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Vol. 27. Num. 5.September - October 2016Pages 207-262
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Vol. 27. Num. 5.September - October 2016Pages 207-262
Clinical Research
DOI: 10.1016/j.neucir.2016.01.003
Survival analysis of surgically evacuated supratentorial spontaneous intracerebral hemorrhage with intraventricular extension
Estudio de supervivencia en hemorragia intracerebral espontánea con extensión intraventricular evacuada quirúrgicamente
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Ricardo Rivera-Fernándeza, Francisco Guerrero-Lópezb, David Rodríguez-Rubioc, Francisco Javier Gómez-Jiménezd, Francisco Rodríguez-Vilanovae, Juan Mora-Ordóñeze, Victoria Olea-Jiméneze, María Dolores Arias-Verdúe, Guillermo Quesada-Garcíae, Faustino Acebal-Blancof, Encarnación Castillo-Lorentef,
, Miguel Ángel Arráez-Sánchezg
a Intensive Care Medicine, Hospital de la Serranía, Ronda, Málaga, Spain
b Intensive Care Medicine, Hospital Virgen de las Nieves, Granada, Spain
c Neurosurgery Department, Hospital del Mar, Barcelona, Spain
d Universidad de Granada, Spain
e Intensive Care Medicine, Hospital Carlos Haya, Málaga, Spain
f Intensive Care Medicine, Hospital Neurotraumatológico, Jaén, Spain
g Neurosurgery Department, Hospital Carlos Haya, Málaga, Spain
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Tables (6)
Table 1. Relationship between mortality and rest of variables (age expressed in years, GCS and APACHE-II in points, length of ICU stay in days).
Table 2. Hospital mortality rates according to cathegorized GCS and age, confronted to patients with and without intraventricular hemorrhage (IVH).
Table 3. Relatioship between intraventricular hemorrhage (IVH) and rest of variables.
Table 4. Multivariant analysis of mortality in patients with intraventricular hemorrhage (n=163).
Table 5. Multivariant analysis of mortality in patients with supratentorial spontaneous intracerebral hemorrhage (n=263).
Table 6. Propensity score matching in two paired groups of 26 patients with intraventricular hemorrhage (surgical vs. medical treatment). No significant difference can be seen between both groups in considered variables except in mortality.
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Abstract
Objective

To conduct a survival study and evaluation of surgical treatment in a cohort of patients with diagnosis of supratentorial spontaneous intracerebral hemorrhage (ICH).

Materials and methods

The study included all consecutive patients with supratentorial ICH admitted to the Intensive Care Units of three Spanish hospitals with Neurosurgery Department between 2009 and 2012. Data collected: age, APACHE-II, Glasgow Coma Score (GCS), and pupillary anomalies on admission, intracerebral hemorrhage (ICH) score, location/volume of hematoma, intraventricular hemorrhage (IVH), surgical evacuation alone or with additional external ventricular drain, and 30-days survival and at hospital discharge

Results

A total of 263 patients were included. Mean age: 59.74±14.14 years. GCS: 8±4 points, APACHE II: 20.7±7.68 points. ICH Score: 2.32+1.04 points. Pupillary anomalies were observed in 30%. The 30-day mortality: 51.3% (45.3% predicted by ICH-score), and 53.2% at hospital discharge. A significant difference (p=0.004) was observed in hospital mortality rates between surgically treated patients (39.7%, n=78) versus those conservatively managed (58.9%, n=185); specifically in those with IVH surgically treated (34.2%, n=38) versus non-operated IVH (67.2%, n=125), p<0.001. No significant difference was found between mortality rates in patients without IVH. Multiple logistic regression analysis showed an OR for surgery of 1.04 (95% CI; 0.33–3.22) in patients without IVH versus 0.19 (95% CI; 0.07–0.53) in patients with IVH (decreased mortality with surgical treatment). The propensity score analysis for IVH patients showed improved survival of operated group (OR 0.23, 95% CI; 0.07–0.75), p=0.01.

Conclusions

Hospital mortality was lower in patients who underwent surgery compared to patients conservatively managed, specifically for the subgroup of patients with intraventricular hemorrhage.

Keywords:
Intracerebral hemorrhage
Surgery
Treatment
Resumen
Objetivo

Estudio de supervivencia y evaluación del tratamiento quirúrgico en una cohorte de pacientes con hematoma intracerebral espontáneo supratentorial.

