and at the 6-months routine outpatient clinical follow-up was recorded using the modified Rankin Scale (mRS).¹⁷

Study endpoints and statistical analysis

The goal of the study was the analysis of the impact of previous medical history/medication and complications at the beginning or during of SAH on the outcome of SAH in elderly patients. The following primary endpoints were addressed: [a] occurrence of cerebral infarcts; [b] in-hospital mortality, and [c] unfavorable outcome at 6 months after SAH defined as mRS>3. As secondary study endpoints, the impact of comorbidities and medication on the initial severity of SAH was analyzed.

For statistical analyses, the initial WFNS scale was dichotomized as Grades I-III vs IV-V, and the Fisher scale – as Grades I-II vs III-IV. Fist, the associations were tested in univariate analysis using the Student’s t- test for normally-distributed and the Mann-Whitney U test for non-normally-distributed continuous data, as well as the Fisher exact or chi square tests for categorical variables. The significant associations were then included in the multivariable binary logistic regression analysis additionally adjusted for patients’ age. Of the radiographic SAH characteristics, the parameter with the highest significance level throughout all primary endpoints was included in the multivariate analysis.

Statistical analysis was performed using IBM SPSS Statistics version 26 (SPSS Inc., IBM Corp., North Castle, New York, USA). Nominal data were expressed as absolute numbers and valid percent and continuous variables were expressed as mean and standard deviations (SD), or range, as appropriate. Differences with a P < 0.05 were regarded as statistically significant. Missing data were addressed using the multiple imputation.

Results:

Population characteristics

Between 01/2003 and 06/2016, 246 persons aged 65 years and older at the time of admission were treated in our institution. After the exclusion of 28 individuals without aneurysm treatment (due to poor initial prognosis and/or according to the restrictions in patients’ decree), 218 elderly SAH patients who underwent aneurysm clipping (n=85, 39%) or coiling (n=133, 61%) were included in the final analysis. 159 (72.9%) were female and 59 (27.1%) male, mean age was 73.4 (range 65-90 years). On admission, 95 (43.6%) patients presented with a high grade of the WFNS (4-5), a high radiographic severity (Fisher grade 3-4) was found in 183 (92%) subjects. The detailed data on the initial cohort characteristics and complications during SAH is shown in table 1.

Initial SAH severity was not related to the baseline characteristics and previous medical history of elderly SAH patients (seep supplementary Table S1 in Online Supplements). Regarding the impact of age on the SAH course, there was a decreasing probability of angiographic vasospasms (p=0.021) and intracranial hypertension requiring treatment (p=0.038) with increasing age, as it has been illustrated in figure 1.

Cerebral infarction

Cerebral infarcts were documented in 111 (51.2%) individuals in the follow-up CT scans. Figure 2A shows the frequency of cerebral infarcts depending on patients’ age. Interestingly, the probability of cerebral infarction rather decreased with increasing age (r=-0.143, p=0.035). The previous medical history showed no impact on the risk of cerebral infarction during SAH (table 2). Regarding the regular medication, daily aspirin treatment during SAH as only significant parameter, which indicated a reduced occurrence of cerebral infarction (odds ratio [OR] =0.28, p<0.0001). A bad clinical condition on arrival (WFNS=4-5, OR=2.21, p=0.006), and aneurysm clipping (OR=2.29, p=0.004) were also linked to cerebral infarction.

Complications that were significantly associated with the occurrence of infarction in the univariate analysis were aneurysmal rebleeding (OR=5.15, p=0.034), IVH (OR=1.98, p=0.018), sustained intracranial hypertension > 20 mmHg requiring conservative or surgical (craniectomy) treatment (OR=3.18, p<0.0001), evidence of cerebral vasospasm in DSA requiring endovascular treatment (OR=0.28, p<0.0001), and the occurrence of systemic infection(s) during SAH (OR=1.76, p=0.049).

In the multivariate analysis (table 3), only two parameters were independently associated with the occurrence of cerebral infarct – in particular, angiographic vasospasm increased (aOR=3.11, p=0.022), and aspirin use decreased (aOR=0.25, p=0.001) the probability of cerebral infarcts in elderly SAH patients.

In-hospital Mortality

Fifty patients (22.9%) did not survive the initial SAH treatment. In contrast to the inverse age effect on the infarct risk, an increasing probability of in-hospital mortality with increasing age was observed (r=0.179, p=0.008, see Figure 2B). The univariate analysis (table 2) revealed high WFNS (OR=2.13, p=0.023) and Fisher grades (OR=1.36, p=0.014), presence of IVH (OR=2.40, p=0.020), daily aspirin treatment (OR=0.21, p<0.0001), intracranial hypertension (OR=3.75, p<0.0001), and acute renal failure (OR=8.75, p=0.009) as factors related to in-hospital-mortality. The multivariate analysis (table 3) revealed that patients’ age (adjusted OR [aOR]=1.11 per-age-increase, p=0.002), intracranial hypertension (aOR=3.32, p=0.006) and acute kidney failure (aOR=6.65, p=0.035) during SAH were independent predictors of in-hospital mortality.

