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Time Trends in Outcomes After Aneurysmal Subarachnoid Hemorrhage Over the Past 30 Years
ORIGINAL ARTICLE
Time Trends in Outcomes After Aneurysmal Subarachnoid Hemorrhage Over the Past 30 Years Biagia La Pira, MD; Tarun D. Singh, MBBS; Alejandro A. Rabinstein, MD; and Giuseppe Lanzino, MD Abstract Objective: To analyze trends in mortality rates, functional outcomes, and treatment in patients with aneurysmal subarachnoid hemorrhage (aSAH) over the past 3 decades. Patients and Methods: We conducted a retrospective review of consecutive patients with aSAH treated at Mayo Clinic in Rochester, Minnesota, between January 1, 1985, and December 31, 2014. Results: A total of 1173 patients identified were grouped by decade of treatment: 1985 to 1994, n¼274; 1995 to 2004, n¼461; and 2005 to 2014, n¼438. Overall, the use of endovascular techniques increased progressively from 5.1% (14) in 1985 to 1994 to 65.5% (287) in 2005 to 2014. This corresponded to a progressive decrease in the rate of clipping from 78.8% (216) in 1985 to 2004 to 21.5% (94) in 2005 to 2014 (P<.001). The percentage of patients admitted with poor clinical grade also increased from 22.3% (61) in 1985 to 1994 to 24.1% (111) in 1995 to 2004 and 29.5% (129) in 2005 to 2014 (P¼.06). The inhospital mortality rate decreased from 22.6% (62) in 1985 to 1994 to 16.3% (75) in 1995 to 2004 and remained relatively constant at 16.7% (73) in 2005 to 2014. Good functional outcome at 3- to 6-month follow-up improved significantly from 64.8% (173) in 1985 to 1994 to 72% (332) in 1995 to 2004 and 78.8% (345) in 2005 to 2014 (P<.001). Conclusion: Outcomes in patients with aSAH have markedly improved over the past 3 decades, in terms of both in-hospital survival and functional recovery of survivors. Higher rates of endovascular coiling over time paralleled these improvements in clinical outcomes. More detailed investigation is necessary to determine whether this or other factors may directly explain the favorable trends in survival and functional recovery over time. ª 2018 Mayo Foundation for Medical Education and Research From the Department of Neurologic Surgery (B.L.P., G.L.), Department of Neurology (T.D.S., A.A.R.), and Department of Radiology (G.L.), Mayo Clinic, Rochester, MN.
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uring the past 3 decades, the management of aneurysmal subarachnoid hemorrhage (aSAH) has changed substantially. Early treatment of the ruptured aneurysm has decreased the incidence of rebleeding,1 and the development of coiling has provided a valid alternative to clipping.2,3 In addition, progress in neurocritical care and better understanding of the pathophysiology of delayed cerebral ischemia have improved our ability to minimize ischemic sequelae.4 Despite these advances, however, little information is available on their effects on the overall outcomes in patients with aSAH. Some population-based studies have reported decreasing case-fatality rates,5-13 but there are scant data on trends in functional outcomes over time. In the present study, we analyzed
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trends in mortality rates and functional outcomes at a single tertiary care institution over the past 3 decades. PATIENTS AND METHODS Patient Consent The study was approved by the Mayo Clinic Institutional Review Board. All included patients or their representatives had signed a general informed consent form allowing their medical records to be used for research purposes. Study Design We conducted a retrospective review of all consecutive patients with aSAH who were treated at Mayo Clinic in Rochester,
Mayo Clin Proc. n December 2018;93(12):1786-1793 n https://doi.org/10.1016/j.mayocp.2018.06.027 www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research
OUTCOMES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE
Minnesota, between January 1, 1985, and December 31, 2014. Study Definitions Subarachnoid hemorrhage was diagnosed by computed tomography (CT) of the head or by a finding of cerebrospinal fluid xanthochromia in case of negative CT findings but a history suggestive of aSAH. Patients were included only if an aneurysm was documented by a vascular study (usually catheter angiography) and if they had been admitted to the hospital within 48 hours of symptom onset. We excluded patients with angiographically negative aSAH and those with subarachnoid hemorrhage secondary to an arteriovenous malformation. Patients with a final diagnosis of aSAH were initially identified using our electronic data search system, and the diagnosis was confirmed by manual review of the medical records. Collected Variables and Study Definitions Electronic health records of patients were abstracted for patient demographic characteristics, World Federation of Neurosurgical Societies (WFNS) and Hunt and Hess (HH) grading of aSAH at initial evaluation, location of the aneurysm, type of treatment, rebleeding, symptomatic vasospasm or delayed cerebral ischemia, in-hospital death, outcome at discharge, and outcome at 3- to 6-month follow-up. Clinical aSAH severity was classified using the HH scale during the first decade (19851994) and the WFNS scale during the last 2 decades (1995-2004 and 2005-2014). Poor clinical grade was defined as grade 4 or 5 on either scale. Location of the ruptured aneurysm was classified as anterior circulation (anterior communicating artery, anterior cerebral artery, pericallosal artery, middle cerebral artery, internal carotid artery, posterior communicating artery, or ophthalmic artery) or posterior circulation (vertebral artery, basilar artery, or posterior cerebral artery). Rebleeding was defined as a documented increase in the previous amount of aSAH, increased blood in the ventricular system on repeat head CT in the presence of sudden neurological deterioration, or both. Symptomatic vasospasm was defined as documented vasospasm (by ultrasonographic or Mayo Clin Proc. n December 2018;93(12):1786-1793 www.mayoclinicproceedings.org
