original papers Adv Clin Exp Med 2013, 22, 1, 101–109 ISSN 1899–5276
© Copyright by Wroclaw Medical University
Milan Mijailovic1, A, D–F, Snezana Lukic1, A, D–F, Dragomir Laudanovic2, B, C, F, Marko Folic3, C–F, Nevena Folic3, C–F, Slobodan Jankovic3, A, C–F
Effects of Nimodipine on Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage Treated by Endovascular Coiling* Wpływ nimodypiny na skurcz naczyń mózgowych u chorych z krwotokiem podpajęczynówkowym z pękniętego tętniaka leczonych przez embolizację wewnątrznaczyniową Radiology Department, Medical Faculty, University of Kragujevac and Kragujevac Clinical Center, Kragujevac, Serbia Radiology Department, City Hospital, Uzice, Serbia 3 Pharmacology Department, Medical Faculty, University of Kragujevac and Kragujevac Clinical Center, Kragujevac, Serbia 1 2
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of article; G – other
Abstract Background. An aneurysmal subarachnoid hemorrhage could be complicated with cerebral vasospasm and resultant ischemia, causing neurological deficit. Objectives. The aim of this study was to compare early and late outcomes in patients with subarachnoidal hemorrhage (SAH) treated by endovascular coiling, who either received or did not receive prophylaxis of cerebral vasospasm with nimodipine. Material and Methods. In this retrospective cross-sectional study, the data was collected from the histories of 68 patients (38 females and 30 males, age range 29–71 years) with spontaneous aneurysmal SAH in clinical stage HH I–IV, treated at Kragujevac Clinical Center, Serbia, from January 2008 till June 2009. The study population was divided into two groups: (1) the group of 42 patients who received intravenous prophylaxis with nimodipine for 3 weeks, and (2) the group of 26 patients who did not receive nimodipine prophylaxis. Results. Prophylactic use of nimodipine did not decrease the rate of neurological deficit after one month, but the rates of both cerebral vasospasm (symptomatic and asymptomatic) and the morphological signs of ischemia using nuclear magnetic resonance imaging (MRI) were significantly lower in the nimodipine-protected group. Cerebral vasospasm was detected by Digital Subtraction Angiography (DSA) in the group protected by nimodipine as discrete in 2 patients (5%), and as apparent in 0 patients (0%). On the other hand, in the group unprotected by nimodipine, cerebral vasospasm was detected by DSA as discrete in 9 patients (35%), and as apparent in 6 patients (23%). Up to one month after the endovascular coiling, in the nimodipine-protected group, the T1W hypointense zones were detected by MRI as “small” in 5 patients (12%), as “medium” in 1 patient (2.5%), as “large” in 1 patient (2.5%), and as “multiple” in 2 patients (5%). In the nimodipine-unprotected group, the T1W hypointense zones were detected by MRI as “small” in 4 patients (16%), as “medium” in 2 patients (8%), as “large” in 3 patients (12%), and as “multiple” in 4 patients (16%). The difference between the groups was significant. Conclusions. When a patient with SAH is treated with the endovascular clipping procedure, prophylactic administration of nimodipine is mandatory due to the reduced rate of cerebral vasospasm and delayed cerebral ischemia (Adv Clin Exp Med 2013, 22, 1, 101–109). Key words: subarachnoidal hemorrhage, endovascular coiling, cerebral vasospasm, nimodipine. * This study was partially funded through a grant awarded by the Medical Faculty, University of Kragujevac, and through a grant given by the Montenegro Ministry of Science.
