Outcome after Hunt and Hess Grade V subarachnoid hemorrhage: a comparison of pre-coiling era (1980–1995) versus post-ISAT era (2005–2014)

Juergen Konczalla MD, PhD, Volker Seifert MD, PhD, Juergen Beck MD, PhD, Erdem Güresir MD, PhD, Hartmut Vatter MD, PhD, Andreas Raabe MD, PhD, and Gerhard Marquardt MD, PhD
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  • Department of Neurosurgery, Goethe-University Hospital, Frankfurt am Main, Germany
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OBJECTIVE

Outcome analysis of comatose patients (Hunt and Hess Grade V) after subarachnoid hemorrhage (SAH) is still lacking. The aims of this study were to analyze the outcome of Hunt and Hess Grade V SAH and to compare outcomes in the current period with those of the pre–International Subarachnoid Aneurysm Trial (ISAT) era as well as with published data from trials of decompressive craniectomy (DC) for middle cerebral artery (MCA) infarction.

METHODS

The authors analyzed cases of Hunt and Hess Grade V SAH from 1980–1995 (referred to in this study as the earlier period) and 2005–2014 (current period) and compared the results for the 2 periods. The outcomes of 257 cases were analyzed and stratified on the basis of modified Rankin Scale (mRS) scores obtained 6 months after SAH. Outcomes were dichotomized as favorable (mRS score of 0–2) or unfavorable (mRS score of 3–6). Data and number needed to treat (NNT) were also compared with the results of decompressive craniectomy (DC) trials for middle cerebral artery (MCA) infarctions.

RESULTS

Early aneurysm treatment within 72 hours occurred significantly more often in the current period (in 67% of cases vs 22% in earlier period). In the earlier period, patients had a significantly higher 30-day mortality rate (83% vs 39% in the current period) and 6-month mortality rate (94% vs 49%), and no patient (0%) had a favorable outcome, compared with 23% overall in the current period (p < 0.01, OR 32), or 29.5% of patients whose aneurysms were treated (p < 0.01, OR 219). Cerebral infarctions occurred in up to 65% of the treated patients in the current period.

Comparison with data from DC MCA trials showed that the NNTs were significantly lower in the current period with 2 for survival and 3 for mRS score of 0–3 (vs 3 and 7, respectively, for the DC MCA trials).

CONCLUSIONS

Early and aggressive treatment resulted in a significant improvement in survival rate (NNT = 2) and favorable outcome (NNT = 3 for mRS score of 0–3) for comatose patients with Hunt and Hess Grade V SAH compared with the earlier period. Independent predictors for favorable outcome were younger age and bilateral intact corneal reflexes. Despite a high rate of cerebral infarction (65%) in the current period, 29.5% of the patients who received treatment for their aneurysms during the current era (2005–2014) had a favorable outcome. However, careful individual decision making is essential in these cases.

ABBREVIATIONS

ARR = absolute risk reduction; CVS = cerebral vasospasm; DC = decompressive craniectomy; DCI = delayed cerebral ischemia; EVD = external ventricular drain; GCS = Glasgow Coma Scale; ICH = intracerebral hematoma; ICU = intensive care unit; ISAT = International Subarachnoid Aneurysm Trial; MCA = middle cerebral artery; mRS = modified Rankin Scale; NNT = number needed to treat; PERRLA = pupils equal, round, and reactive to light and accommodation; SAH = subarachnoid hemorrhage; WFNS = World Federation of Neurosurgical Societies.

OBJECTIVE

Outcome analysis of comatose patients (Hunt and Hess Grade V) after subarachnoid hemorrhage (SAH) is still lacking. The aims of this study were to analyze the outcome of Hunt and Hess Grade V SAH and to compare outcomes in the current period with those of the pre–International Subarachnoid Aneurysm Trial (ISAT) era as well as with published data from trials of decompressive craniectomy (DC) for middle cerebral artery (MCA) infarction.

METHODS

The authors analyzed cases of Hunt and Hess Grade V SAH from 1980–1995 (referred to in this study as the earlier period) and 2005–2014 (current period) and compared the results for the 2 periods. The outcomes of 257 cases were analyzed and stratified on the basis of modified Rankin Scale (mRS) scores obtained 6 months after SAH. Outcomes were dichotomized as favorable (mRS score of 0–2) or unfavorable (mRS score of 3–6). Data and number needed to treat (NNT) were also compared with the results of decompressive craniectomy (DC) trials for middle cerebral artery (MCA) infarctions.

RESULTS

Early aneurysm treatment within 72 hours occurred significantly more often in the current period (in 67% of cases vs 22% in earlier period). In the earlier period, patients had a significantly higher 30-day mortality rate (83% vs 39% in the current period) and 6-month mortality rate (94% vs 49%), and no patient (0%) had a favorable outcome, compared with 23% overall in the current period (p < 0.01, OR 32), or 29.5% of patients whose aneurysms were treated (p < 0.01, OR 219). Cerebral infarctions occurred in up to 65% of the treated patients in the current period.

Comparison with data from DC MCA trials showed that the NNTs were significantly lower in the current period with 2 for survival and 3 for mRS score of 0–3 (vs 3 and 7, respectively, for the DC MCA trials).

CONCLUSIONS

Early and aggressive treatment resulted in a significant improvement in survival rate (NNT = 2) and favorable outcome (NNT = 3 for mRS score of 0–3) for comatose patients with Hunt and Hess Grade V SAH compared with the earlier period. Independent predictors for favorable outcome were younger age and bilateral intact corneal reflexes. Despite a high rate of cerebral infarction (65%) in the current period, 29.5% of the patients who received treatment for their aneurysms during the current era (2005–2014) had a favorable outcome. However, careful individual decision making is essential in these cases.

ABBREVIATIONS

ARR = absolute risk reduction; CVS = cerebral vasospasm; DC = decompressive craniectomy; DCI = delayed cerebral ischemia; EVD = external ventricular drain; GCS = Glasgow Coma Scale; ICH = intracerebral hematoma; ICU = intensive care unit; ISAT = International Subarachnoid Aneurysm Trial; MCA = middle cerebral artery; mRS = modified Rankin Scale; NNT = number needed to treat; PERRLA = pupils equal, round, and reactive to light and accommodation; SAH = subarachnoid hemorrhage; WFNS = World Federation of Neurosurgical Societies.