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angiographic criteria) associated with otherwise unexplained neurological decline.14 Delayed cerebral ischemia was defined as symptomatic vasospasm or the appearance of new infarction on CT or magnetic resonance imaging attributable to vasospasm, thus excluding periprocedural complications. For the purpose of the analysis, delayed ischemia is defined as the combination of symptomatic vasospasm and delayed cerebral ischemia. Clinical outcome was categorized at discharge and at 3 to 6 months after discharge using the Glasgow Outcome Scale (during 1985-1994), with good outcome defined as a score of 4 or 5, or using the modified Rankin Scale (mRS; during 1995-2014), with good outcome defined as a score of 0 to 2. Statistical Analyses Patients were grouped by decade for comparative analyses: 1985 to 1994, 1995 to 2004, and 2005 to 2014. Analyses were also performed with year as a continuous variable to identify a possible single year interval during which major changes could have occurred. Grouping patients in the 3 decades is based on the major changes occurring in the interval under study: increasing role of endovascular therapy for patients at high surgical risk in the mid-1990s and publication of the results of the International Subarachnoid Aneurysm Trial in 2002 to 2004. Descriptive summaries were reported as medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and the 2-sample t test or Kruskal-Wallis test was used for continuous variables, as applicable. Outcomes of interest were in-hospital death and functional outcome. All tests were 2-sided, and P values less than .05 were considered statistically significant. Statistical analyses were performed with JMP 12.0.0 (SAS Institute Inc.). RESULTS Our search identified, after exclusions, 1173 patients with aSAH seen from 1985 to 1994 (n¼274), 1995 to 2004 (n¼461), and 2005 to 2014 (n¼438). Patient demographic characteristics, worse severity of aSAH at the initial evaluation (grades 4 and 5), and location of
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the ruptured aneurysm are summarized in the Table. During the study period, the median age increased slightly from 53 (44-65) to 55 (47-64) years. There was also a progressive increase in the percentage of patients admitted with poor clinical grade, from 22.3% (61) in 1985 to 1994 to 111 (24.1%) in 1995 to 2004 and 29.5% (129) in 2005 to 2014, although the difference did not reach statistical significance (P¼.06). Treatment modalities used during the 3 time periods are presented in Figure 1. Overall, there was a progressive increase in the use of endovascular techniques from 14 (5.1%) in 1985 to 1994 to 287 (65.5%) in 2005 to 2014. This corresponded to a progressive decrease in the rate of clipping from 216 (78.8%) in 1985 to 2004 to 94 (21.5%) in 2005 to 2014 (P<.001). The rate of rebleeding remained constant across the 3 decades (P¼.52) (Table). The rate of delayed ischemia increased from 97 (35.4%) in 1985 to 1994 to 199 (43.2%) in 1995 to 2004 and then decreased again to 149 (34%) in 2005 to 2014. The inhospital mortality rate decreased from 62 (22.6%) in 1985 to 1994 to 73 (16.7%) in 2005 to 2014 (P¼.07) (Figure 2). Among patients who survived hospitalization, the number of patients who completed follow-up in the first, second, and third decade was 184 (85.8%), 244 (63.2%), and 216 (59.2%), respectively. Good functional
outcome at 3- to 6-month follow-up improved significantly from 173 (64.8%) in 1985 to 1994 to 345 (78.8%) in 2005 to 2014 (P<.001). The percentage of patients with good functional outcome at follow-up increased over time in patients with aneurysms in the anterior and posterior circulation (P¼.03 and P¼.04, respectively) (Figure 3). Analysis of outcome using time as a continuous variable did not identify any specific time point at which a significant change was noted. In patients admitted with good clinical grade, functional survival significantly improved over time (P<.001), although mortality did not (P¼.11). In patients admitted with poor clinical grade, there was a significant improvement in both functional outcome (P¼.008) and mortality (P¼.02) across the decades studied. DISCUSSION In a review of outcomes after aSAH at our institution over the past 30 years, we found decreased case-fatality rates, constant rates of early rebleeding, increased use of endovascular techniques, and improved rates of good functional outcome, despite an increasing percentage of patients being admitted in poor neurological condition. Population-based studies have reported improved case-fatality rates after aSAH over time.5-13 In patients in Australia and New Zealand admitted to the intensive care unit with
TABLE. Patient and Aneurysm Characteristicsa,b Time period 1985-1994 (n¼274)
1995-2004 (n¼461)
2005-2014 (n¼438)
P value
Age (y)
Characteristic
53 (44-65)
55 (46-66)
55 (47-64)
.21
Men
91 (33.2)
161 (34.9)
c
156 (35.6)
d
d
.80
61 (22.3)
111 (24.1)
129 (29.5)
.06
(n¼271) 202 (74.5) 61 (22.5) 8 (3.0)
(n¼452) 313 (69.2) 136 (30.1) 3 (0.7)
(n¼429) 324 (75.5) 102 (23.8) 3 (0.7)
.009
Rebleeding
29 (10.6)
56 (12.1)
58(13.2)
.52
Delayed ischemia (symptomatic vasospasm or DCI)
97 (35.4)
199 (43.2)
149 (34.0)
.01
Poor clinical grade Location of aneurysm AC PC Both
AC ¼ anterior circulation; DCI ¼ delayed cerebral ischemia; PC ¼ posterior circulation. b Data are presented as median (interquartile range) or as No. (percentage). c Classified as Hunt and Hess scale grade of 4 or 5 (vs 1-3). d Classified as World Federation of Neurosurgical Societies grade of 4 or 5 (vs 1-3). a
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Percentage
Clipping 90 80 70 60 50 40 30 20 10 0
Coiling
78.8 65.5 57.9
32.3 21.5 5.1
1985-1994
1995-2004
2005-2014
Years
FIGURE 1. Percentage of patients undergoing clipping and coiling in the 3 time periods.
aSAH, the case-fatality rate decreased from 35.4% in 2000 to 27.2% in 2015.13 Similarly, in a study of patients hospitalized in Scotland between 1986 and 2005, Macpherson et al8 reported a decreasing case-fatality rate over time, especially in those aged 40 to 59 years. Among patients aged 40 to 49 years, the case-fatality rate decreased from 30% in 1986 to 1990 to 21.4% in 2001 to 2005 in men and from 32.6% to 18.8% in women. These observations were mirrored in a population-based study in the United States, which reported progressive decreases from
Percentage
Hospital mortality Good functional outcome at last follow up 90 80 70 60 50 40 30 20 10 0
78.8 72 64.8
22.6
1985-1994
16.3
16.7
1995-2004
2005-2014
Years
FIGURE 2. Percentage of patients with good functional outcome and in-hospital death in the 3 time periods.