Material y métodos

Incluidos todos los pacientes con hematoma cerebral espontáneo supratentorial ingresados en las unidades de cuidados intensivos de 3 hospitales españoles con servicios de neurocirugía (2009-2012). Se recogieron la edad, APACHE-II, escala de coma de Glasgow y alteraciones pupilares al ingreso, intracerebral haemorrhage (ICH) score, localización/volumen del hematoma, presencia de hemorragia intraventricular (IVH), evacuación quirúrgica±drenaje ventricular externo, supervivencia a los 30 días y hospitalaria.

Resultados

Doscientos sesenta y tres pacientes, con edad media 59,74±14,14 años, escala de coma de Glasgow: 8±4 puntos e ICH score: 2,32±1,04 puntos. El 30% presentaba alteraciones pupilares. Mortalidad a los 30 días: 51,3% (predicha por ICH score 45,3%) y hospitalaria 53,2%. Hubo diferencia estadísticamente significativa (p=0,004) entre la mortalidad-hospitalaria de los pacientes intervenidos quirúrgicamente (39,7%; n=78) frente a los tratados de modo conservador (58,9%; n=185), y específicamente para los pacientes intervenidos con IVH (34,2%; n=38) frente a los no operados con IVH (67,2%; n=125), (p<0,001). No hubo diferencias en la mortalidad de los pacientes sin IVH. En el análisis de regresión logística múltiple la OR para la cirugía fue 1,04 (IC 95%: 0,33-3,22) en pacientes sin IVH, frente a 0,19 (IC 95%: 0,07-0,53) en pacientes con IVH. El análisis con índice de propensión para pacientes con IVH demostró mejoría en la supervivencia del grupo operado (OR: 0,23; IC 95%: 0,07-0,75), p=0,01.

Conclusión

La mortalidad hospitalaria fue menor en los pacientes intervenidos quirúrgicamente en comparación con los tratados de modo conservador, específicamente para el subgrupo de pacientes con IVH.

Palabras clave:
Hemorragia intracerebral
Cirugía
Tratamiento
Full Text
Introduction

Non-traumatic, spontaneous intracerebral hemorrhage (ICH) remains a major public health problem, being responsible of 9–27% of all strokes worldwide with an annual incidence of 10–30 per 100,000.1,2 It is also a growing concern for health economies, with hospital admissions for ICH having increasing by 18% over the past 10 years,3 likely attributable to population aging.4 Among stroke patients, the highest mortality rate is observed in those with spontaneous ICH, with a 30 day mortality close to 50%.2 Intraventricular hemorrhage (IVH) is a factor significantly associated with worse prognosis in patients with spontaneous ICH, carrying a reported mortality rate of 50–80%.5,6 Several studies have confirmed that IVH is a prognostic factor7–9 including the major randomized STICH trial (Surgical Trial in IntraCerebral Hemorrhage)7 reporting the presence of IVH in 42% of ICH patients (23% of them with associated hydrocephalus). Good outcome was observed in only 15% of patients with IVH in comparison to 31% of ICH patients without IVH in a further study.8

Infratentorial location represents 10–15% of spontaneous ICH and is also an independent predictor of outcome. In infratentorial ICH the role of surgery has been well described including clearly defined surgical indications in the recent guidelines of the American Heart Association/American Stroke Association (AHA/ASA).10 Surgery is generally accepted as playing a major role in the management of patients with infratentorial ICH. Factors influencing the surgical decision making include conscious level, size of hematoma, presence of hydrocephalus and degree of any brain stem compression.11 The role of medical versus surgical treatment in spontaneous supratentorial ICH remains controversial however, as does timing and type of neurosurgical intervention in this condition. Given the absence of strong scientific evidence to indicate surgery, this treatment is usually taken on a tailored manner based on surgeon preference in supratentorial locations.12 Recent clinical guidelines10 state that early hematoma evacuation is not clearly beneficial when compared with hematoma evacuation when conscious level deteriorates (Class IIb; level of evidence A), and that supratentorial hematoma evacuation in deteriorating patients might be considered as life-saving measure (Class IIb; level of evidence C).

This was largely based on the findings of the STICH and STICH-II studies,7,13 the two largest randomized trials comparing surgery to conservative management, neither which demonstrated a clear benefit for early surgical intervention. Three meta-analyses from the STICH authors14–16 have also reported that surgery improves prognosis when it is performed in selected groups of patients, the topic of surgical treatment in spontaneous supratentorial ICH therefore remains controversial.