A substantial proportion of patients with subarachnoid hemorrhage (SAH) are in very poor clinical condition at presentation, but most of the data on the outcome of SAH for such patients are derived from studies that include patients with Hunt and Hess Grades IV and V SAH and/or World Federation of Neurosurgical Societies (WFNS) Grades IV and V,3,27,33 resulting in a very heterogeneous group, with Glasgow Coma Scale (GCS) scores potentially ranging from 3 to 12. In addition, there are currently no guidelines or consensus for the treatment of comatose SAH patients. Whether comatose patients should be treated, how they should be treated (conservatively or with clip ligation or coil embolization), and the timing of treatment (early or late) are all controversial, and there is a need for reliable data on outcomes of treatment strategies for these patients. We therefore reviewed our collected data on patients treated at Goethe-University Hospital to determine whether early and aggressive treatment (our current practice) is worthwhile in patients with Grade V SAH. We compared the data from the current period with data from an earlier period when patients were treated conservatively and also with the results of a meta-analysis of the prospective trials for decompressive craniectomy (DC) after malignant middle cerebral artery (MCA) infarction (randomized within 48 hours: HAMLET, DECIMAL, DESTINY)11 to investigate whether the SAH guidelines should possibly be revised. Also, multivariate analysis of data from the current period was performed to assess predictors of favorable outcome.

Methods

Study Design

Data from cases involving patients treated in our center between 1980 and 1995 (early period) were compared with data from patients treated during the current period (2005–2014). Between 1980 and 2014, over 2500 patients with SAH were admitted to our institution. Of those 2500 patients, 1828 were admitted during the periods covered by this study, and 257 (14%) of those 1828 had Hunt and Hess Grade V SAH. The data from those 257 cases (54 from the early period and 203 from the current period) were analyzed for this study. For the early period, the data were obtained from regular patient records. For the current period, the data were obtained from a prospectively designed database of neurovascular cases. SAH was confirmed on CT and/or lumbar puncture.17 Basic demographic data and clinical data (neurological admission status according to Hunt and Hess grade, treatment, clinical course, and outcome according to the modified Rankin Scale [mRS]) were collected. The study was approved by the local ethics committee.

Only patients who were comatose on admission (i.e., those with Hunt and Hess Grade V SAH) were included in the analysis. All patients who showed an improvement in Hunt and Hess grade within 24 hours were excluded. If aneurysm treatment was performed within 24 hours after external ventricular drain (EVD) insertion, clinical improvement to a better Hunt and Hess grade on the day after treatment led to a revision and patient exclusion. Data were compared between the 2 periods.

Patient Treatment

A more detailed description of our management of Hunt and Hess Grade V SAH is provided in the Supplemental Material. In the earlier period, a more conservative treatment strategy was followed; typically, in patients with devastating SAH and Hunt and Hess Grade V clinical status, the aneurysm was only treated at a later stage and only if the patient's condition improved. From 1999 on, an early and aggressive treatment strategy was followed. Only a minority of patients with an inoperable status received no further aneurysm treatment. Patients with a unilateral dilated pupil or those who had been successfully resuscitated received an EVD; in these cases, the patients' clinical status was reassessed (with re-evaluation of Hunt and Hess grade) after EVD insertion, and the decision of whether or not to undertake aneurysm treatment was made on an interdisciplinary basis.17,18,23,24

Outcome

Outcomes were compared between the early and current treatment periods. In the current period (prospective database), outcome was assessed 6 months after ictus by study nurses or physicians from the neurosurgical department. For the earlier period, the outcome was assessed retrospectively from medical records according to the modified Rankin Scale (mRS). The outcomes were stratified into favorable (mRS score of 0–2) and unfavorable (mRS score of 3–6).

Due to the complexity of cerebral vasospasm (CVS) detection in unconscious patients, imaging was routinely performed on Day 7 ± 2 (see Supplemental Material). Infarctions seen in the post-treatment CT were considered to be treatment related and were not considered to be delayed cerebral infarctions. We divided cerebral infarctions into 4 groups (vascular distribution, watershed stroke, cortical ischemia, and multiple infarctions) to make our data more comparable, because CVS in an unknown number of instances could be undetected.

Statistical Analysis

Unpaired t-tests were used for parametric statistics. Categorical variables were analyzed in contingency tables using chi-square and Fisher exact tests. Results with a p value less than 0.05 were considered statistically significant. All calculations were made with standard commercial software (IBM SPSS). Absolute risk reduction (ARR) and number needed to treat (NNT) were calculated with the early period as reference.

Subsequently, a multivariate analysis was performed on data from current-period cases in which aneurysms were treated to identify independent predictors of favorable outcome after 6 months and to find confounding effects between potentially independent predictors. Variables from univariate analyses were considered to be potentially independent factors in multivariate analysis. A backward stepwise method was used to construct a multivariate logistic regression model in relation to favorable outcome as a dependent variable with an inclusion criterion of p < 0.1.

Comparison With DC After Malignant MCA Stroke

Outcome and NNT were then compared with findings of a meta-analysis of the prospective trials for DC after MCA infarction (randomized within 48 hours: HAMLET,11 DECIMAL,30 and DESTINY13) that was included in the 2009 report of the HAMLET results.11 In these trials a favorable outcome was defined as an mRS score of 0–3. For comparison, only patients with Hunt and Hess Grade V SAH treated within 48 hours were selected, and NNT for survival and favorable outcome (mRS score of 0–3) were calculated. For the ARR and NNT, the 1-year meta-analysis data were used. For outcome analysis, as for the SAH data, the 6-month data were used, except for the HAMLET trial, which only published 1-year outcome data.

The DC MCA trials had restrictive inclusion and exclusion criteria (Supplemental Material). Only patients randomized within 48 hours were included in the meta-analysis. Every patient had to be younger than 61 years, and the majority of patients were not unconscious in these trials. Also, all patients with conditions that could confound treatment assessment (e.g., those who required resuscitation) as well as all patients who had bilateral fixed and dilated pupils were excluded.