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Streszczenie Wprowadzenie. Krwotok podpajęczynówkowy może być powikłany skurczem naczyń mózgowych i następującym niedokrwieniem, co powoduje deficyt neurologiczny. Cel pracy. Porównanie wyników wczesnych i odległych u chorych z krwotokiem podpajęczynówkowym (SAH) leczonych przez embolizację wewnątrznaczyniową, którzy otrzymali lub nie otrzymywali nimodypinę jako profilaktykę skurczu naczyń mózgowych. Materiał i metody. W tym retrospektywnym badaniu przekrojowym zebrano historie 68 pacjentów (38 kobiet i 30 mężczyzn, w wieku 29–71 lat) ze spontanicznym krwotokiem podpajęczynówkowym z pękniętego tętniaka w klinicznym stadium HH I-IV, leczonych w Centrum Klinicznym w Kragujevac, Serbia, od stycznia 2008 do czerwca 2009 roku. Badanych podzielono na dwie grupy: (1) grupa 42 pacjentów, którzy otrzymywali dożylnie profilaktycznie nimodypinę przez 3 tygodnie i (2) grupa 26 pacjentów, którzy nie otrzymywali nimodypiny. Wyniki. Profilaktyczne stosowanie nimodypiny nie zmniejszyło odsetka deficytu neurologicznego po miesiącu, ale częstotliwość zarówno skurczu naczyń mózgowych (objawowego i bezobjawowego), jak i morfologicznych objawów niedokrwienia w badaniu MRI były istotnie mniejsze w grupie, w której podawano nimodypinę. Skurcz naczyń mózgowych został wykryty za pomocą badania DSA w grupie, w której podawano nimodypinę jako nieciągły u 2 (5%), i jako widoczny u 0 pacjentów (0%). Z drugiej strony, w grupie bez podawania nimodypiny, skurcz naczyń mózgowych wykryto za pomocą metody DSA jako nieciągły u 9 pacjentów (35%), i widoczny u 6 pacjentów (23%). W ciągu jednego miesiąca po embolizacji wewnątrznaczyniowej w grupie, w której podawano nimodypinę hipointensywne obszary T1W zostały wykryte w badaniu MR jako „małe” u 5 chorych (12%), jako „średnie” u 1 chorego (2,5%), jako „duże” u 1 (2,5%), jako „liczne” u 2 (5%). W grupie bez podawania nimodypiny, hipointensywne obszary T1W wykryte w badaniu MR jako „małe” u 4 (16%), jako „średnie” u 2 (8%), jako „duże” u 3 (12%), i jako „liczne” u 4 chorych (16%). Różnica między grupami była istotna statystycznie. Wnioski. Kiedy pacjent z krwotokiem podpajęczynówkowym jest leczony za pomocą embolizacji wewnątrznaczyniowej, profilaktyczne podawanie nimodypiny jest obowiązkowe ze względu na zmniejszenie ryzyka skurczu naczyń mózgowych i opóźnianie niedokrwienia mózgu (Adv Clin Exp Med 2013, 22, 1, 101–109). Słowa kluczowe: krwotok podpajęczynówkowy, embolizacja wewnątrznaczyniowa, skurcz naczyń mózgowych, nimodypina.
An aneurysmal subarachnoid hemorrhage (SAH) could be complicated with cerebral vasospasm, which adversely affects the outcome: it accounts for up to 23% of disability and deaths related to SAH [1–5]. Although the incidence of vasospasm ranges from 40% to 70% of aneurismal SAH patients (vasospasm documented by angiography), it causes symptoms due to delayed ischemic neurological deficit (DID) (symptomatic vasospasm) in only 17–40% of patients with aneurismal SAH [6–9]. However, every second patient with symptomatic vasospasm will develop ischemic infarct [10]. SAH-induced vasospasm is a complex and poorly understood entity due in part to a delayed and reversible vasculopathy, impaired autoregulatory function, and hypovolemia causing regional reduction of cerebral perfusion to the point of causing ischemia [11, 12]. Histologically, there are structural alterations in the endothelial and smooth muscle cells of the arterial wall [13]. The presence of oxyhemoglobin in subarachnoid space seems to be a triggering event, necessary to produce these changes [14–16]. However, the specific mechanisms leading to vasoconstriction are not completely identified. In vitro, oxyhemoglobin stimulates secretion of potent vasoconstrictor endothelin-1 in endothelial cells, inhibits the vasodilator nitric oxide (NO) and produces reactive oxygen species, leading to lipid peroxidation and structural changes in the vessels [17–19].