Based on this subgroup analysis our study hypothesis proposed that surgical treatment could improve survival outcomes in patients with supratentorial cerebral hemorrhage admitted to the intensive care unit (ICU). This hypothesis was supported by a previous non-published observation on a group of patients with supratentorial ICH admitted to Regional University Hospital of Málaga (Andalusia, Southern Spain) that showed better survival outcomes in the surgically treated group. We proposed a mutlicenter analysis of outcomes including two additional Hospitals with a Neurosurgery Department in the region. The objective of our study was to evaluate the benefit of surgery versus conservative management in survival outcomes in patients admitted to ICU with ICH.

Materials and methods

The study design is a multicenter cohort study including all patients presenting with a diagnosis of spontaneous supratentorial ICH from October 2009 to January 2012 to the ICUs of three Hospitals in Andalusia (Regional University Hospital of Málaga, University Hospital Virgen de las Nieves, Granada and Neurotrauma Hospital, Jaén). All participating hospitals are tertiary referral centers for neurosurgical conditions in the region, providing comprehensive facilities for treatment of patients with acute stroke, including neurology, neuroradiology, neurosurgery and critical care.

The inclusion criteria were patients over 14 years of age with supratentorial ICH confirmed on computed tomography (CT) imaging of the brain with or without intraventricular extension. Patients with a history of trauma, those with associated subarachnoid hemorrhage or underlying parenchymal lesions, and hemorrhages of infratentorial location were excluded.

After admission patients underwent diagnostic imaging and treatment procedures according to the best clinical practice guidelines at the time of inclusion. Cardiovascular and respiratory stabilization of the patient was routinely performed on admission to the emergency department, standard assessment of clotting disorders was made and treated if required. General multimodal cardiovascular monitoring and intermittent pneumatic compression for prevention of venous thromboembolism beginning the day of hospital admission were considered standard of care. Intensive management of blood pressure with glycaemic, temperature and seizure control (no prophylactic anticonvulsant given) and early aggressive management of any medical complications were also routinely performed. Patients with a Glasgow Coma Score (GCS)8, those with clinical evidence of transtentorial herniation, significant IVH or hydrocephalus were considered for intracranial pressure (ICP) monitoring. Management of raised ICP maintaining a cerebral perfusion pressure (CPP) of 50–70mm Hg was performed depending on the status of cerebral autoregulation.

The attending neurosurgeon was routinely consulted to assess the need for surgical hematoma evacuation and/or insertion of external ventricular drainage (EVD). The decision for surgical treatment was made following local guidelines for clinical practice or when the attending neurosurgeon considered it necessary. When a surgical decision was made for clot evacuation, a standard craniotomy with corticotomy and hematoma aspiration was carried out in all cases, with or without EVD placement.

For this cohort study data was collected by specifically-trained physicians in each hospital. Data collected at admission included age, admission GCS, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores, pupillary changes at ICU admission, hematoma volume17 (<30ml, 30–50ml, 50–100ml and >100ml) and location (lobar versus basal ganglia/thalamic), presence of IVH and ICH score.18 Intervention and outcome data was subsequently collected including insertion of EVD and/or surgical evacuation of the clot, length of ICU admission and overall survival. Most of these variables were routinely registered in the clinical notes and easily identifiable from the electronic records with a low rate of exclusion of patients caused by incomplete or missed data. Data collection was prospective in Málaga (111 patients) and Granada (78 patients). Jaén Hospital (74 patients) joined the study later (January 2010) so data collection there was partially retrospective.

We received approval from the Research Ethics Committee of each of the three participating hospitals. Data was analyzed anonymously. No consent form was provided because our study was observational and retrospective (in some cases as previously described). This issue was discussed and approved by the Ethics Committees of all three hospital involved in this study.

Quantitative variables were expressed as means (±standard deviation) and qualitative variables as percentages and frequencies. The Student's t-test was used to compare means and the chi-square test to compare proportions. Multivariate analysis was performed using a multiple logistic regression model. A propensity score matching was performed at the end of the study in patients with and without intraventricular extension of the hemorrhage to estimate the effect of the surgical treatment on both groups and to reduce bias due to confounding variables. Matching on the propensity score has previous been identified as a useful and reliable statistic tool that can provide an unbiased estimation of a treatment effect.19

PSPP (psppire.exe 0.7.8.), and “R 2.14.2” were used for statistical analysis. A literature search was performed through Medline, with a search strategy using spontaneous, intracerebral, hemorrhage, supratentorial, surgical and treatment as medical subject headings (MeSH). The search was restricted to publications of the current century, and the original papers were obtained with authorized access to the electronic libraries of the Universities of Málaga and Granada.