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1988 through 2010 in all-cause 5-day, 30-day, and 90-day case-fatality rates.7 In agreement with these trends in populationbased studies, we also observed a progressive decrease in in-hospital mortality rate from 22.6% (62) in 1985 to 1994 to 16.3% (75) in 1995 to 2004, with subsequent stability at 16.7% (73) in 2005 to 2014. Mortality rates provide an objective, albeit crude, outcome assessment. However, in a disease such as aSAH, which often affects young persons with many years of productive life ahead of them, it is important to understand whether improved survival rates are accompanied by better functional outcomes in survivors. In our series, good functional outcome within 3 to 6 months after aSAH improved consistently, from 64.8% (173) in 1985 to 1994 to 72% (332) in 1995 to 2004 and 78.8% (345) in 2005 to 2014. This considerable improvement in functional outcome is even more remarkable considering that it occurred despite a substantial increase in the percentage of patients admitted in poor neurological condition, from 22.3% (61) in 1985 to 1994 to 24.1% (111) in 1995 to 2004 and 29.5% (129) in 2005 to 2014. This information on changes in functional outcome over time after aSAH is novel, because data are scant on this topic. In residents of the Greater Cincinnati/Northern Kentucky region admitted with aSAH, the median mRS score at discharge decreased markedly from 5 to 3 between 1988 and 2010,7 although this study did not provide information on functional recovery after discharge. Changes in the Management of aSAH That May Have Led to Better Outcomes In the past 30 years, the management of aSAH has undergone several changes that may have contributed to this improvement in outcomes. In the early 1990s, publication of the results of the International Cooperative Study on the Timing of Aneurysm Surgery1 and improving microneurosurgical techniques generated a shift toward earlier surgery to secure the ruptured aneurysm. Early surgery decreases the incidence of rebleeding (an often deadly complication of aSAH) and allows more aggressive treatment of vasospasm.1 Comparing causes of in-hospital death within the same institution in 2 time periods (1999-2002 and
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90
AC
PC 80.4
Percentage
80
79.9
75
70 60
67
72.2
62.5
50 1985-1994
1995-2004 Years
2005-2014
FIGURE 3. Percentage of patients with good functional outcome at follow-up in the 3 time periods for patients with either anterior circulation (AC) (P¼.03) or posterior circulation (PC) (P¼.04) aneurysms.
2009-2012), Vergouwen et al15 observed a significant decrease in 90-day case-fatality rate, from 39% in 1999 to 2002 to 30% in 2009 to 2012, which was ascribed in part to a decrease in the incidence of in-hospital rebleeding from 24% to 17% in the 2 periods. This decrease in the incidence of rebleeding coincided with earlier treatment of aneurysms (median day decreased from day 4 to day 1).15 In our study, the incidence of rebleeding did not change over time, but this may be related to our center being highly specialized in microsurgery and one of the first centers in the world to adopt early aneurysm repair to prevent rebleeding.16 Therefore, the improved outcome and casefatality rates observed in our study are not related to decreased rates of rebleeding. The next major change in the management of aSAH occurred in 1990, with the introduction in the United States of Guglielmi detachable coils17 for the treatment of cerebral aneurysms, as part of a US Food and Drug Administration investigational device exemption, and its subsequent approval in 1995 for the treatment of patients at high surgical risk. Consequently, coil embolization throughout the 1990s was reserved primarily for patients at high surgical risk, such as those with posterior circulation aneurysms, those with medical comorbid conditions, and those in poor neurological condition at admission.18 This shift may have been a main contributor to the important decrease in mortality rate we observed from 1790
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the first decade (22.6%; 62) to the second decade (16.3%). As development of less invasive neuroendovascular techniques has encouraged a more aggressive approach to poor grade aSAH, other authors have also observed decreasing mortality rates for patients with poor grade aneurysms.19-21 Lantigua et al20 noted a 20% absolute risk reduction for inhospital death in patients with worse clinical grades (over the course of the study, 19962009), although the mortality rate for those with less severe disease remained constant. Similarly, Konczalla et al19 observed a decrease in 30-day mortality rate in patients with grade 5 aSAH, from 83% in 1980 to 1995 (“precoiling era” at their institution) to 39% in 2005 to 2014. In 1994, the International Subarachnoid Aneurysm Trial, a prospective randomized trial comparing endovascular coil embolization with surgical clipping for acutely ruptured aneurysms, was initiated and then conducted mostly in the United Kingdom. In 2002, the trial was halted after an interim analysis revealed that patients assigned to the endovascular arm had better 1-year functional outcomes than did patients in the open surgery arm.22 Publication of the preliminary results of the trial in 2002 and definitive results in 2005 established the legitimacy of endovascular coil embolization, not only for patients with ruptured aneurysms considered candidates at high surgical risk but also for other patients with aneurysms amenable to coil embolization.2,3,22,23 The results of the International Subarachnoid Aneurysm Trial led to a progressive increase in the proportion of patients treated with endovascular coil embolization. Meanwhile, the introduction of intraoperative microvascular Doppler ultrasonography and intraoperative indocyanine green angiography has allowed refinement of open surgical techniques. These developments have generated a new paradigm using which case-by-case decisions are made by a team of specialists with endovascular and open surgical expertise to select the best treatment option (balancing efficacy against risk of each therapeutic modality) for each patient.24 In our study, the rate of coiling increased progressively over time, from 5.1% (14) in 1985 to 1994 to 32.3% in 1995 to 2004 and