Risk factors for vasospasm and DID are the amount and duration of exposure to subarachnoid blood and presence of blood in cerebral ventricles [20–23]. Interestingly, endovascular coiling of the ruptured aneurysm, a procedure that does not involve a craniotomy and washing out of the subarachnoid blood, does not increase the risk of vasospasm in comparison to surgical clipping [24, 25]). Advanced age [26], race [27], poor neurological status on admission [5, 26, 28] and use of antifibrinolytic agents [4, 22, 29] are also associated with the development of DID. Factors less strongly linked to a higher incidence of DID are a longer duration of unconsciousness following the initial hemorrhage [30], history of hypertension [26, 31], smoking [32, 33] and excess weight [31]. Nimodipine is a dihydropyridine derivative that blocks calcium influx through the L-type calcium channels. It is well studied and the only drug approved by drug agencies in the majority of countries for use in the prevention and treatment of cerebral vasospasm. It has been shown in clinical studies to be a safe [34] and cost-effective drug [35–39] when cerebral vasospasm itself was the main outcome; however, its effectiveness has remained unclear when mortality and neurological sequelae were studied as the main outcomes [36–39]. On the other hand, prevention of cerebral vasospasm and DID by nimodipine in patients after aneurismal SAH treated by endovascular coil-
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ing has rarely been studied in larger patient series [40], and was never compared with non-prevention in the same study period, due to ethical reasons. However, in hospitals without established local protocols for administration of nimodipine after SAH, it may happen that a certain percentage of patients remain unprotected by this drug, giving an opportunity to study cerebral vasospasm and DID after endovascular coiling itself. The aim of this study was to investigate the effect of nimodipine on the prevention of cerebral vasospasm and DID in patients with SAH treated by endovascular coiling, comparing patients who received nimodipine prophylaxis with those who did not .
Material and Methods Study Design This study was designed as a retrospective cross-sectional study, including all patients hospitalized at the study site due to aneurysmal SAH during a pre-defined time period.
Patient Population During the time period from January 2008 till June 2009, there were 68 patients (38 females and 30 males, age range 29–71 years) with spontaneous aneurysmal SAH in clinical stage HH I–IV, treated at Kragujevac Clinical Center, in Kragujevac, Serbia. The diagnosis of SAH was confirmed by the evidence of blood in the subarachnoid space during computerized tomography (CT) scans. All patients were subjected to endovascular coiling of the ruptured aneurysm. During the endovascular procedure, if cerebral vasospasm was induced, an intraarterial bolus injection of 0.4 mg nimodipine was administered. Characteristics of the patient population are listed in Table 1.
Nimodipine Prophylaxis In 42 patients with aneurysmal SAH, nimodipine was administered prophylactically immediately after the diagnosis was confirmed. Nimodipine was given as a continuous intravenous infusion in a daily dose of 60 mg daily during the first week, 40 mg daily in the second week and 20 mg daily in the third week. In 26 patients, nimodipine was not administered prophylactically, by individual decision of the responsible physician. This study revealed such an obsolete practice, and served as the background for adoption and
implementation of local guidelines for the obligatory prophylactic administration of nimodipine in the year 2009. The study patients were followed by a neurologist and neuroradiologist up to nine months from SAH onset.