Results

The study included 263 patients: 111 from Málaga, 78 from Granada and 74 from Jaén Hospital. Mean age was 59.74±14.14 years, GCS at ICU admission was 8±4 points, and worst GCS on first ICU day was 7±4 points. On admission APACHE-II severity score was 20.70±7.68 points and ICH Score was 2.32±1.04 points. IVH was present in 163 (62%) of the 263 patients. 29.7% (n=78) underwent craniotomy and evacuation of the clot, and EVD was performed in 16.7% (n=44). Among 100 patients without IVH, 40 were operated through a standard craniotomy with corticotomy and hematoma evacuation. In the group of 163 patients with IVH, 38 were surgically treated (32 through craniotomy with clot evacuation alone and 6 with additional EVD insertion following clot evacuation). Of the 125 hematomas with IVH that were not surgically evacuated, 37 were treated with percutaneous insertion of EVD alone and 87 were managed conservatively. ICU stay was 8.74±10.95 days, being ICU mortality 43.3%, with an overall hospital mortality of 53.2%. 30-day mortality rate was 51.3%, with a 30-day ICH score predicted mortality rate of 45.3%.

30% of patients (n=79), presented with pupillary anomalies (anisocoria or bilateral midriasis), with an observed 30-day mortality of 83% (ICH score predicted 30-day mortality of 62% in this group). In the majority of patients (n=184) with no pupillary abnormalities on admission, the observed 30-day mortality was 37%, very close to the ICH score predicted mortality (38%).

Patients who died during their hospital stay were older, had lower GCS on admission and on first day, higher APACHE-II scores and higher incidence of pupillary changes on admission. Additional factors increasing mortality were larger hematoma volume, the presence of IVH and conservative management (Table 1). Mortality rate significantly increased with age above 75 years and was significantly higher with GCS below 8. The relationship of these two variables with mortality was not linear (Table 2) therefore they were divided into intervals for the multivariate analysis. The global hospital mortality rate was 59.5% (97/163) in patients with IVH versus (vs.) 43% (43/100) in patients without (p=0.009), and it was 39.7% in the 78 patients who underwent clot evacuation surgery versus 58.9% in the 185 who did not (p=0.004). EVD was placed in 44 patients (1 patient with hydrocephalus without IVH and 43 patients with both ICH and IVH) and mortality rate was 51.2% in patients with EVD and 62% in patients without (not significant, n.s., p=0.1).

Table 1.

Relationship between mortality and rest of variables (age expressed in years, GCS and APACHE-II in points, length of ICU stay in days).

Variables  Survivors (n=123)  Non survivors (n=140)  p 
Age  55.16±14.76  63.76±12.27  <0.001 
Admission GCS  10.25±3.78  6.51±3.42  <0.001 
Worst GCS on first ICU day  8.84±3.93  5.31±2.87  <0.001 
Length of ICU stay  11.41±12.26  6.41±9.08  <0.001 
APACHE-II  17.06±7.18  23.91±6.61  <0.001 
ICH score  1.82±0.94  2.75±0.91  <0.001 
Admission pupillary changes
Normal  90.2% (n=111)  52.1% (n=73)  <0.001
Anisocoria  9.8% (n=12)  26.4% (n=37) 
Bilateral non-reactive mydriasis  0% (n=0)  21.4% (n=30) 
Volumen of hematoma*
<30ml  36.5% (n=42)  20.5% (n=26)  0.001
30–50ml  25.2% (n=29)  20.5% (n=26) 
50–100ml  33.9% (n=39)  42.5% (n=54) 
>100ml  4.3% (n=5)  16.5% (n=21) 
Site of hematoma
Lobar  55.7% (n=68)  52.5% (n=73)  0.6
Basal ganglia/thalamic  44.3% (n=54)  47.5% (n=66) 
Intraventricular hemorrhage  53.7% (n=66)  69.3% (n=97)  0.009 
External ventricular drain  17.1% (n=21)  16.4% (n=23)  0.8 
Surgical treatment  38.2% (n=47)  22.1% (n=31)  0.004 
*

Hematoma volume estimation was missed in 19 patients.

Table 2.

Hospital mortality rates according to cathegorized GCS and age, confronted to patients with and without intraventricular hemorrhage (IVH).