Results

Outcome in the Earlier Period

Patient characteristics are summarized in Table 1.

TABLE 1.

Comparison of patient characteristics from the pre-coiling era (earlier period) and post-ISAT era (current period)

CharacteristicEarlier Period (1980–1995)Current Period (2005–2014)p Value*OR (95% CI)
H & H Grade V SAH54 of 654 (8%)203 of 1174 (17%)<0.00012.3 (1.7–3.2)
Aneurysm location
  ACA & distal10 (19%)61 (30%)NS
  MCA & distal13 (24%)49 (24%)NS
  ICA10 (19%)32 (16%)NS
  Posterior circulation4 (7%)41 (20%)<0.053.2 (1.1–9.3)
  No aneurysm1 (2%)7 (3%)NS
  Unknown16 (30%)13 (6%)<0.00016.2 (2.7–13.8)
EVD18 (33%)161 (79%)<0.00017.7 (4.0–14.8)
Early treatment w/in 72 hrs12 (22%)137 (67%)<0.00017.3 (3.6–14.7)
Late treatment2 (4%)2 (1%)NS
Mean age in yrs52.5 ± 13.457.5 ± 12.8<0.05
Hypertension18 (33%)53 (26%)NS
Fisher Grade 3 or 453 (98%)184 (91%)NS
Favorable outcome (mRS score of 0–2)0 (0%)46 (23%)<0.000132 (1.9–532)

ACA = anterior cerebral artery; H & H = Hunt and Hess; ICA = internal carotid artery; MCA = middle cerebral artery; NS = not statistically significant (p > 0.05).

Values represent numbers of patients unless otherwise indicated. Mean values are given with standard deviations.

Fisher exact test for categorical variables; unpaired t-test for continuous variables (age).

In the earlier period, 54 (8%) of 654 SAH patients had Grade V SAH; in 60% of the patients, aneurysms were located in the anterior circulation; in 7%, in the posterior circulation; and in 30%, diagnostic angiography was not performed. Eighteen patients (33%) in the earlier period received an EVD, and 40 (74%) of the 54 patients did not receive aneurysm treatment (Table 1).

Two patients were treated with late clipping during the earlier period, and both died within 3 months, whereas 2 of the 12 patients who were treated with clipping within the first 72 hours (the early clipping group) survived. During this period, the 30-day and 6-month mortality rates were both very high (83% and 94%, respectively), and no patient had a favorable outcome (mRS score of 0–2). Moreover, 37% of the patients (n = 20) died within the first 2 days, 65% (n = 35) within the 1st week, and 81% (n = 44) within 2 weeks. Three patients (6%) survived until 6 months' follow-up—one with an mRS score of 3 and two with mRS scores of 5.

The main cause of death was brain swelling/infarctions/brainstem areflexia in over 60% (n = 34) of cases, followed by rebleeding in 17% (n = 9). Fatal rebleeding occurred in 5 (56%) of 9 patients within the first week.

Outcome in the Current Period

In the current period, 203 (17%) of 1174 SAH patients were admitted with Grade V SAH (Table 1).

An EVD was inserted in 161 (79%) of 203 cases. The aneurysm was treated in 139 cases (68%)—within 48 hours in 134 of the cases (96%) and within 72 hours in 137 (99%). Only 1 of the 5 patients who underwent aneurysm treatment more than 48 hours after ictus had a favorable outcome (mRS score of 1); the other 4 patients died. Sixty-four (32%) of the patients received no aneurysm treatment. A total of 99 patients (49%) died before 6 months' followup. A favorable outcome was achieved in 23% of cases (n = 46) overall and in 29.5% of the cases (n = 41) in which the aneurysm was treated. The rate of favorable outcome was similar for clipping and coil embolization (28% vs 31%, respectively).

During the current period, 17% of patients (n = 35) died within the first 2 days after ictus, 29% (n = 59) within the 1st week, and 37% (n = 76) within 2 weeks. The overall survival rate at follow-up was 51% (n = 104) for all patients and 68% (n = 94) for those who received aneurysm treatment. Every patient had a GCS score less than 6 (range 3–5). Therefore, this group seems to be more homogeneous but is smaller than one would expect if the group had been selected based on a WFNS grade of V (GCS score range 3–6).

Comparison of Earlier and Current Periods

Patients were significantly younger in the earlier period than in the current period (52.5 vs 57.5 years, p < 0.05), and the proportion of SAH patients with Hunt and Hess Grade V SAH was significantly smaller (8% in the earlier period vs 17% in the current period, p < 0.001; Table 1). Both identification of the aneurysm location and insertion of an EVD occurred significantly less often in the earlier period, and 74% of patients did not receive any treatment (vs 32% in the current period, p < 0.0001). Early aneurysm treatment within 72 hours also occurred significantly less often (22% in the earlier period vs 67% in the current period, p < 0.0001). However, in both periods almost every comatose patient had Fisher Grade 3 or 4 hemorrhage.

The 30-day and 6-month mortality rates were both significantly higher in the earlier period than in the current period (30-day mortality 83% vs 39%, OR 7.7, p < 0.001; 6-month mortality 94% vs 49%, OR 17.9, p < 0.001). Whereas in the earlier period no patient (0%) had a favorable outcome (mRS score of 0–2), in the current period 23% of patients overall (p < 0.0001), and 29.5% of patients whose aneurysms were treated (p < 0.0001), had a favorable outcome (Table 2). In the earlier period, coil embolization was not available; however, in the current period, half of the treated patients underwent this treatment (p < 0.001), although as mentioned above, the rate of favorable outcome was similar for the 2 treatment modalities (28% for clipping vs 31% for coiling).

TABLE 2.