Study Outcomes The main study outcomes were cerebral vasospasm, delayed ischemic neurological deficit and incidence of cerebral infarction. The cerebral vasospasm was diagnosed by Digital Subtracting Angiography (DSA) or by Nuclear Magnetic Resonance (MRI) diffusion. Delayed ischemic neurological deficit was diagnosed by MRI, and cerebral infarction was confirmed by the presence of T1W hypointense zones accompanied with focal neurological deficits appropriate for those zones. The T1W hypointense zones were classified by the same observer radiologist on a visual analogue scale (with a range from 0 to 10) as “small“ (values 0–4), “medium“ (values 5, 6 and 7), and “large“ (values 8–10). The patients were evaluated on the first, third and seventh day after endovascular coiling, and then after one, three and nine months.
Statistics The characteristics of the study groups are described with frequencies (for discrete variables) or with mean values ± standard deviation (for continuous variables). The significance of differences between groups was tested by Chi-square test (for frequencies) or by Student’s T-test for small independent samples (for continuous variables). When less than 80% of observed frequencies are greater than 5, the Fisher exact probability test was used for comparison between the study groups. A comparison of two groups of paired observations for frequencies was made using a McNemar test. The differences were considered significant if the probability of the null hypothesis was less than 0.05. Calculations of the Chi-square test and Fisher exact probability test were made using online interactive calculation tools [41, 42]), while calculations of the Student’s T-test and McNemar test were made manually.
Results The endovascular coiling procedure in this study led to a significant decrease in aphasia frequency (χ2McNemar = 5.818, p < 0.05). Before the procedure, 38 patients (56%) experienced aphasia, and one month after endovascular coiling only 14 patients (21%) still had aphasia at a neurological eval-
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Table 1. Baseline characteristics of the study groups. For discrete variables, figures in the table show absolute number of patients and percentage of the total number of patients in the respective group in parentheses Tabela 1. Charakterystyka wyjściowa badanych grup. Dla zmiennych dyskretnych dane w tabeli pokazują bezwzględną liczbę pacjentów i odsetek całkowitej liczby pacjentów w danej grupie w nawiasach Factor (Czynnik)
Group with prophylaxis with nimodipine (Grupa z profilaktyką za pomocą nimodypiny)
Group without prophylaxis with nimodipine (Grupa bez profilaktyki za pomocą nimodypiny)
Number of patients (Liczba pacjentów)
42
26
Sex – male/female (Płeć)
20/22 (48%/52%)
10/16 (38%/62%)
χ2 = 0.398, p > 0.05
Age – years (Wiek – lata)
52 ± 10.34
54 ± 11.42
T-test = 2.445, p < 0.05*
Body weight – kg (Masa ciała – kg)
73 ± 12.57
75 ± 14.78
T-test = 2.189, p < 0.05*
Smokers (Palacze)
32 (76%)
22 (85%)
χ2 = 0.533, p > 0.05
Diabetes mellitus (Cukrzyca)
10 (24%)
5 (19%)
χ2 = 0.216, p > 0.05
Hypercholesterolemia (Hipercholesterolemia)
21 (50%)
11 (42%)
χ2 = 0.433, p > 0.05
Hypertension (Nadciśnienie tętnicze)
18 (43%)
14 (54%)
χ2 = 0.317, p > 0.05
Multiple aneurisms (Wiele tętniaków)
4 (10%)
3 (12%)
χ2 = 0.416, p > 0.05
12 (29%) 8 (19%) 6 (14%) 3 (7%) 4 (10%) 6 (14%) 3 (7%)
7 (27%) 6 (23%) 3 (11.5%) 1 (4%) 3 (11.5%) 3 (11.5%) 3 (11.5%)
3.80 ± 2.32
4.45 ± 1.75
Location of aneurysm (Umiejscowienie tętniaka) internal carotid artery middle cerebral artery anterior communicating artery anterior cerebral artery posterior communicating artery vertebrobasilar circulation other Interval (days) between SAH onset and endovascular coiling (Czas w dniach od rozpoczęcia krwotoku podpajęczynówkowego do przeprowadzenia embolizacji wewnątrznaczyniowej) Hunt and Hess (HH) grade (Stopień) I II III IV
Comparison between the groups (Porównanie między grupami)
χ2 = 0.985, p > 0.05
T-test = 1.796, p > 0.05
χ2 = 0.763, p > 0.05 10 (24%) 16 (38%) 13 (31%) 3 (7%)
6 (23%) 11 (42%) 8 (31%) 1 (4%)
For continuous variables, mean values ± standard deviation are shown in the table. * significant difference. Dla zmiennych ciągłych dane są przedstawione w tabeli jako wartości średnie ± odchylenie standardowe. * Różnica istotna statystycznie.