Variables  Total (n=263)  No IVH (n=100)  IVH (n=163) 
Admission GCS(a)
14–15  41 (17.1%)  21 (9.5%)  20 (25%) 
9–13  69 (33.3%)  30 (26.7%)  39 (38.5%) 
6–8  71 (63.4%)  24 (54.2%)  47 (68.1%) 
<6  82 (79.3%)  25 (80%)  57 (78.9%) 
Age(b)
<50  62 (35.5%)  32 (34.4%)  30 (36.7%) 
50–74  163 (52.1%)  54 (38.9%)  109 (58.7%) 
≥75  38 (86.8%)  14 (78.6%)  24 (91.7%) 

(a), (b): statistically significant differences in mortality among the different admission GCS intervals (p<0.001) and different age intervals (p<0.05) in patients with and without IVH.

Table 3 reports the characteristics of the groups with and without IVH, showing no difference in age, pupillary changes, APACHE-II score, and volume of hematoma. Although in patients with IVH, a lower GCS scores, higher ICH scores, higher ICU and hospital mortality rates, lower frequency of surgery (23.3% vs. 40%, p=0.004), and lower incidence on lobar hematoma was observed, in comparison to those patients without IVH.

Table 3.

Relatioship between intraventricular hemorrhage (IVH) and rest of variables.

Variables  No IVH (n=100)  IVH (n=163)  p 
Age  58.09±14.61  60.75±13.78  0.1 
Admission GCS  9.06±4.18  7.77±3.75  0.01 
Worst GCS on first day in ICU  7.63±4.09  6.56±3.62  0.02 
APACHE-II  19.54±7.82  21.42±7.55  0.05 
ICH score  1.61±0.84  2.75±0.9  <0.001 
Length of ICU stay  6.26±6.87  10.27±12.61  0.004 
Surgical treatment  40% (n=40)  23.3% (n=38)  0.004 
Admission pupillary changes
Normal  72% (n=72)  68.7% (n=112)  0.3
Anisocoria  20% (n=20)  17.8% (n=29) 
Bilateral non-reactive mydriasis  8% (n=8)  13.5% (n=22) 
Volume of hematoma*
<30ml  20.9% (n=18)  32.1% (n=50)  0.3
30–50ml  26.7% (n=23)  20.5% (n=32) 
50–100ml  40.7% (n=35)  37.2% (n=58) 
>100ml  11.6% (n=10)  10.3% (n=16) 
Site of hematoma
Lobar  68.7% (n=68)  45.1% (n=73)  <0.001
Basal ganglia/thalamic  31.3% (n=31)  54.9% (n=89) 
ICU mortality  35% (n=35)  48.5% (n=79)  0.03 
Hospital mortality  43% (n=43)  59.5% (n=97)  0.009 
*

Hematoma volume estimation was missed in 19 patients.

In the group of 163 patients with IVH, mortality was 34.2% (n=13) in the 38 who underwent craniotomy and evacuation of the clot versus 67.2% (n=84) in the 125 who did not (p<0.001). In the group of 100 ICH patients without IVH, mortality was 45% in the 40 who underwent clot evacuation surgery and 41.7% in the 60 who did not (n.s.; p=0.7). Therefore surgery did not diminish the mortality rate in patients without IVH but significantly reduced the mortality in those with IVH.

Multiple logistic regression analysis of the data for the 163 patients with IVH showed that hospital mortality rate was significantly related to admission GCS, age, volume of hematoma, and surgery (odds ratio OR=0.14; confidence interval CI 95% 0.05–0.41). The variable “admission pupillary changes” (p=0.1) was not included in the multivariable model (Table 4).

Table 4.

Multivariant analysis of mortality in patients with intraventricular hemorrhage (n=163).

Variables  OR  CI 95% 
Surgical evacuation  0.14  (0.05–0.41) 
Age
<50   
50–74  2.09  (0.78–5.58) 
≥75  18.72  (2.66–131.14) 
GCS on admission
14–15   
9–13  2.87  (0.6–13.68) 
6–8  9.07  (1.98–41.38) 
<6  10.19  (1.92–53.96) 
Volumen
<30ml   
30–50ml  (1.32–12.15) 
50–100ml  3.45  (1.2–9.97) 
>100ml  19.87  (2.46–160.07) 

Mortality multiple logistic regression analysis of the data for all 263 patients in the study revealed a relationship between surgery and IVH: the OR for surgery was 1.04 (CI 95% 0.33–3.22) in patients without IVH (with no lower mortality observed comparing these with the medically treated group). The OR for surgery was 0.19 (CI 95% 0.07–0.53) for patients with IVH (lower mortality observed in the surgically treated group). This model also included the admission GCS, age, volume of hematoma and pupil abnormalities (Table 5). The “EVD” variable showed no significant relationship with mortality rate and therefore it was not considered for the multivariate analysis.