Comparison of survival, favorable outcome, ARR, and NNT depending on differences in treatment and era

VariableSurvivalp Value*OR (95% CI)Favorable Outcomep Value*OR (95% CI)
Current period, aneurysm treated vs not<0.000111.3 (5.3–24)<0.0014.9 (1.8–13)
  Treated (n = 139)94 (67.6%)41 (29.5%)
  Not treated (n = 64)10 (15.6%)5 (7.8%)
  ARR52.0%21.7%
  NNT2 (1.923)5 (4.612)
Current vs earlier period<0.000117.9 (5.4–59)<0.000141.8 (2.5–688)
  Current period (n = 203)104 (51.2%)46 (22.6%)
  Earlier period (n = 54)3 (5.6%)0 (0%)
  ARR45.7%22.6%
  NNT3 (2.189)5 (4.413)
Current vs earlier period, aneurysm treated w/in 72 hrs<0.00113 (2.8–61)<0.0510.8 (0.6–186)
  Current period (n = 137)94 (68.6%)41 (29.9%)
  Earlier period (n = 12)2 (16.7%)0 (0%)
  ARR51.9%29.9%
  NNT2 (1.925)4 (3.341)

Values represent numbers of patients unless otherwise indicated. NNT values are rounded up, with calculated NNT values shown in parentheses.

Fisher exact test for categorical variables.

Favorable outcome defined here as mRS score of 0–2.

In the current period, over 60% (n = 39) of the 64 patients who did not receive aneurysm treatment died due to swelling/infarctions/brainstem areflexia, and 19% (n = 12) died due to fatal rebleeding. The rates for these causes of death are similar to those observed in the earlier period.

Comparing the current with the earlier period, in the current period the ARR for survival was 46% for the overall group (all patients) (NNT = 3) and 52% for patients who received aneurysm treatment (NNT = 2). For favorable outcome (mRS score of 0–2), the NNT was 5 for all patients with Grade V SAH and 4 for the patients who received aneurysm treatment (see Table 2).

Comparison of Current Period With DC in Patients With MCA Infarction

A meta-analysis of DC in patients with MCA infarction randomized within 48 hours showed a survival rate of 79% and favorable outcome in 40% of the patients after 1 year.11 In that analysis, favorable outcome was defined as an mRS score of 0–3, and the author calculated an NNT of 2–3 for survival and 7 for favorable outcome.1 As presented in Table 3, patients with Grade V SAH (our current cohort) had a better rate of favorable outcome (42%), but a slightly reduced rate of survival (69%) compared with the surgically treated patients with MCA infarction in the meta-analysis (DC MCA group). However, the NNT was better in both groups than in the DC MCA group (2 for survival and 3 for favorable outcome instead of 3 and 7, respectively). The rate of achieving a favorable outcome, using the definition of an mRS score of 0–2, also was significantly better in the Grade V SAH group (Table 3 and Fig. 1B).

TABLE 3.

Comparison of NNT between our cohort of patients with Hunt and Hess Grade V SAH from the current period and surgically treated patients from the DC MCA trials

Favorable Outcome Groups Treated w/in 48 HrsDC MCA RCTs (n = 58)Our Current Period Cohort (n = 134)p Value*OR (95% CI)
Favorable outcome (mRS score of 0–2)2 (3.4%)40 (29.9%)<0.000111.9 (2.8–51)
Favorable outcome (mRS score of 0–3)18 (31.0%)56 (41.8%)NS
Survival46 (79.3%)93 (69.4%)NS
NNT favorable outcome (mRS score of 0–3)7 (6.201)3 (2.886)
NNT survival3 (2.004)2 (1.814)

RCT = randomized controlled trial.

Values represent numbers of patients unless otherwise indicated. Data for favorable outcome and survival are based on the 6-month data for DESTINY13 (n = 20) and DECIMAL30 (n = 17) and 12-month data for HAMLET11 (n = 21) (best available). For our own cohort, 6-month data were used, including only patients who were treated within 48 hours (n = 134). For more details see also Supplemental Material.

Fisher exact test for categorical variables.

1-year meta-analysis data.

FIG. 1.
FIG. 1.

A: Outcome after Hunt and Hess Grade V SAH. Patients' outcomes from the earlier and current periods are compared. The outcome was significantly better during current period. Whereas in the earlier period no patient (0%) had a favorable outcome (mRS score of 0–2), in the current period 23% of all patients (p < 0.0001, OR 32) and 29% of the patients who received treatment for their aneurysms (p < 0.0001, OR 219) had a favorable outcome. B: Outcome of Grade V SAH compared with DC MCA trials. The Grade V SAH group had a significantly better outcome as determined on the basis of mRS score, although there was a trend toward a higher mortality rate (p > 0.05). H&H V = Hunt and Hess Grade V; mRS = mRS score. Figure is available in color online only.

Outcome and Prognostic Factors of Current Period

Detailed characteristics of all 203 of our current-period Grade V SAH patients are presented in the Supplemental Material (Supplemental Table I). The distribution of aneurysm locations was similar in the treated or untreated subgroups (i.e., patients who did or did not receive aneurysm treatment). However, in the untreated group the patients were significantly older, had a significantly lower rate of EVD placement, had a significantly lower rate of having round and equal pupils or bilateral intact corneal reflexes, and had a significantly worse outcome.

Detailed characteristics of all treated patients with Hunt and Hess Grade V SAH (n = 139) are shown in Table 4. Seventy-nine (57%) of the patients were treated within 12 hours after onset of SAH. In 134 cases (96.4%), the aneurysms were treated within 48 hours. However, in 3 cases (2.1%), the aneurysms were treated after 48 hours but within 72 hours, and in an additional 2 cases (1.4%), the aneurysms were treated after 1 week. In 109 cases (78.4%) an EVD was placed within 24 hours. Timing of treatment (within 12, 24, or 48 hours after onset of SAH) did not influence the outcome (Table 4), whereas treatment itself emerged as an independent predictor (Table 5). It should be noted that we could not compare treatment after 48 hours due to the low number of patients (n = 5).

TABLE 4.