uation. However, the frequency of aphasia before and after endovascular coiling was not significantly different in groups with and without nimodip-
ine prophylaxis. Before the procedure, there were 24 patients (57%) with aphasia in the nimodipine group, and 14 patients (54%) with aphasia in the
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Cerebral Vasospasm and Nimodipine Table 2. Differences in outcomes among the study groups Tabela 2. Różnice w wynikach między grupami badanych Factor (Czynnik)
Group with prophylaxis with nimodipine (Grupa z profilaktyką za pomocą nimodypiny)
Group without prophylaxis with nimodipine (Grupa bez profilaktyki za pomocą nimodypiny)
Comparison between the groups (Porównanie między grupami)
before the endovascular coiling
24 (57%)
14 (54%)
χ2 = 0.071, p > 0.05
after the endovascular coiling
6 (14%)
8 (31%)
χ2 = 2.669, p > 0.05
Frequency of motor deficit in upper extremities (Częstotliwość deficytu ruchowego kończyn górnych)
before the endovascular coiling
25 (60%)
14 (54%)
χ2 = 0.212, p > 0.05
after the endovascular coiling
7 (17%)
7 (27%)
χ2 = 1.033, p > 0.05
Frequency of motor deficit in lower extremities (Częstotliwość deficytu ruchowego kończyn dolnych)
before the endovascular coiling
23 (55%)
14 (54%)
χ2 = 0.005, p > 0.05
after the endovascular coiling
6 (14%)
7 (27%)
χ2 = 1.659, p > 0.05
Frequency of confusion (Częstotliwość stanu splątania)
before the endovascular coiling
28 (67%)
18 (69%)
χ2 = 0.048, p > 0.05
after the endovascular coiling
5 (12%)
5 (19%)
χ2 = 0.484, p > 0.05
Cerebral vasospasm (Skurcz naczyń mózgowych
before the endovascular coiling
discrete: 4 (10%)
discrete: 4 (15%)
P = 0.001462*
apparent: 1 (4%)
apparent: 7 (27%)
P = 0.001462*
discrete: 2 (5%)
discrete: 9 (35%)
P = 0.0000008*
apparent: 0 (0%)
apparent: 6 (23%)
P = 0.0000008*
small: 2 (5%)
small: 2 (8%)
medium: 1 (2.5%)
medium: 1 (4%)
large: 0 (0%)
large: 1 (4%)
multiple: 2 (5%)
multiple: 3 (12%)
small: 5 (12.5%)
small: 4 (16%)
medium: 1 (2.5%)
medium: 2 (8%)
large: 1 (2.5%)
large: 3 (12%)
multiple: 2 (5%)
multiple: 4 (16%)
Mortality rate 9 months after endovascular coiling (Śmiertelność 9 miesięcy po embolizacji wewnątrznaczyniowej)
1 (2%)
3 (11.5%)
Fisher’s exact test: p = 0.152446
Neurological deficit 9 months after endovascular coiling (Deficyt neurologiczny 9 miesięcy po embolizacji wewnątrznaczyniowej)
7 (17%)
9 (39%)
χ2 = 3.823, p > 0.05
Frequency of aphasia (Częstotliwość afazji)
after the endovascular coiling T1W hypointense zones detected by MRI (T1W hipointensywne obszary wykryte przez MR)
before the endovascular coiling
after the endovascular coiling
χ2 = 3.410, p > 0.05
χ2 = 5.990, p < 0.05*
For discrete variables, figures in the table show the absolute number of patients and percentage of the total number of patients in the respective group in parentheses. For continuous variables, mean values ± standard deviation are shown in the table. * significant difference. Dla zmiennych dyskretnych dane w tabeli pokazują bezwzględną liczbę pacjentów i odsetek całkowitej liczby pacjentów w danej grupie w nawiasach. Dla zmiennych ciągłych dane są przedstawione w tabeli jako wartości średnie ± odchylenie standardowe. * Różnica istotna statystycznie.