Table 5.

Multivariant analysis of mortality in patients with supratentorial spontaneous intracerebral hemorrhage (n=263).

Variables  OR  CI 95% 
GCS on admission
14–15   
9–13  2.32  (0.78–6.95) 
6–8  5.71  (1.9–17.16) 
<6  7.23  (1.99–26.56) 
ICU admission pupilsa  3.52  (1.47–8.43) 
Volumen of hematoma
<30ml   
30–50ml  2.21  (0.88–5.51) 
50–100ml  3.51  (1.42–8.69) 
>100ml  7.40  (1.7–32.31) 
Age (years)
<50   
50–75  1.38  (0.64–2.97) 
>75  8.78  (2.39–32.26) 
IVH  3.84  (1.47–10.04) 
Surgical evacuation
IVH  0.19  (0.07–0.53) 
No IVH  1.04  (0.33–3.22) 
a

ICU admission pupil are codified as 0 “Normal” and 1 “Anisocoria or Bilateral non-reactive midriasis”.

A propensity score matching analysis was also performed in the group of 163 patients with IVH. For this purpose, we conducted a logistical multivariable analysis with a dependent variable of surgical treatment (yes/no) and different independent variables. These variables were GCS on admission, age, volume of hematoma (<30ml, 30–50ml, 50–100ml and >100ml), pupil changes (isochoric, anisocoria and bilateral non-reactive mydriasis), and hematoma site (lobar vs. basal ganglia/thalamic). With this model we assigned each patient a probability to receive surgical treatment (propensity score). The discrimination ability of this model was evaluated by the receiver operating characteristic (ROC) area under the curve. The ROC area under the curve had a value of 0.92 (0.88–0.97) for propensity score.

In the group of 163 patients with IVH, 26 operated cases were matched with 26 from the conservatively managed group, with similar values of propensity score. No significant differences between both paired groups for potentially confounding variables was observed, as shown in Table 6. Mortality rate with this analysis was 30.8% in the surgical group (n=26), and 65.4% in the conservatively managed one (n=26), with a statistically significant p value of 0.01 (OR 0.23; CI 95% 0.07–0.75). A similar propensity score matching analysis was applied to patients with no IVH, showing no significant reduction in the mortality rate in the operated group (OR 0.83; CI 95% 0.25–2.76).

Table 6.

Propensity score matching in two paired groups of 26 patients with intraventricular hemorrhage (surgical vs. medical treatment). No significant difference can be seen between both groups in considered variables except in mortality.

Variables  Medical group (n=26)  Surgical group (n=26)  p 
Age*,**  59.92±11.64  58.31±12.65  0.6 
Admission GCS (A)*  8.5±3.5  8.6±3.4  0.9 
Worst GCS on first ICU day (W)  6.9±3.5  6.9±3.4  0.9 
Difference A-W  1.6±2.2  1.7±3.5  0.9 
APACHE-II  19.27±7.1  20.85±5.7  0.4 
ICH score  2.88±0.65  2.92±0.56  0.8 
Volume of hematoma*
< 30ml  7.7% (n=2)  3.8% (n=1)  0.8
30–50ml  34.6% (n=9)  26.9% (n=7) 
50–100ml  50% (n=13)  61.5% (n=16) 
>100ml  7.7% (n=2)  7.7% (n=2) 
Site of hematoma*
Lobar  69.2% (n=18)  73.1% (n=19)  0.8
Basal Ganglia/thalamic  30.8% (n=8)  26.9% (n=7) 
Left side of hematoma  42.3% (n=11)  46.2% (n=12)  0.8 
ICU admission pupils*
Normal  88.5% (n=23)  88.5% (n=23)  1
Anisocoria  11.5% (n=3)  11.7% (n=3) 
Bilateral non-reactive mydriasis  0% (n=0)  0% (n=0) 
Mortality Predicted by ICH score  63.43±24.82  66.04±21.47  0.7 
Hospital Mortality  65.4%  30.8%  0.01 
*

Variables included in propensity score calculation are shown with an asterisk.

**

Eldest age was 76 years in the surgically treated group, and 78 years in the conservatively managed one.