Outcome and prognostic factors for current-period patients with Hunt and Hess Grade V SAH who received aneurysm treatment

CharacteristicTreated PtsOutcomeUnivariate AnalysisMultivariate Analysis
FavorableUnfavorablep Value*OR (95% CI)p Value*OR (95% CI)
No. of pts13941 (29.5%)98 (70.5%)
Mean age in yrs55.4 ± 11.752.3 ± 12.356.8 ± 11.3<0.05
Female99 (71.2%)34 (82.9%)65 (66.3%)NS
Fisher Grade 3 or 4120 (86.3%)35 (85.4%)86 (87.8%)NS
Early hydrocephalus109 (78.4%)37 (90.2%)72 (73.5%)<0.053.3 (1.1–10.3)NS
EVD w/in 24 hrs109 (78.4%)34 (82.9%)75 (76.5%)NS
Aneurysm size8.5 ± 5.27.7 ± 4.59.2 ± 5.3NS
Coiling71 (51.1%)22 (53.6%)49 (50%)NS
Clipping68 (48.9%)19 (46.3%)49 (50%)NS
Early treatment w/in 12 hrs79 (56.8%)21 (51.2%)58 (59.2%)NS
Early treatment w/in 24 hrs121 (87.1%)33 (80.5%)88 (89.8%)NS
Early treatment w/in 48 hrs134 (96.4%)40 (97.6%)94 (95.9%)NS
Late treatment after 48 hrs5 (3.6%)1 (2.4%)4 (4.1%)NS
PERRLA78 (56.1%)29 (70.7%)49 (50%)<0.052.4 (1.1–5.3)NS
Bilat intact corneal reflexes85 (61.2%)33 (80.5%)52 (53.1%)<0.013.6 (1.5–8.7)0.0093.5 (1.4–8.9)
Age <60 yrs91 (65.4%)33 (80.5%)58 (59.2%)<0.052.8 (1.2–6.8)0.0123.3 (1.3–8.6)

Pt = patient.

Values represent numbers of patients unless otherwise indicated. Mean values are given with standard deviations.

Treated/treatment refers specifically to aneurysm treatment. Presented are detailed patients' characteristics and prognostic factors of the treated patients with Hunt and Hess Grade V SAH (n = 139). Whereas univariate analysis identified younger age, early hydrocephalus, PERRLA, and bilateral intact corneal reflexes as prognostic factors, in multivariate analysis only younger age and bilateral intact corneal reflexes were identified as independent outcome predictors (Nagelkerke R2 = 0.162).

Unpaired t-test for continuous variables (age and aneurysm size); Fisher exact test for categorical variables (all others).

TABLE 5.

Outcome and prognostic factors for all current-period patients with Hunt and Hess Grade V SAH

VariableAll PtsOutcomeUnivariate AnalysisMultivariate Analysis
FavorableUnfavorablep Value*OR (95% CI)p ValueOR (95% CI)
All pts w/H & H Grade V SAH20346 (23%)157 (77%)
Mean age in yrs†57.5 ± 12.853.3 ± 12.558.7 ± 12.6<0.05
Early hydrocephalus16141 (89%)120 (76%)0.062.5 (0.9–6.9)NS
PERRLA9131 (67%)60 (38%)<0.0013.4 (1.7–6.7)NS
Bilat intact corneal reflexes10437 (80%)67 (43%)<0.00015.5 (2.5–12.2)<0.014.0 (1.7–9.5)
Age <60 yrs12034 (74%)87 (55%)<0.052.3 (1.1–4.7)<0.052.4 (1.0–5.4
Treated13941 (89%)98 (62%)<0.0014.9 (1.8–13.2)0.053.1 (1.0–9.6)

Values represent numbers of patients unless otherwise indicated. Mean values are given with standard deviations. Univariate analysis identified younger age, PERRLA, bilateral intact corneal reflexes, and treatment as prognostic factors; multivariate analysis identified only younger age, bilateral intact corneal reflexes, and treatment as independent outcome predictors (Nagelkerke R2 = 0.214).

Unpaired t-test for continuous variables (age); Fisher exact test for categorical variables.

Positive prognostic factors for favorable outcome were younger age, early hydrocephalus, pupil function (PERRLA [pupils equal, round, and reactive to light and accommodation]), and a bilateral positive corneal reflex.

Multivariate analysis identified younger age and bilateral intact corneal reflex as independent predictors.

The same independent predictors for favorable outcome were also identified for all patients of the current period—with the additional independent predictor “aneurysm treatment” (see Table 5).

Treatment Decisions and Cerebral Infarction in the Current Period

Of 203 patients, 64 (32%) received no aneurysm treatment. In 20 (31%) of these cases, treatment was not continued due to a combination of reasons (such as rebleeding and cardiac instability with multiple infarctions). However, when the 64 cases are categorized by only the major reason that aneurysm treatment was not provided, the distribution is as follows. In 15 cases (23%) the aneurysm was not treated due to unfavorable resuscitation or other severe internal problems (most often cardiac instability); in 8 cases (13%) treatment was withheld according to the patients' previously expressed instructions; in 12 cases (19%) the patients showed signs of hypoxia or multiple infarctions on admission CT; in 17 cases (27%) the patients showed signs of brainstem areflexia (no EVD was placed in 5 of these cases, and the areflexia continued after EVD insertion in the other 12); and in 12 cases (19%) a fulminant early rebleeding led to the decision not to treat the aneurysm.

In the group of 64 patients who did not receive aneurysm treatment, only 6 patients had a follow-up CT (including CT angiography) more than 3 days after ictus. Cerebral infarctions with severe CVS occurred in at least 2 cases. Two other patients also had cerebral infarctions. In the group of 139 patients with treated aneurysms, 13 patients died before undergoing a second post-treatment CT scan. Severe CVS was detected in 44 (35%) of the remaining 126 patients and cerebral infarctions in 82 (65%) (Table 6). In nearly half of the patients with infarctions, the infarctions were related to a vascular territory (vascular distribution).

TABLE 6.