106 group without nimodipine (χ2 = 0.071, p > 0.05); one month after endovascular coiling, there were 6 patients (14%) with aphasia in the nimodipine group, and 8 (31%) patients with aphasia in the group without nimodipine (χ2 = 2.669, p > 0.05). The frequency of motor deficit in the upper extremities was decreased by the endovascular coiling procedure in this study (χ2McNemar = 4.667, p < 0.05). Before the procedure, 40 patients (59%) experienced motor deficit in upper extremities, and one month after endovascular coiling, only 14 patients (21%) still had such a deficit at the neurological evaluation. However, the frequency of motor deficit in upper extremities before and after endovascular coiling was not significantly different in groups with and without nimodipine prophylaxis. Before the procedure, there were 25 patients (60%) with motor deficit in upper extremities in the nimodipine group, and 14 patients (54%) with motor deficit in upper extremities in the group without nimodipine (χ2 = 0.212, p > 0.05); one month after endovascular coiling there were 7 patients (17%) with motor deficit in upper extremities in the nimodipine group, and 7 patients (27%) with motor deficit in upper extremities in the group without nimodipine (χ2 = 1.033, p > 0.05). The frequency of motor deficit in the lower extremities was decreased by the endovascular coiling procedure in our study (χ2McNemar=7.364, p<0.01). Before the procedure 37 patients (54%) experienced motor deficit in lower extremities, and one month after endovascular coiling only 13 patients (19%) still had such a deficit at the neurological evaluation. However, the frequency of motor deficit in lower extremities before and after endovascular coiling was not significantly different in groups with and without nimodipine prophylaxis. Before the procedure there were 23 patients (55%) with motor deficit in lower extremities in the nimodipine group, and 14 patients (54%) with motor deficit in lower extremities in the group without nimodipine (χ2=0.005, p>0.05); one month after endovascular coiling there were 6 patients (14%) with motor deficit in lower extremities in the nimodipine group, and 7 patients (27%) with motor deficit in lower extremities in the group without nimodipine (χ2=1.659, p>0.05). The endovascular coiling procedure in this study led to a significant decrease of confusion frequency (χ2McNemar = 4.500, p < 0.05). Before the procedure, 46 patients (68%) were confused, and one month after endovascular coiling only 10 patients (15%) still were confused at the neurological evaluation. However, the frequency of confusion before and after endovascular coiling was not significantly different in groups with and without nimodipine prophylaxis. Before the procedure,
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there were 28 patients (67%) with confusion in the nimodipine group, and 18 patients (69%) with confusion in the group without nimodipine (χ2 = 0.048, p > 0.05); one month after endovascular coiling, there were 5 patients (12%) with aphasia in the nimodipine group, and 5 patients (19%) with confusion in the group without nimodipine (χ2 = 0.484, p > 0.05). Throughout the whole hospital treatment of the patients, symptomatic vasospasm appeared more often in the group without nimodipine (in 12 patients out of 26, or 46%) than in the group protected by nimodipine (in 5 patients out of 42, or 12%), and this difference was significant (χ2 = 10.046, p < 0.01). Before the endovascular coiling, cerebral vasospasm detected by Digital Subtracting Angiography in the group protected by nimodipine was characterized as discrete in 4 patients (10%), and as apparent in 1 patient (4%). On the other hand, in the group unprotected by nimodipine, cerebral vasospasm was detected by DSA as discrete in 4 patients (15%), and as apparent in 7 patients (27%). The difference between the groups in frequency of cerebral vasospasm before the endovascular coiling