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65.5% (287) in 2005 to 2014. Recent studies have also found progressive increases in the rate of ruptured aneurysms treated with coiling, with an associated improvement in casefatality rates.7,25 For instance, Mackey et al7 observed that the percentage of patients with subarachnoid hemorrhage in their population undergoing coiling increased from 0% in 1993 to 1994 to 13% in 2010. Neurocritical Care and Better Understanding of aSAH and Its Complications Aneurysmal subarachnoid hemorrhage is one of the most complex acute conditions a physician may encounter. Outcome is largely affected by the damage that occurs at the time of the original hemorrhage, but in the first 2 to 3 weeks, patients are exposed to the danger of secondary injury from neurological complications (eg, rebleeding, delayed cerebral ischemia from vasospasm, increased intracranial pressure, and hydrocephalus), systemic complications, pulmonary complications,26 cardiovascular complications,27 fluid shifts and hyponatremia,18 and complications associated with a prolonged intensive care unit stay in a severely ill patient.4 The evolution in our understanding of the pathophysiology of aSAH and its complications and improvements in critical care over the past 30 years are factors that may have contributed to better outcomes for our patients. In particular, there has been a progressive shift toward the inclusion of neurointensivists in the management of aSAH in dedicated neurocritical care units.7 The establishment of such units has led to a population of physicians and nurses trained to minimize the risk of secondary brain damage.28 Several studies have found that involvement of neurointensivists in the management of aSAH in specialized neurocritical care units is associated with improved mortality rates and functional outcomes.29-32 Study Limitations Our study has limitations inherent to its retrospective design. However, all patients, regardless of the initial clinical grade, were admitted to the neurological intensive care unit throughout the entire study period and treated in the hyperacute phase by a limited number of specialists (4 interventional neuroradiologists, 7 neurosurgeons with major subspecialty Mayo Clin Proc. n December 2018;93(12):1786-1793 www.mayoclinicproceedings.org
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interest in cerebrovascular disorders, and 5 neurointensivists). Therefore, clinical grading and assessment of rebleeding and delayed ischemia were relatively consistent over time. Greater availability of magnetic resonance imaging, noninvasive angiography, and CT perfusion, however, has probably increased our sensitivity for the detection of delayed cerebral ischemia in more recent years. More sensitive detection of ischemia in the past 2 decades of our study period may have underestimated favorable changes in the rates of ischemia compared with the first decade. Our analysis did not include other relevant factors, such as radiological grade to assess the risk of vasospasm, comorbid conditions, and acute systemic complications. However, these deficiencies should not affect our main results. Our findings may be affected by referral bias, but we tried to limit this by considering only patients admitted within 48 hours from their ictus and therefore more likely to come from our direct catchment area. Using HH scale and Glasgow Outcome Scale in the first decade and WFNS and mRS scores of 0 to 2 in the second and third decades under study for clinical grade at admission and definition of good outcome may introduce some variability. However, we think that this is unlikely to affect the results. By convention, in most studies of subarachnoid hemorrhage, patients with HH or WFNS grades 1 to 3 have been pooled under “good” clinical condition and those with HH or WFNS grades 4 and 5 have been categorized under the “poor” category irrespective of the scale used. For the assessment of outcome, Glasgow Outcome Scale grades 4 and 5 are more inclusive than the stricter mRS score of 0 to 2 and, if anything, this could make the conclusions stronger as some patients who would have been categorized under the “good” outcome category in the first decade of the study may have been classified under the “poor” outcome category in the past 2 decades. Unlike several other studies on this topic in which the diagnosis of aSAH could not be confirmed, or in which patients with other causes of subarachnoid hemorrhage were included, our study included the population that was homogeneous and included only patients with ruptured aneurysms. The
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availability of data on postdischarge functional outcome in our cohort also represents an improvement over previous studies.
10.
CONCLUSION Our results clearly indicate that outcomes in patients with aSAH have markedly improved over the past 3 decades, in terms of both in-hospital mortality rates and functional recovery of survivors. Higher rates of endovascular coiling over time paralleled these improvements in clinical outcomes, but a more detailed investigation is necessary to determine whether this or other factors may directly explain the favorable trends in survival and functional recovery over time.
11.
Abbreviations and Acronyms: aSAH = aneurysmal subarachnoid hemorrhage; CT = computed tomography; HH = Hunt and Hess; mRS = modified Rankin Scale; WFNS = World Federation of Neurosurgical Societies
15.
Potential Competing Interests: Dr Rabinstein has received grants from DJO Global and royalties from Elsevier, Oxford, and UptoDate. Dr Lanzino is a consultant for Medtronic. The rest of the authors report no competing interests.
17.
Correspondence: Address to Giuseppe Lanzino, MD, Department of Neurologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (lanzino.giuseppe@mayo. edu).
19.
12.
13.
14.
16.
18.
20. 21.
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outcomes in patients with subarachnoid hemorrhage after initiation of neurointensivist co-management. J Neurosurg. 2010;112(3):626-630. 31. Lerch C, Yonekawa Y, Muroi C, Bjeljac M, Keller E. Specialized neurocritical care, severity grade, and outcome of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2006; 5(2):85-92. 32. Samuels O, Webb A, Culler S, Martin K, Barrow D. Impact of a dedicated neurocritical care team in treating patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;14(3): 334-340.