Rates of CVS and delayed infarctions in the current period

VariableAneurysm TreatedAneurysm Not Treated
Multiple infarctions or hypoxia on initial CT0/139 (0%)12/64 (19%)
No. of pts w/2nd CT after treatment or CT >3 days after SAH (untreated group)126/139 (91%)6/64 (9%)
No. of pts w/severe CVS (>66%)44/126 (35%)2/6 (33%)
No. of pts w/infarctions82/126 (65%)4/6 (67%)
No. of pts w/DCI related to severe CVS (<66%)33/126 (26%)2/6 (33%)
Type of infarction
  Vascular distribution39/82 (48%)2/4 (50%)
  Watershed stroke6/82 (7%)
  Cortical ischemia7/82 (9%)
  Multiple infarctions30/82 (37%)2/4 (50%)

Presented is the rate of CVS detected by imaging (CTA, MRA, or DSA). Most patients died in the nontreatment group within the first week. Also, CVS-related DCI was calculated. However, this rate seems to be low, probably due to a low CVS detection rate in comatose patients. Therefore, we additionally divided the delayed cerebral infarctions into 4 subgroups.

Discussion

In this study we examined the influence of conservative management versus early aggressive treatment on outcome after Hunt and Hess Grade V SAH. The decision of whether to treat the aneurysms in these cases, the timing of treatment, and treatment modalities are still controversial. Nonetheless, there are some data on poor-grade SAH (most often combining WFNS Grades IV and V).8,27,33 To the best of our knowledge, this is the first study to investigate the outcome of comatose patients with Hunt and Hess Grade V SAH. However, no guidelines or consensus exists regarding how to treat these patients. Data on treatment strategies are still needed. However, high-grade SAH occurs quite often (in more than 15% of patients with SAH in our series), indicating the importance of this patient cohort. For all of these reasons, we reviewed our collected data to identify whether early and aggressive treatment is worthwhile in patients with Hunt and Hess Grade V SAH.

Comparison of Early and Current Periods

In the current, post–International Subarachnoid Aneurysm Trial (ISAT) period (2005–2014), significantly more patients had a Hunt and Hess Grade V SAH than in the earlier period (1980–1995), and the patients were significantly older (Table 1). Possible reasons include, as previously described by Lovelock et al.,20 a shortening of the time lag between ictus and admission to a tertiary neurosurgical center, due to a more widespread availability of CT and MR scanners and due to development of CT angiography and MR angiography. Almost any hospital now can perform rapid CT scanning, most likely leading to faster diagnosis of SAH with faster referral to a specialized tertiary care center.

However, this is described for the first time also for comatose patients. The outcome is significantly better in the current period than it was in the early period (Fig. 1A, Table 2), resulting in an ARR for survival of 46% (NNT = 3) for all patients and 52% (NNT = 2) for patients who received aneurysm treatment. For favorable outcome (mRS score of 0–2), the ARR was 23% (NNT = 5) for all patients and 30% (NNT = 4) in the group that received aneurysm treatment.

During the last 35 years, treatment strategies (early vs late clipping vs no treatment), treatment modalities (“clipping alone” vs “coiling or clipping with indocyanine green [ICG] angiography”), diagnosis and treatment of cerebral vasospasm, and ICU standards have changed dramatically. We cannot and do not want to provide a sole reason for the improvement in outcome. We think that the combination of several factors and the sum of rather small improvements contribute to the significant improvement in the outcome of high-grade SAH,6,8,31 but if we had to identify a single most important factor it would be the changed attitude toward more aggressive treatment in these patients, and at least the current results further support such an aggressive attitude. Delaying or withholding treatment for patients with Hunt and Hess Grade V SAH is no longer justified.

Although a detailed exploration of the reasons for the improvement in outcome is beyond the scope of this paper, some of the factors that are particularly likely to have contributed to the overall change should be noted. Due to the more widespread availability of CT scanners nowadays, there might be a shortening of the time between ictus and admission to our tertiary neurosurgical center.6,20,31 Additionally, coiling was introduced in our department in 1998 and has been used regularly since ISAT.22 Furthermore, treatment of CVS has evolved; patients may be treated with endovascular rescue therapy (intra-arterial nimodipine or balloon angioplasty),4,19,26 and/or triple-H (hypertension, hypervolemia, and hemodilution) or hypertensive therapy is used to prevent cerebral infarction.2,25 Also not to be underestimated are the contributions of objective methods to detect the beginning and reversal of CVS (CT and/or MRI), the use of somatosensory evoked potentials, intraoperative ICG angiography, and more invasive treatment in severe cases (e.g., DC in addition to surgical aneurysm clipping in patients with large intracerebral hematoma [ICH] or subdural hematoma [SDH]).24,28 Invasive monitoring of brain tissue oxygenation was performed in patients who were not able to cooperate for adequate neurological assessment, e.g., poor-grade patients (Hunt and Hess Grades IV and V). Nonetheless, patient management protocols vary from hospital to hospital and especially among countries and continents. The approach to management of poor-grade SAH during the earlier period in our series seems to be more conservative than the treatment paradigm that was followed in North America,9,21 because the practice of performing aneurysm treatment within 72 hours of rupture was only adopted in our institution after the 1990 publication of the International Cooperative Study on Timing of Aneurysm Surgery.14,15

Nontreatment and Patient Selection

The outcome for patients who did not receive aneurysm treatment was very similar in both periods. However, due to the different strategy, 43 of 64 patients who did not receive aneurysm treatment during the current period did undergo EVD placement despite worse admission status. Reasons for not securing aneurysms in patients who underwent EVD placement included 1) persistence of bilateral dilated pupils after EVD insertion; 2) written evidence of a patient's desire to forgo treatment (i.e., a written healthcare directive [Patientenverfügung] produced by spouse or children); or 3) evidence of multiple infarctions or hypoxia on subsequent imaging studies (CT or MRI).

In 47 (73%) of these 64 cases, further treatment was not indicated or not possible due to the patient's will (n = 8), unfavorable results of a resuscitation effort (n = 15), global hypoxia on initial CT (n = 12), or persistent brainstem areflexia after EVD insertion (n = 12). Five patients did not receive an EVD due to documented brainstem areflexia lasting longer than 3 hours and additional factors (like severe comorbidities or age). In 12 cases a fulminant early rebleeding led to the decision not to treat the aneurysm. In 50% of these cases, the decision was based on the presence of additional complications (e.g., severe cardiac instability, infarction), but in all 6 of these cases, the decision was made soon after rebleeding. Also, 4 patients had loss of corneal reflexes, and after rebleeding we decided not to treat the aneurysm.