was significant (Fisher exact test with Freeman-Halton extension: PA = 0.001462, PB = 0.001462). Up to one month after the endovascular coiling, cerebral vasospasm was detected by Digital Subtracting Angiography in the group protected by nimodipine as discrete in 2 patients (5%), and as apparent in 0 patients (0%). On the other hand, in the group unprotected by nimodipine, cerebral vasospasm was detected by DSA as discrete in 9 patients (35%), and as apparent in 6 patients (23%). The difference between the groups in frequency of cerebral vasospasm after the endovascular coiling was significant (Fisher exact test with Freeman-Halton extension: PA = 0.0000008, PB = 0.0000008). If nimodipine prophylaxis is not taken into account, out of 68 study patients total, there were 8 (12%) with discrete and 8 (12%) with apparent cerebral vasospasm before the endovascular coiling, and 11 (16%) with discrete and 6 (9%) with apparent cerebral vasospasm up to one month after the endovascular coiling. The difference in rate of cerebral vasospasm before and after endovascular coiling was not significant (χ2McNemar = 0.769, p > 0.05). There were in total 20 cases (29%) of cerebral vasospasm induced by the endovascular coiling procedure, regardless of the nimodipine prophylaxis. Twelve cases were classified as “mild“, and 8 as “severe“. Intraarterial injection of nimodipine during the procedure successfully reversed vasospasm in 4 “mild“ cases (33%), and in 6 “severe” cases (75%). Before the endovascular coiling, in the nimo-
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dipine-protected group, the T1W hypointense zones were detected by MRI as “small“ in 2 patients (5%), as “medium“ in 1 patient (2.5%), as “large“ in 0 patients, and as “multiple“ in 2 patients (5%). In the nimodipineunprotected group, the T1W hypointense zones were detected by MRI as “small“ in 2 patients (8%), as “medium“ in 1 patient (4%), as “large“ in 1 patient (4%), and as “multiple“ in 3 patients (12%). However, the difference between the groups in frequency of the T1W hypointense zones (the subgroups merged) was not significant (χ2 = 3.410, p > 0.05). Up to one month after the endovascular coiling, in the nimodipine-protected group, the T1W hypointense zones were detected by MRI as “small“ in 5 patients (12.5%), as “medium“ in 1 patient (2.5%), as “large“ in 1 patient (2.5%), and as “multiple“ in 2 patients (5%). In the nimodipine-unprotected group, the T1W hypointense zones were detected by MRI as “small“ in 4 patients (16%), as “medium“ in 2 patients (8%), as “large“ in 3 patients (12%), and as “multiple“ in 4 patients (16%). The difference between the groups in frequency of the T1W hypointense zones (the subgroups merged) was significant (χ2 = 5.990, p < 0.05). If nimodipine prophylaxis is not taken into account, out of 68 study patients total, there were “small“ T1W hypointense zones in 4 patients (6%), “medium“ in 2 patients (3%), “large“ in 1 patient (1.5%), and “multiple“ 5 patients (7.5%) before the endovascular coiling, and “small“ T1W hypointense zones in 9 patients (13.5%), “medium“ in 3 patients (4.5%), “large“ in 4 patients (6%), and “multiple“ 6 patients (9%) up to one month after the endovascular coiling. The difference in frequency of T1W hypointense zones before and after endovascular coiling was not significant (χ2McNemar=3.457, p > 0.05). Finally, nine months after the endovascular coiling, in the nimodipine-protected group there was one case of death due to SAH (2% mortality) and 7 patients with any kind of neurological deficit (17%). In the nimodipine-unprotected group, there were 3 cases of death due to SAH (11.5% mortality) and 9 patients with any kind of neurological deficit (39%). The difference between the groups in the rate of neurological deficit was not significant (χ2 = 3.823, p > 0.05). The difference between the groups in mortality rate was also not significant (Fisher’s exact test: p = 0.152446).