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Time Trends in Outcomes After Aneurysmal Subarachnoid Hemorrhage Over the Past 30 Years Biagia La Pira, MD; Tarun D. Singh, MBBS; Alejandro A. Rabinstein, MD; and Giuseppe Lanzino, MD Abstract Objective: To analyze trends in mortality rates, functional outcomes, and treatment in patients with aneurysmal subarachnoid hemorrhage (aSAH) over the past 3 decades. Patients and Methods: We conducted a retrospective review of consecutive patients with aSAH treated at Mayo Clinic in Rochester, Minnesota, between January 1, 1985, and December 31, 2014. Results: A total of 1173 patients identified were grouped by decade of treatment: 1985 to 1994, n¼274; 1995 to 2004, n¼461; and 2005 to 2014, n¼438. Overall, the use of endovascular techniques increased progressively from 5.1% (14) in 1985 to 1994 to 65.5% (287) in 2005 to 2014. This corresponded to a progressive decrease in the rate of clipping from 78.8% (216) in 1985 to 2004 to 21.5% (94) in 2005 to 2014 (P<.001). The percentage of patients admitted with poor clinical grade also increased from 22.3% (61) in 1985 to 1994 to 24.1% (111) in 1995 to 2004 and 29.5% (129) in 2005 to 2014 (P¼.06). The inhospital mortality rate decreased from 22.6% (62) in 1985 to 1994 to 16.3% (75) in 1995 to 2004 and remained relatively constant at 16.7% (73) in 2005 to 2014. Good functional outcome at 3- to 6-month follow-up improved significantly from 64.8% (173) in 1985 to 1994 to 72% (332) in 1995 to 2004 and 78.8% (345) in 2005 to 2014 (P<.001). Conclusion: Outcomes in patients with aSAH have markedly improved over the past 3 decades, in terms of both in-hospital survival and functional recovery of survivors. Higher rates of endovascular coiling over time paralleled these improvements in clinical outcomes. More detailed investigation is necessary to determine whether this or other factors may directly explain the favorable trends in survival and functional recovery over time. ª 2018 Mayo Foundation for Medical Education and Research From the Department of Neurologic Surgery (B.L.P., G.L.), Department of Neurology (T.D.S., A.A.R.), and Department of Radiology (G.L.), Mayo Clinic, Rochester, MN.
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uring the past 3 decades, the management of aneurysmal subarachnoid hemorrhage (aSAH) has changed substantially. Early treatment of the ruptured aneurysm has decreased the incidence of rebleeding,1 and the development of coiling has provided a valid alternative to clipping.2,3 In addition, progress in neurocritical care and better understanding of the pathophysiology of delayed cerebral ischemia have improved our ability to minimize ischemic sequelae.4 Despite these advances, however, little information is available on their effects on the overall outcomes in patients with aSAH. Some population-based studies have reported decreasing case-fatality rates,5-13 but there are scant data on trends in functional outcomes over time. In the present study, we analyzed
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trends in mortality rates and functional outcomes at a single tertiary care institution over the past 3 decades. PATIENTS AND METHODS Patient Consent The study was approved by the Mayo Clinic Institutional Review Board. All included patients or their representatives had signed a general informed consent form allowing their medical records to be used for research purposes. Study Design We conducted a retrospective review of all consecutive patients with aSAH who were treated at Mayo Clinic in Rochester,
Mayo Clin Proc. n December 2018;93(12):1786-1793 n https://doi.org/10.1016/j.mayocp.2018.06.027 www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research
OUTCOMES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE
Minnesota, between January 1, 1985, and December 31, 2014. Study Definitions Subarachnoid hemorrhage was diagnosed by computed tomography (CT) of the head or by a finding of cerebrospinal fluid xanthochromia in case of negative CT findings but a history suggestive of aSAH. Patients were included only if an aneurysm was documented by a vascular study (usually catheter angiography) and if they had been admitted to the hospital within 48 hours of symptom onset. We excluded patients with angiographically negative aSAH and those with subarachnoid hemorrhage secondary to an arteriovenous malformation. Patients with a final diagnosis of aSAH were initially identified using our electronic data search system, and the diagnosis was confirmed by manual review of the medical records. Collected Variables and Study Definitions Electronic health records of patients were abstracted for patient demographic characteristics, World Federation of Neurosurgical Societies (WFNS) and Hunt and Hess (HH) grading of aSAH at initial evaluation, location of the aneurysm, type of treatment, rebleeding, symptomatic vasospasm or delayed cerebral ischemia, in-hospital death, outcome at discharge, and outcome at 3- to 6-month follow-up. Clinical aSAH severity was classified using the HH scale during the first decade (19851994) and the WFNS scale during the last 2 decades (1995-2004 and 2005-2014). Poor clinical grade was defined as grade 4 or 5 on either scale. Location of the ruptured aneurysm was classified as anterior circulation (anterior communicating artery, anterior cerebral artery, pericallosal artery, middle cerebral artery, internal carotid artery, posterior communicating artery, or ophthalmic artery) or posterior circulation (vertebral artery, basilar artery, or posterior cerebral artery). Rebleeding was defined as a documented increase in the previous amount of aSAH, increased blood in the ventricular system on repeat head CT in the presence of sudden neurological deterioration, or both. Symptomatic vasospasm was defined as documented vasospasm (by ultrasonographic or Mayo Clin Proc. n December 2018;93(12):1786-1793 www.mayoclinicproceedings.org