In 21 cases, no EVD was placed. The reasons included bilateral dilated pupils for hours and age greater than 90 years, ineffective attempted cardiopulmonary resuscitation, signs of hypoxia, and/or multiple rebleedings (with or without multiple ICHs and unfavorable prognosis). As expected, in the untreated group more patients died during the 1st week, whereas in the treated group significantly more patients died in the 2nd week. Depending on whether they were in the treated or untreated group, patients died significantly more often due to initial infarctions (untreated group) or delayed CVS-related infarctions (treated group).

Cerebral Infarctions

Due to the complexity of CVS detection in unconscious patients, imaging was routinely performed at Day 7 ± 2. In addition, transcranial Doppler ultrasound examinations were performed at least once a day. Despite these efforts, it is possible that a substantial number of cases of CVS could have remained undetected. Additionally, treatment of high intracranial pressure (ICP) is often challenging in patients with Hunt and Hess Grade V SAH, and the increased ICP could also lead to infarctions. Therefore we divided the infarctions into subgroups (see Table 6). As described by Foreman et al.,10 the development of delayed cerebral ischemia (DCI) is dependent on Fisher grade (Grades 3 and 4 conveying the highest risk) and Hunt and Hess grade at admission. Foreman et al. defined DCI as “cerebral infarctions corresponding to a vascular distribution” and detected it in 53% of patients with combined risk factors (Fisher Grade 3 or 4 and Hunt and Hess Grade IV or V). Similarly, infarction with vascular distribution was detected in 48% of patients in the treated group of the current period (all with Fisher Grade 3 or 4 SAH).

Comparison of Current Period With DC MCA Trials

Due to the restrictive inclusion criteria of the DC MCA trials (see Supplemental Material), we adapted our analysis, and only patients treated within 48 hours were included in the comparison. Therefore, 5 patients were excluded. Also, any untreated patients (as for the best medical treatment in the DC MCA trials) were excluded. In contrast to the DC MCA trials, in our Grade V SAH group more than 33% of patients were older than 60 years and 10% had both pupils fixed and dilated initially (before EVD insertion), and all patients had a GCS score of less than 6 (Supplemental Material). Also, our cohort included patients who had undergone cardiopulmonary resuscitation. These are known to be negative prognostic factors and therefore could have influenced the outcome negatively in the Grade V SAH group.

Nonetheless, despite the favorable inclusion criteria for the DC MCA trials, the Grade V SAH patients who received aneurysm treatment during the current period had a significantly better outcome (higher rate of mRS scores from 0 to 2). The survival rates were similar, but the NNTs for favorable outcome and survival were lower in the Grade V SAH group (Table 3).

After the DC MCA trials the guidelines were changed, and decompressive surgery is actually in favor for large MCA infarctions.12 We therefore would recommend that SAH guidelines7 should particularly favor early and aggressive treatment in comatose patients.

Outcome and Prognostic Factors in the Current Period

Interestingly, there was no significant difference with respect to aneurysm location between the periods or between the patients who did or did not receive aneurysm treatment (Table 1 and Supplemental Table I). However, in comparison with data from the Barrow Ruptured Aneurysm Trial (BRAT), we identified MCA aneurysms significantly more often in our current-period Grade V SAH cohort (27% of detected aneurysms in our series vs 15% in BRAT, p < 0.001) and identified internal carotid artery (ICA) aneurysms significantly less often (17% vs 32% in BRAT, p < 0.001).29 One reason could be the large number of hospitals with neurosurgical departments in and around Frankfurt am Main, allowing for rapid transfer of patients from hospitals that cannot provide the specialized neurosurgical treatment patients with ruptured MCA aneurysms are likely to require. In our patient cohort, 16 (33%) of 49 patients with MCA aneurysms presented with a large ICH (> 50 cm3). The presence of a large ICH (n = 32) seems to be associated with MCA aneurysms (n = 16, 50%), because ICH was identified only in 4 patients with ICA aneurysms (13%). The aneurysm location is not only a predictor for vasospasm1 or associated with the rate of DCI,24 but is also associated with the patient's clinical status at admission in the present study and a recently published study.32

A recently published meta-analysis of patients with poor-grade SAH (WFNS Grade IV and V) identified a favorable outcome in 38% of those treated endovascularly and 39% of those treated microsurgically.3 Another recently published study involving patients with WFNS Grades IV and V SAH identified admission status (WFNS Grade V) as a predictive factor for unfavorable outcome.27 Our favorable outcome rate of 29.5% for treated Hunt and Hess Grade V SAH seems reasonable in light of these previous findings.

In univariate analysis, we found, in contrast to others,5,16 that early hydrocephalus was a positive prognostic factor, which underscores the “positive selection bias” in our cohort. If the patients in our cohort were in worse condition overall due to the inclusion of patients with hydrocephalus, they would have been more likely to receive early and aggressive treatment (early insertion of EVD), which might be expected to have led to a significant improvement in survival rate and favorable outcome, but patients with significant improvement after EVD insertion were not included in our analysis, because they received a better Hunt and Hess grade at reassessment (see Methods).

In multivariate analysis, aneurysm treatment, younger age, and bilateral intact corneal reflex were the only independent prognostic factors (Table 5). We hope to answer the questions of whether, when, and how comatose patients with Hunt and Hess Grade V SAH should be treated. First, we recommend that these patients be treated—at least by the insertion of a potentially life-saving EVD. Additionally, we recommend treating their aneurysms as soon as possible (within 48 hours of ictus), with the decision of how to treat the aneurysm made on an interdisciplinary basis (i.e., based on discussion involving both the endovascular and microsurgical teams).

Limitations and Generalizability

The study has several limitations. It is a single-center statistical analysis that is partially purely retrospective (pre-coiling era) and partially based on data from a prospective database (post-ISAT era). Due to the retrospective design, there are typical restrictions such as the lack of data documented initially in the medical records. In the current period, the physicians decided whether an individual patient would be treated or not, which resulted in a selection bias. However, we think that these decisions were reasonable, and decision details are described in the Results and Discussion.