Discussion Of the two most significant complications after subarachnoid hemorrhage (SAH), rebleeding and delayed cerebral ischemia, the first is effectively prevented by neurosurgical clipping or endovascular obliteration of ruptured aneurysms [43]. For
107 prevention of the second complication, oral or intravenous nifedipine is used; however, the relation between the prevention of cerebral vasospasm/ delayed cerebral ischemia and the improvement of long-term patient outcomes is not completely clear. In a recent study with 232 subarachnoid hemorrhage survivors, the frequency of neurological sequelae after one year from SAH was only loosely related to cerebral vasospasm and delayed cerebral ischemia (3.6 times greater risk) [44]. In this study, the endovascular coiling procedure by itself decreased the rate of neurological deficit in the short term (decreased rate of aphasia, motor deficit in lower and upper extremities, and confusion after one month), but this was not accompanied by a decreased frequency of morphological signs of ischemia in an MRI of the brain (T1W hypointense zones) or decreased rate of cerebral vasospasm. On the contrary, the endovascular coiling procedure may induce cerebral vasospasm [45], requiring immediate intra-arterial administration of nimodipine. Twentynine percent of present patients developed cerebral vasospasm during the endovascular procedure, and intraarterial nimodipine successfully reversed the vasospasm in the majority of cases. Similar results were obtained in other studies, achieving reversal of vasospasm in three-fourths of cases [46]. On the other hand, prophylactic use of nimodipine did not decrease the rate of neurological deficit after one month, but the rates of both cerebral vasospasm (symptomatic and asymptomatic) and morphological signs of ischemia in an MRI were significantly lower in the nimodipine-protected group. In other studies [40], the beneficial effect of nimodipine on cerebral vasospasm was also observed in patients with SAH treated by neurosurgical clipping of ruptured aneurysms, further strengthening the recommendation to use nimodipine in all cases of SAH, regardless of the method used for mechanical prevention of rebleeding. In this study, prophylactic use of nimodipine did not affect the long-term outcomes of SAH, like mortality and the rate of neurological sequelae after nine months, although there was a tendency towards improvement of the sequelae. Similar results were observed in a recent study [47], confirming present findings, but one early study [34] did relate nimodipine use with better neurological outcome after 3 months. It seems that the prevention of cerebral vasospasm and delayed cerebral ischemia achieved by nifedipine prophylaxis does not translate directly into improvement of functional neurological impairment. There are alternative causes of neurological deterioration and poor outcome after SAH, such as the delayed effects of acute global cerebral ischemia, thromboembolism and microcirculatory dysfunction [48]. Cerebral
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vasospasm probably just initiates complex processes in brain tissue, leading eventually to loss of function. In order to improve the final outcomes after SAH, it is not enough to prevent or reverse cerebral vasospasm; additional therapy is needed to prevent or reverse the adverse processes which impair microcirculation and oxygen transport within the brain areas affected by vasospasm. When a patient with SAH is treated with the endovascular clipping procedure, prophylactic ad-
ministration of nimodipine is mandatory due to the reduced rate of delayed cerebral ischemia. If such a patient develops vasospasm during the endovascular coiling procedure, intraarterial administration of nimodipine will reverse the vasospasm with high probability. However, further studies are needed to search for additional therapeutic measures which will improve the final outcome of patients with SAH.
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Address for correspondence: Slobodan M. Jankovic Medical Faculty, University of Kragujevac ul. Svetozara Markovica 69 34000 Kragujevac Serbia Tel.: +381 61 320 63 92 E-mail: slobodan.jankovic@medf.kg.ac.rs
Conflict of interest: None declared Received: 3.11.2011 Revised: 22.04.2012 Accepted: 11.02.2013