Unfavorable outcome at 6 months after SAH

The clinical follow-up data at 6 months after SAH were available in 192 individuals. Of them, in 106 patients (55.5%) unfavorable outcome was documented (see also Figure 2C for the distribution of the frequency of unfavorable outcome in the age range between 65 and 90 years, r=0.090, p=0.216). In the univariate analysis (table 2), preexisting cardiac diseases (OR=2.43, p=0.022), aspirin premedication (OR=0.27, p<0.0001), acute hydrocephalus (OR=3.40, p=0.001), poor initial WFNS (OR=7.24, p<0.0001) and Fisher grades (OR=6.11, p=0.004), presence of IVH (OR=4.85, p<0.0001) and ICH (OR=5.32, p=0.000), aneurysm clipping (OR=4.83, p<0.0001), intracranial hypertension (OR=6.52, p<0.0001) and systemic infections (OR=2.03, p=0.023) were significantly associated with unfavorable outcome at 6 months after SAH. Finally, patients’ age (aOR=1.09, p=0.022), poor initial clinical condition (WFNS=4-5, aOR=7.5, p<0.0001), IVH presence (aOR=4.38, p=0.007), aneurysm clipping (aOR=4.07, p=0.018), and intracranial hypertension during SAH (aOR=4.08, p=0.006) were confirmed as independent predictors of unfavorable outcome at 6 months in the multivariate analysis (table 3).

Discussion

In times of demographic change and an average life expectancy of 83 (female) and 78 (male) years in Europe ¹⁸, it is becoming increasingly important to focus on older patients. Fittingly, we observed a trend to an increase in the portion of elderly SAH patients treated in our center throughout the observational period 2003 – 2016 (Figure 3). The impact of previous medical history on the course and outcome of elderly SAH patients, and the identification of outcome-relevant complications in this patient’s population was the main interest of our study. Interestingly, medical history showed no remarkable clinical impact. Rather the initial severity and secondary complications occurring during SAH are of clinical relevance for SAH outcome in this age population.

Elderly patients are at high risk of poor functional outcome after SAH.^5,8,9,19 So far, previous literature dealing with elderly and SAH mostly state a poor outcome for elderly, but the reasons remain controversial.²⁰ In line with previous studies, elderly SAH patients in our cohort also showed considerable rates of poor outcome with regard to the risk of cerebral infarcts (51.2%), in-hospital mortality (22.9%) and unfavorable outcome at 6 months after SAH (55.5%). Therefore, the identification of outcome-relevant risk factors is essential for elderly SAH patients and might help to apply preventive measures and to develop targeted therapy concepts on the intensive care unit.

It is generally acknowledged that the initial clinical condition is the decisive point impacting the outcome of older SAH individuals.^{5,9,12,21,22,19} We confirmed the high relevance of the initial clinical condition for the outcome of SAH patients in advanced age. As the comorbidities were supposed to impact the outcome of older individuals requiring intensive care unit treatment due to different acute conditions²³, and the literature addressing the association between previous medical history and SAH outcome is very sparse, the detailed analysis of this relationship was in the focus of present study. There are conflicting reports on the role of comorbidities for SAH patients. So, Kanamaru et al. identified hypertension as a significant factor influencing poor outcome at an age over 75.²⁴ Another study also found out that age and hypertension were independently associated with poor outcome, while diabetes mellitus, cardiac disease, renal disease and pulmonal disease had no influence.²⁵ At the same time, the absence of any impact of premorbid conditions like arterial hypertension, arteriosclerosis, hyperlipidemia, and diabetes mellitus on the outcomes of SAH was also previously reported.^26,27 As to the regular medication, statin use was shown to reduce vasospasm and infarction risk after SAH in elderly.²⁸ Previous studies showed negative impact of anticoagulants on the outcome of patients with non-aneurysmal²⁹ and aneurysmal³⁰ SAH. At the same time, Dasenbrock et al. stated that neither long-term aspirin nor anticoagulant use were associated with differential mortality or complication rates after SAH.³¹ In summary, our data do not confirm the relevance of previous medical history (neither of comorbidities, nor of previous medication) for the initial severity and outcome of SAH. Further studies on larger cohorts are necessary to clarify the impact of comorbid conditions for patients with ruptured aneurysms.