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angiographic criteria) associated with otherwise unexplained neurological decline.14 Delayed cerebral ischemia was defined as symptomatic vasospasm or the appearance of new infarction on CT or magnetic resonance imaging attributable to vasospasm, thus excluding periprocedural complications. For the purpose of the analysis, delayed ischemia is defined as the combination of symptomatic vasospasm and delayed cerebral ischemia. Clinical outcome was categorized at discharge and at 3 to 6 months after discharge using the Glasgow Outcome Scale (during 1985-1994), with good outcome defined as a score of 4 or 5, or using the modified Rankin Scale (mRS; during 1995-2014), with good outcome defined as a score of 0 to 2. Statistical Analyses Patients were grouped by decade for comparative analyses: 1985 to 1994, 1995 to 2004, and 2005 to 2014. Analyses were also performed with year as a continuous variable to identify a possible single year interval during which major changes could have occurred. Grouping patients in the 3 decades is based on the major changes occurring in the interval under study: increasing role of endovascular therapy for patients at high surgical risk in the mid-1990s and publication of the results of the International Subarachnoid Aneurysm Trial in 2002 to 2004. Descriptive summaries were reported as medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and the 2-sample t test or Kruskal-Wallis test was used for continuous variables, as applicable. Outcomes of interest were in-hospital death and functional outcome. All tests were 2-sided, and P values less than .05 were considered statistically significant. Statistical analyses were performed with JMP 12.0.0 (SAS Institute Inc.). RESULTS Our search identified, after exclusions, 1173 patients with aSAH seen from 1985 to 1994 (n¼274), 1995 to 2004 (n¼461), and 2005 to 2014 (n¼438). Patient demographic characteristics, worse severity of aSAH at the initial evaluation (grades 4 and 5), and location of
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the ruptured aneurysm are summarized in the Table. During the study period, the median age increased slightly from 53 (44-65) to 55 (47-64) years. There was also a progressive increase in the percentage of patients admitted with poor clinical grade, from 22.3% (61) in 1985 to 1994 to 111 (24.1%) in 1995 to 2004 and 29.5% (129) in 2005 to 2014, although the difference did not reach statistical significance (P¼.06). Treatment modalities used during the 3 time periods are presented in Figure 1. Overall, there was a progressive increase in the use of endovascular techniques from 14 (5.1%) in 1985 to 1994 to 287 (65.5%) in 2005 to 2014. This corresponded to a progressive decrease in the rate of clipping from 216 (78.8%) in 1985 to 2004 to 94 (21.5%) in 2005 to 2014 (P<.001). The rate of rebleeding remained constant across the 3 decades (P¼.52) (Table). The rate of delayed ischemia increased from 97 (35.4%) in 1985 to 1994 to 199 (43.2%) in 1995 to 2004 and then decreased again to 149 (34%) in 2005 to 2014. The inhospital mortality rate decreased from 62 (22.6%) in 1985 to 1994 to 73 (16.7%) in 2005 to 2014 (P¼.07) (Figure 2). Among patients who survived hospitalization, the number of patients who completed follow-up in the first, second, and third decade was 184 (85.8%), 244 (63.2%), and 216 (59.2%), respectively. Good functional
outcome at 3- to 6-month follow-up improved significantly from 173 (64.8%) in 1985 to 1994 to 345 (78.8%) in 2005 to 2014 (P<.001). The percentage of patients with good functional outcome at follow-up increased over time in patients with aneurysms in the anterior and posterior circulation (P¼.03 and P¼.04, respectively) (Figure 3). Analysis of outcome using time as a continuous variable did not identify any specific time point at which a significant change was noted. In patients admitted with good clinical grade, functional survival significantly improved over time (P<.001), although mortality did not (P¼.11). In patients admitted with poor clinical grade, there was a significant improvement in both functional outcome (P¼.008) and mortality (P¼.02) across the decades studied. DISCUSSION In a review of outcomes after aSAH at our institution over the past 30 years, we found decreased case-fatality rates, constant rates of early rebleeding, increased use of endovascular techniques, and improved rates of good functional outcome, despite an increasing percentage of patients being admitted in poor neurological condition. Population-based studies have reported improved case-fatality rates after aSAH over time.5-13 In patients in Australia and New Zealand admitted to the intensive care unit with
TABLE. Patient and Aneurysm Characteristicsa,b Time period 1985-1994 (n¼274)
1995-2004 (n¼461)
2005-2014 (n¼438)
P value
Age (y)
Characteristic
53 (44-65)
55 (46-66)
55 (47-64)
.21
Men
91 (33.2)
161 (34.9)
c
156 (35.6)
d
d
.80
61 (22.3)
111 (24.1)
129 (29.5)
.06
(n¼271) 202 (74.5) 61 (22.5) 8 (3.0)
(n¼452) 313 (69.2) 136 (30.1) 3 (0.7)
(n¼429) 324 (75.5) 102 (23.8) 3 (0.7)
.009
Rebleeding
29 (10.6)
56 (12.1)
58(13.2)
.52
Delayed ischemia (symptomatic vasospasm or DCI)
97 (35.4)
199 (43.2)
149 (34.0)
.01
Poor clinical grade Location of aneurysm AC PC Both
AC ¼ anterior circulation; DCI ¼ delayed cerebral ischemia; PC ¼ posterior circulation. b Data are presented as median (interquartile range) or as No. (percentage). c Classified as Hunt and Hess scale grade of 4 or 5 (vs 1-3). d Classified as World Federation of Neurosurgical Societies grade of 4 or 5 (vs 1-3). a
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Percentage
Clipping 90 80 70 60 50 40 30 20 10 0
Coiling
78.8 65.5 57.9
32.3 21.5 5.1
1985-1994
1995-2004
2005-2014
Years
FIGURE 1. Percentage of patients undergoing clipping and coiling in the 3 time periods.
aSAH, the case-fatality rate decreased from 35.4% in 2000 to 27.2% in 2015.13 Similarly, in a study of patients hospitalized in Scotland between 1986 and 2005, Macpherson et al8 reported a decreasing case-fatality rate over time, especially in those aged 40 to 59 years. Among patients aged 40 to 49 years, the case-fatality rate decreased from 30% in 1986 to 1990 to 21.4% in 2001 to 2005 in men and from 32.6% to 18.8% in women. These observations were mirrored in a population-based study in the United States, which reported progressive decreases from
Percentage
Hospital mortality Good functional outcome at last follow up 90 80 70 60 50 40 30 20 10 0
78.8 72 64.8
22.6
1985-1994
16.3
16.7
1995-2004
2005-2014
Years
FIGURE 2. Percentage of patients with good functional outcome and in-hospital death in the 3 time periods.