A bias regarding undetected CVS-related DCI should also be mentioned. However, in addition to the CVS-related DCI rate, we also provided data for detailed subtypes of infarctions in Table 6.

Nevertheless, our series is a large one, and to the best of our knowledge this is the first study investigating the outcome of comatose patients with SAH (Hunt and Hess Grade V). Additionally, we compared the data with stroke trial data, which confirmed that early and aggressive treatment is worthwhile.

We were able to show that early and aggressive treatment led to improved outcomes compared with outcomes from the early period, but our data are influenced by several factors (e.g., coiling and improved treatment in the ICU).

Also, in comparison with patients in the randomized controlled trial (RCT) of DC after MCA infarction (granted, a different entity), our patients with Hunt and Hess Grade V SAH, treated early and aggressively, had a significantly higher chance for independent living (mRS score of 0–2), a better NNT for dependent living (mRS score of 0–3), and a better NNT for survival despite worse admission status and several negative prognostic factors, such as advanced age. If we were to partially apply the criteria of the DC MCA trials (that is, applying the criterion of treatment within 48 hours but, in contrast to the trials, not excluding patients who were comatose), our patients with Grade V SAH would also have significantly better outcomes with respect to independent (mRS score of 0–2) and dependent (mRS score of 0–3) living (Supplemental Material). However, the inclusion criteria for the DC after MCA infarction trials were very restrictive, so the generalizability of the comparison with Hunt and Hess Grade V SAH is limited.

We identified treatment as an independent prognostic factor in the current period, by comparing the outcomes for treated patients with those for untreated patients (Table 5), who had a clinical course that was similar to that of the (conservatively treated) patients in the earlier period. However, the selection bias in the current period is enormous, and this comparison is therefore very limited and not really relevant.

Conclusions

Early and aggressive treatment (early insertion of EVD, early aneurysm treatment, and application of advanced therapeutic capabilities in the ICU) resulted in a significant improvement in survival rate (NNT = 2) and favorable outcome (NNT = 4 for the mRS score of 0–2 group or NNT = 3 for the mRS score of 0–3 group) of patients with Hunt and Hess Grade V SAH. Therefore, patients with Hunt and Hess Grade V SAH should receive early treatment. Independent prognostic factors for favorable outcome were younger age and bilateral intact corneal reflexes. However, careful individual decision making is essential in these cases. Despite a high rate of cerebral infarction (65%) in the current period, 29.5% of treated patients had a favorable outcome.

Because we found that the benefit of early treatment was confirmed by comparison to results obtained in the earlier period (with early treatment emerging as an independent prognostic factor in the current period) as well as by the better outcome and lower NNT found in comparison with published RCT data, we recommend that SAH guidelines should particularly favor early treatment in comatose patients—at least in patients who have bilateral intact corneal reflexes and are younger than 61 years.

Acknowledgments

We thank Anne Sicking and Marina Heibel for their excellent technical support.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Konczalla, Marquardt. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Konczalla. Critically revising the article: Seifert, Beck, Güresir, Vatter, Raabe, Marquardt. Reviewed submitted version of manuscript: Marquardt. Approved the final version of the manuscript on behalf of all authors: Konczalla. Statistical analysis: Konczalla. Study supervision: Marquardt.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

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Contributor Notes

Correspondence Juergen Konczalla, Department of Neurosurgery, Goethe-University Hospital Frankfurt/Main, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. email: j.konczalla@med.uni-frankfurt.de.

INCLUDE WHEN CITING Published online February 24, 2017; DOI: 10.3171/2016.8.JNS161075.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    A: Outcome after Hunt and Hess Grade V SAH. Patients' outcomes from the earlier and current periods are compared. The outcome was significantly better during current period. Whereas in the earlier period no patient (0%) had a favorable outcome (mRS score of 0–2), in the current period 23% of all patients (p < 0.0001, OR 32) and 29% of the patients who received treatment for their aneurysms (p < 0.0001, OR 219) had a favorable outcome. B: Outcome of Grade V SAH compared with DC MCA trials. The Grade V SAH group had a significantly better outcome as determined on the basis of mRS score, although there was a trend toward a higher mortality rate (p > 0.05). H&H V = Hunt and Hess Grade V; mRS = mRS score. Figure is available in color online only.

  • 1

    Abla AA, Wilson DA, Williamson RW, Nakaji P, McDougall CG, Zabramski JM, et al. : The relationship between ruptured aneurysm location, subarachnoid hemorrhage clot thickness, and incidence of radiographic or symptomatic vasospasm in patients enrolled in a prospective randomized controlled trial. J Neurosurg 120:391397, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Awad IA, Carter LP, Spetzler RF, Medina M, Williams FC Jr: Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke 18:365372, 1987

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bing Z, Rabinstein AA, Murad MH, Lanzino G, Panni P, Brinjikji W: Surgical and endovascular treatment of poor-grade aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. J Neurosurg Sci 2015

    • Search Google Scholar
    • Export Citation
  • 4

    Biondi A, Ricciardi GK, Puybasset L, Abdennour L, Longo M, Chiras J, et al. : Intra-arterial nimodipine for the treatment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: preliminary results. AJNR Am J Neuroradiol 25:10671076, 2004

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Bruder M, Schuss P, Konczalla J, El-Fiki A, Lescher S, Vatter H, et al. : Ventriculostomy-related hemorrhage after treatment of acutely ruptured aneurysms: the influence of anticoagulation and antiplatelet treatment. World Neurosurg 84:16531659, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Chua MH, Griessenauer CJ, Stapleton CJ, He L, Thomas AJ, Ogilvy CS: Documentation of improved outcomes for intracranial aneurysm management over a 15-year interval. Stroke 47:708712, 2016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. : Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43:17111737, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    De Marchis GM, Lantigua H, Schmidt JM, Lord AS, Velander AJ, Fernandez A, et al. : Impact of premorbid hypertension on haemorrhage severity and aneurysm rebleeding risk after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 85:5659, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Findlay JM: Current management of aneurysmal subarachnoid hemorrhage guidelines from the Canadian Neurosurgical Society. Can J Neurol Sci 24:161170, 1997

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