Although previous medication failed to show an effect on the treatment results, but continuous use of aspirin during SAH significantly lowered the risk of cerebral infarction. According to the American Heart and American Stroke Associations, aspirin is a common medication for the secondary stroke prevention.³² A meta-analysis of several randomized trials by Lei et al. states that aspirin decreases risk of stroke as primary prevention in healthy and lesser in patients with cardiovascular disease, however under consideration of an increased risk of severe bleeding events.³³ Other studies state that dual platelet inhibition do not have an even better effect on delayed cerebral ischemia (DCI) occurrence but provoked a higher risk of bleeding.¹⁴ There is some evidence in the literature that antiplatelet therapy has a beneficial effect on lower DCI/infarct occurrence after SAH.^14,34,35 A probable higher risk of re-rupture under aspirin treatment has to be considered.³⁶ The effect of aspirin on ischemia and the functional outcome of SAH still remains controversial, some state no effect of aspirin therapy on DIND.^37,38

In summary, although the use of aspirin carries a non-negligible risk of rebleeding, its routine use might be useful for certain SAH patient contingents, particularly those with higher risk of delayed cerebral ischemia and low burden of surgical interventions.

Secondary complications during SAH might significantly worsen the further course and outcome of SAH. In our elderly SAH population, cerebral vasospasm, sustained ICP increase and acute kidney failure were significantly associated with one or more of the primary study endpoints. Of note, cerebral vasospasm^39,40 and pathologic ICP increase^41,42 are acknowledged risk factors for poor outcome of SAH patients. We could confirm the significance of these common SAH complications also for older individuals. Moreover, we observed a decrease in the risk of cerebral vasospasm and intracranial hypertension with increasing age, as it has also been reported previously.^43,44 This age-dependent pattern of SAH complications might explain the inverse association between the patients’ age and infarct risk in our cohort.

In contrast, we found further increase of the mortality and long-term morbidity rates with increasing age. Therefore, the older were our SAH patients, the higher was the probability of poor outcome without evidence of cerebral infarction. This kind of decoupling of poor SAH outcome from the infarct-risk with increasing age is one of the interesting study findings. Rather the initial characteristics of SAH like poor WFNS grade, presence of IVH and treatment modality (clipping) seem to play the crucial role for the final outcome of elderly SAH patients. This circumstance might be the consequence of decreasing recovery capacities of the aging brain after an acute brain injury.⁴⁵ As our study cannot provide a causal explanation of these age effects on SAH complications and outcome, further researches of this eventual infarct-decoupling of poor outcome in SAH patients with increasing age are mandatory.

Limitations

The major limitation of this study is its retrospective and single-center observational design with all related information and selection biases. Particularly, there are concerns on the accuracy of the evaluation of the previous medical history based on the screening of the electronic medical records of patients. For this reason, some relevant parameters like tobacco and alcohol consumption could not be analyzed in the present study. Moreover, long-term functional outcome was missing in 11.9% of the final cohort, particularly in more aged SAH individuals with poor outcome at discharge. Nevertheless, our analysis is based on one of the largest series of elderly SAH patients and can provide insights for further researches aiming to optimize the treatment concepts for SAH individuals in advanced age.

Conclusion

About the half of elderly SAH patients face poor outcome after aneurysm securing. Not the previous comorbidities, but rather the initial severity of and complications during SAH are the major contributors to poor treatment results. The older are SAH patients, the higher is the probability of poor outcome without evidence of cerebral infarction. Our findings might help to optimize the treatment strategies in elderly SAH patients.

Acknowledgements

xxx

Table 1: Descriptive analysis of the cohort characteristics

     only 192 of 218 appeared for the follow-up control after 6 months

    SAH subarachnoid hemorrhage

Table 2: Univariate analysis for the association between previous medical history, complications and primary endpoints of SAH

OR- odds ratio, CI- confidence interval. Significant variables are marked in bold type

mRS modified Rankin Scale, CNS central nervous system

Table 3: Multivariable analysis for the associations between medical history, SAH complications (selected through the univariable analysis) and the primary study endpoints adjusted for patients’ age.

OR- odds ratio, CI- confidence interval. Significant variables are marked in bold type.

Significant variables from previous univariate correlations were included.

Figures

Figure 1: Boxplot- Analysis: Age differences in different complication groups

   *sig. p < 0.05

Figure 2: Endpoints rates in the different age groups between 65 and 90 years of age.

1. Endpoint: Cerebral infarction
2. Endpoint: In-hospital mortality
3. Endpoint: Unfavorable outcome at 6 months after SAH

a)

b)

c)

Figure 3: demographic change of patients’ age in our cohort

Supplementary material

Supplementary table S1: Correlation between initial SAH severity and baseline characteristics/previous medical history

odds ratio, CI- confidence interval. Significant variables are marked in bold type

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