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1988 through 2010 in all-cause 5-day, 30-day, and 90-day case-fatality rates.7 In agreement with these trends in populationbased studies, we also observed a progressive decrease in in-hospital mortality rate from 22.6% (62) in 1985 to 1994 to 16.3% (75) in 1995 to 2004, with subsequent stability at 16.7% (73) in 2005 to 2014. Mortality rates provide an objective, albeit crude, outcome assessment. However, in a disease such as aSAH, which often affects young persons with many years of productive life ahead of them, it is important to understand whether improved survival rates are accompanied by better functional outcomes in survivors. In our series, good functional outcome within 3 to 6 months after aSAH improved consistently, from 64.8% (173) in 1985 to 1994 to 72% (332) in 1995 to 2004 and 78.8% (345) in 2005 to 2014. This considerable improvement in functional outcome is even more remarkable considering that it occurred despite a substantial increase in the percentage of patients admitted in poor neurological condition, from 22.3% (61) in 1985 to 1994 to 24.1% (111) in 1995 to 2004 and 29.5% (129) in 2005 to 2014. This information on changes in functional outcome over time after aSAH is novel, because data are scant on this topic. In residents of the Greater Cincinnati/Northern Kentucky region admitted with aSAH, the median mRS score at discharge decreased markedly from 5 to 3 between 1988 and 2010,7 although this study did not provide information on functional recovery after discharge. Changes in the Management of aSAH That May Have Led to Better Outcomes In the past 30 years, the management of aSAH has undergone several changes that may have contributed to this improvement in outcomes. In the early 1990s, publication of the results of the International Cooperative Study on the Timing of Aneurysm Surgery1 and improving microneurosurgical techniques generated a shift toward earlier surgery to secure the ruptured aneurysm. Early surgery decreases the incidence of rebleeding (an often deadly complication of aSAH) and allows more aggressive treatment of vasospasm.1 Comparing causes of in-hospital death within the same institution in 2 time periods (1999-2002 and
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90
AC
PC 80.4
Percentage
80
79.9
75
70 60
67
72.2
62.5
50 1985-1994
1995-2004 Years
2005-2014
FIGURE 3. Percentage of patients with good functional outcome at follow-up in the 3 time periods for patients with either anterior circulation (AC) (P¼.03) or posterior circulation (PC) (P¼.04) aneurysms.
2009-2012), Vergouwen et al15 observed a significant decrease in 90-day case-fatality rate, from 39% in 1999 to 2002 to 30% in 2009 to 2012, which was ascribed in part to a decrease in the incidence of in-hospital rebleeding from 24% to 17% in the 2 periods. This decrease in the incidence of rebleeding coincided with earlier treatment of aneurysms (median day decreased from day 4 to day 1).15 In our study, the incidence of rebleeding did not change over time, but this may be related to our center being highly specialized in microsurgery and one of the first centers in the world to adopt early aneurysm repair to prevent rebleeding.16 Therefore, the improved outcome and casefatality rates observed in our study are not related to decreased rates of rebleeding. The next major change in the management of aSAH occurred in 1990, with the introduction in the United States of Guglielmi detachable coils17 for the treatment of cerebral aneurysms, as part of a US Food and Drug Administration investigational device exemption, and its subsequent approval in 1995 for the treatment of patients at high surgical risk. Consequently, coil embolization throughout the 1990s was reserved primarily for patients at high surgical risk, such as those with posterior circulation aneurysms, those with medical comorbid conditions, and those in poor neurological condition at admission.18 This shift may have been a main contributor to the important decrease in mortality rate we observed from 1790
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the first decade (22.6%; 62) to the second decade (16.3%). As development of less invasive neuroendovascular techniques has encouraged a more aggressive approach to poor grade aSAH, other authors have also observed decreasing mortality rates for patients with poor grade aneurysms.19-21 Lantigua et al20 noted a 20% absolute risk reduction for inhospital death in patients with worse clinical grades (over the course of the study, 19962009), although the mortality rate for those with less severe disease remained constant. Similarly, Konczalla et al19 observed a decrease in 30-day mortality rate in patients with grade 5 aSAH, from 83% in 1980 to 1995 (“precoiling era” at their institution) to 39% in 2005 to 2014. In 1994, the International Subarachnoid Aneurysm Trial, a prospective randomized trial comparing endovascular coil embolization with surgical clipping for acutely ruptured aneurysms, was initiated and then conducted mostly in the United Kingdom. In 2002, the trial was halted after an interim analysis revealed that patients assigned to the endovascular arm had better 1-year functional outcomes than did patients in the open surgery arm.22 Publication of the preliminary results of the trial in 2002 and definitive results in 2005 established the legitimacy of endovascular coil embolization, not only for patients with ruptured aneurysms considered candidates at high surgical risk but also for other patients with aneurysms amenable to coil embolization.2,3,22,23 The results of the International Subarachnoid Aneurysm Trial led to a progressive increase in the proportion of patients treated with endovascular coil embolization. Meanwhile, the introduction of intraoperative microvascular Doppler ultrasonography and intraoperative indocyanine green angiography has allowed refinement of open surgical techniques. These developments have generated a new paradigm using which case-by-case decisions are made by a team of specialists with endovascular and open surgical expertise to select the best treatment option (balancing efficacy against risk of each therapeutic modality) for each patient.24 In our study, the rate of coiling increased progressively over time, from 5.1% (14) in 1985 to 1994 to 32.3% in 1995 to 2004 and