Discussion

In our study mortality rate was lower in patients with spontaneous supratentorial ICH who underwent surgery in comparison to those conservatively managed particularly in the subgroup of patients with intraventricular hemorrhage which reached statistical significance.

Indications of surgery for primary supratentorial ICH vary widely worldwide, reflecting uncertainty regarding best management.20 The superiority of surgical treatment when compared to medical treatment is not well established, except in selected patient groups,10–13 and early hematoma evacuation has not been shown to be beneficial in the two largest randomized trials regarding this topic.7,13 In the STICH trial, with 1033 patients randomized to early surgery (<24h) or initial conservative treatment, 26% of the patients in the surgical arm achieved a favorable outcome compared with 24% in the medical arm. STICH found no overall statistically significant difference not only in functional outcomes between treatment groups, but also in mortality. Subgroup analysis suggested that lobar hemorrhage within 1cm of the cortical surface may benefit from surgery. The STICH II trial attempted to answer whether early surgery would be beneficial for conscious patients with superficial lobar hemorrhage of 10–100cm3 within 1cm of the cortical surface, without IVH and who were admitted within 48h of ictus. Favorable outcome was observed in 41% of patients in the early surgery group compared with 38% in the medical arm, and this difference was not statistically significant. In the STICH-II trial a subgroup analysis showed that poor prognosis patients were more likely to have a favorable outcome with early surgery, but there was no advantage to early surgery for patients in the good prognosis category. Exclusion of patients at risk for brain herniation, high crossover rates of patients to surgical intervention (up to 26% in the STICH trial), narrow patient-based inclusion criteria, and the focus on early surgery leave unclarified whether surgery may benefit specific group of patients with supratentorial ICH in these two major trials.

In 2007, Mendelow and Unterberg,14 analyzing 12 prospective randomized trials, found a reduction of the mortality rate in surgically treated patients (OR 0.85; CI 95% 0.71–1.02). A significant benefit was observed both in survival and functional status (OR 0.58; CI 95% 0.36–0.92) in the three studies focusing on superficial (lobar) hematomas. Prasad et al.15 reported in his meta-analysis a significant reduction on mortality and dependence rates (OR 0.71; CI 95% 0.58–0.88) in surgically treated patients. In 2012, Gregson et al.,16 analyzing 8 trials (2186 patients), found that surgery improved prognosis when performed in the first 8h after presentation (p=0.003), with a hematoma volume of 20–50cm3 (p=0.004), GCS 9–12 (p=0.0009), and in the age range of 50–69 years (p=0.01). These meta-analyses emphasize the need of specific subgroup indications when considering surgical evacuation of a spontaneous supratentorial ICH.

In our study, unlike in the STICH trial, hospital mortality rate was significantly lower (p=0.004) in the ICH patients who underwent surgery (39.7%) than in those who did not (58.9%). With a surgical approach recommended only in cases with an admission GCS of ≥5 points patients in the STICH trial were only randomized if the neurosurgeon was substantially uncertain about the need for surgical treatment. This design may have excluded patients who might have benefited from surgery limiting extrapolation of the results. More than half of the patients included in STICH-II were fully conscious or just confused which represents only a small group in the total number of patients admitted to ICU with spontaneous ICH. In addition to those patients others with more severe disease and a higher predicted mortality rate were admitted in our study including those with adverse prognostic factors such as GCS<8 or intraventricular hemorrhage. It is specifically in this subgroup where we found that surgical treatment could be beneficial.

A more detailed analysis of our results revealed that the difference in mortality rates was significant in patients with IVH (mortality rate 34.2% in surgically treated vs. 67.2% in conservatively managed, p=0.001) but not in those without (45% vs. 41.7%, respectively, p=0.742). Multivariate analysis confirmed that surgery only showed a beneficial effect in the patients with IVH (OR for surgery 0.19; CI 95% 0.07–0.53). The propensity score matching revealed a statistically significant benefit in the surgically treated group of ICH with intraventricular extension in survival terms (p=0.01), but not in the group without IVH. Our results mirror those in the STICH study in terms of improved outcomes following surgery in the presence of IVH, with or without hydrocephalus. The STICH group reported more favorable outcomes as measured by Glasgow Outcome Score at 6 months in patients with IVH receiving early surgery vs. initial conservative management, although this difference was not significant.8