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65.5% (287) in 2005 to 2014. Recent studies have also found progressive increases in the rate of ruptured aneurysms treated with coiling, with an associated improvement in casefatality rates.7,25 For instance, Mackey et al7 observed that the percentage of patients with subarachnoid hemorrhage in their population undergoing coiling increased from 0% in 1993 to 1994 to 13% in 2010. Neurocritical Care and Better Understanding of aSAH and Its Complications Aneurysmal subarachnoid hemorrhage is one of the most complex acute conditions a physician may encounter. Outcome is largely affected by the damage that occurs at the time of the original hemorrhage, but in the first 2 to 3 weeks, patients are exposed to the danger of secondary injury from neurological complications (eg, rebleeding, delayed cerebral ischemia from vasospasm, increased intracranial pressure, and hydrocephalus), systemic complications, pulmonary complications,26 cardiovascular complications,27 fluid shifts and hyponatremia,18 and complications associated with a prolonged intensive care unit stay in a severely ill patient.4 The evolution in our understanding of the pathophysiology of aSAH and its complications and improvements in critical care over the past 30 years are factors that may have contributed to better outcomes for our patients. In particular, there has been a progressive shift toward the inclusion of neurointensivists in the management of aSAH in dedicated neurocritical care units.7 The establishment of such units has led to a population of physicians and nurses trained to minimize the risk of secondary brain damage.28 Several studies have found that involvement of neurointensivists in the management of aSAH in specialized neurocritical care units is associated with improved mortality rates and functional outcomes.29-32 Study Limitations Our study has limitations inherent to its retrospective design. However, all patients, regardless of the initial clinical grade, were admitted to the neurological intensive care unit throughout the entire study period and treated in the hyperacute phase by a limited number of specialists (4 interventional neuroradiologists, 7 neurosurgeons with major subspecialty Mayo Clin Proc. n December 2018;93(12):1786-1793 www.mayoclinicproceedings.org
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interest in cerebrovascular disorders, and 5 neurointensivists). Therefore, clinical grading and assessment of rebleeding and delayed ischemia were relatively consistent over time. Greater availability of magnetic resonance imaging, noninvasive angiography, and CT perfusion, however, has probably increased our sensitivity for the detection of delayed cerebral ischemia in more recent years. More sensitive detection of ischemia in the past 2 decades of our study period may have underestimated favorable changes in the rates of ischemia compared with the first decade. Our analysis did not include other relevant factors, such as radiological grade to assess the risk of vasospasm, comorbid conditions, and acute systemic complications. However, these deficiencies should not affect our main results. Our findings may be affected by referral bias, but we tried to limit this by considering only patients admitted within 48 hours from their ictus and therefore more likely to come from our direct catchment area. Using HH scale and Glasgow Outcome Scale in the first decade and WFNS and mRS scores of 0 to 2 in the second and third decades under study for clinical grade at admission and definition of good outcome may introduce some variability. However, we think that this is unlikely to affect the results. By convention, in most studies of subarachnoid hemorrhage, patients with HH or WFNS grades 1 to 3 have been pooled under “good” clinical condition and those with HH or WFNS grades 4 and 5 have been categorized under the “poor” category irrespective of the scale used. For the assessment of outcome, Glasgow Outcome Scale grades 4 and 5 are more inclusive than the stricter mRS score of 0 to 2 and, if anything, this could make the conclusions stronger as some patients who would have been categorized under the “good” outcome category in the first decade of the study may have been classified under the “poor” outcome category in the past 2 decades. Unlike several other studies on this topic in which the diagnosis of aSAH could not be confirmed, or in which patients with other causes of subarachnoid hemorrhage were included, our study included the population that was homogeneous and included only patients with ruptured aneurysms. The
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availability of data on postdischarge functional outcome in our cohort also represents an improvement over previous studies.
10.
CONCLUSION Our results clearly indicate that outcomes in patients with aSAH have markedly improved over the past 3 decades, in terms of both in-hospital mortality rates and functional recovery of survivors. Higher rates of endovascular coiling over time paralleled these improvements in clinical outcomes, but a more detailed investigation is necessary to determine whether this or other factors may directly explain the favorable trends in survival and functional recovery over time.
11.
Abbreviations and Acronyms: aSAH = aneurysmal subarachnoid hemorrhage; CT = computed tomography; HH = Hunt and Hess; mRS = modified Rankin Scale; WFNS = World Federation of Neurosurgical Societies
15.
Potential Competing Interests: Dr Rabinstein has received grants from DJO Global and royalties from Elsevier, Oxford, and UptoDate. Dr Lanzino is a consultant for Medtronic. The rest of the authors report no competing interests.
17.
Correspondence: Address to Giuseppe Lanzino, MD, Department of Neurologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (lanzino.giuseppe@mayo. edu).
19.
12.
13.
14.
16.
18.
20. 21.
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25. Brinjikji W, Lanzino G, Rabinstein AA, Kallmes DF, Cloft HJ. Age-related trends in the treatment and outcomes of ruptured cerebral aneurysms: a study of the nationwide inpatient sample 2001-2009. AJNR Am J Neuroradiol. 2013; 34(5):1022-1027. 26. Friedman JA, Pichelmann MA, Piepgras DG, et al. Pulmonary complications of aneurysmal subarachnoid hemorrhage. Neurosurgery. 2003;52(5):1025-1031; discussion 1031-1032.
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27. Dupont SA, Wijdicks EF, Lanzino G, Rabinstein AA. Aneurysmal subarachnoid hemorrhage: an overview for the practicing neurologist. Semin Neurol. 2010;30(5):545-554. 28. Kramer AH, Zygun DA. Do neurocritical care units save lives? Measuring the impact of specialized ICUs. Neurocrit Care. 2011; 14(3):329-333. 29. Cesarini KG, Hårdemark HG, Persson L. Improved survival after aneurysmal subarachnoid hemorrhage: review of case management during a 12-year period. J Neurosurg. 1999;90(4):664-672. 30. Josephson SA, Douglas VC, Lawton MT, English JD, Smith WS, Ko NU. Improvement in intensive care unit
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outcomes in patients with subarachnoid hemorrhage after initiation of neurointensivist co-management. J Neurosurg. 2010;112(3):626-630. 31. Lerch C, Yonekawa Y, Muroi C, Bjeljac M, Keller E. Specialized neurocritical care, severity grade, and outcome of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2006; 5(2):85-92. 32. Samuels O, Webb A, Culler S, Martin K, Barrow D. Impact of a dedicated neurocritical care team in treating patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;14(3): 334-340.
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