Two clinical trials have confirmed that intraventricular hemorrhage and hydrocephalus are independent predictors of poor outcome in spontaneous ICH.7,9,21 Blood in the ventricular system has multiple morbid effects22 on cerebral physiology including damaging the reticular activating system and releasing pyrogens. Hydrocephalus may arise through direct mass-effect with impaired flow of cerebrospinal fluid or because of the toxic effects of blood degradation products on the Pacchionian granulations. External drainage of cerebrospinal fluid through ventricular catheters reduces intracranial pressure, but clots in the catheter and infection prevent sustained beneficial effects on hydrocephalus and neurological status in many patients, even with the use of intraventricular fibrinolytic agents.23 Careful aspiration of the intraventricular clot when ICH extends into the ventricular system can be performed at the same time as clot evacuation. This may reduce mass-effect, ease clearance of ventricular blood and permit accurate positioning of a ventricular catheter utilizing direct vision of the ependymal wall. In our study surgical evacuation only enhanced the survival of ICH patients with IVH (the majority did not require an associated EVD) which may suggest that changes produced by the corticotomy and hematoma evacuation may aid the drainage of cerebrospinal fluid and ventricular blood postoperatively contributing to the improvement observed in this subgroup of patients.

The pathophysiology of spontaneous supratentorial ICH is experimentally and clinically well documented.24–26 There is some evidence to suggest the presence of a potentially recoverable penumbra of ischemic tissue around the ICH. The rationale for surgery in ICH is not only to remove the mass but also to reduce the toxic presence of intracerebral blood products, thereby promoting recovery of the penumbra. Our results suggest that surgery is effective against the mass effect of the hematoma, blood-clot mediated injury and assists the rapid clearance of intraventricular blood in ICH patients, thereby acting on the three key factors that determine prognosis in these patients.

We would like to emphasize that our data are consistent with the most recent AHA/ASA guidelines which assert that supratentorial hematoma evacuation in deteriorating patients might be considered as a life-saving measure.10 Latest European Stroke Organization (ESO) guidelines27 for the management of spontaneous intracerebral hemorrhages advises early surgery may be of value for patients with a GCS score 9–12 (moderate quality of evidence, weak strength of recommendation).

The 30-day mortality rate in our study was 51.3%, with a 30-day ICH score predicted mortality rate of 45.3%. This difference can be explained by a higher rate of patients in our population with pupillary changes on admission with an observed mortality rate of 83% (ICH score predicted mortality rate of 62%) in this group. Patients without pupillary anomalies (70% of cases) showed a 30 day mortality rate of 37% in our study compared to 38% as predicted by the ICH score.

The improvement in the survival rate observed with surgical treatment in our study is only applicable to a specific subgroup of patients (Table 6). The subgroup with intraventricular hemorrhage, mainly lobar hematomas, with a high severity score (as it is pointed by a ICH score predicted mortality rate 66.04%), with no cases of bilateral non-reactive mydriasis and an eldest age of 76 years, was the group of cases who did benefit from surgery in terms of survival.

Limitations in our study include the lack of randomized assignment to conservative or surgical treatment although signs of irreversible cerebral herniation (GCS, pupillary changes) were controlled in multiple logistic regression analyses and with propensity score matching. Randomized controlled trials are generally considered the gold standard for assessing the efficacy of medications, medical procedures or clinical strategies. In observational studies, investigators do not control the treatment assignment, and large differences may exist between the two arms, in both observed and non-observed covariates. Rosenbaum and Rubin28 demonstrated that conditioning on the propensity score allows to obtain unbiased estimation of the treatment effect. The four most common techniques that may use the propensity score are: matching, stratification, regression adjustment and more recently weighting with the propensity score.19 We have used matching on the propensity score, which is probably the most popular method and it allows the reader easily observe the characteristics of the treated and untreated patients.

Our study did not analyze patient or relative wishes regarding medical or surgical treatment nor the attending surgeon decision making process in opting for surgery. We also only analyzed survival figures and no data regarding patients’ functional result was recorded. We considered the improvement in survival rates observed in patients surgically treated of sufficient interest to be reported before focusing on other longer term functional and neurological outcomes.

Conclusions

Surgical hematoma evacuation might improve survival rates in patients with supratentorial spontaneous intracerebral hemorrhage particularly in those with intraventricular clot extension. This particular subgroup of patients is widely associated with poor outcome and any improvement in neurological management that may lead to better survival should be considered.

Conflict of interest

The authors declare no conflict of interest.

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Copyright © 2016. Sociedad Española de Neurocirugía
Neurocirugía (English edition)

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