Neurocrit Care DOI 10.1007/s12028-014-9996-5
ORIGINAL ARTICLE
Milrinone Via Lumbar Subarachnoid Catheter for Vasospasm After Aneurysmal Subarachnoid Hemorrhage Nobutake Sadamasa • Kazumichi Yoshida • Osamu Narumi • Masaki Chin • Sen Yamagata
Ó Springer Science+Business Media New York 2014
Abstract Introduction Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to elucidate the safety and feasibility of intrathecal milrinone infusion via lumber subarachnoid catheter for prevention of DIND after aSAH. Methods We diagnosed 425 consecutive patients with aSAH who received clipping or coil embolization within 48 h after arrival. Patients with the evidence of vasospasm on CT angiography (CTA) received the milrinone therapy via lumbar subarachnoid catheter. DIND, delayed cerebral infarction (DCI), and modified Rankin scale at 3 months after SAH were used for the assessment of outcome. Results Of 425 patients, 170 patients (40.0 %) with CTAproven vasospasm received the milrinone therapy. DIND was observed in 68 patients (16.0 %), DCI in 30 patients (7.1 %), and the overall mortality was 7.2 %. In patients with WFNS grade IV and V aSAH, 26 out of 145 patients (17.9 %) were presented with DIND, 12 (8.3 %) with DCI, and the mortality was 16.0 %. No major complication related to the milrinone injection was observed. Conclusion Intrathecal milrinone injection via lumbar catheter was safe and feasible, and further randomized prospective studies are needed to confirm the effectiveness of this regimen in the patients with SAH.
N. Sadamasa (&) K. Yoshida O. Narumi M. Chin S. Yamagata Department of Neurosurgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki City, Okayama 710-8602, Japan e-mail: [email protected]
Keywords Intracranial aneurysm Milrinone Subarachnoid hemorrhage Vasospasm Treatment Intrathecal injection
Introduction Aneurysmal subarachnoid hemorrhage (aSAH) still remains life-threatening. Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm (SVS) is a major cause of morbidity and mortality after aSAH as well as age, neurological grade, and hematological factors [1]. Various therapeutic strategies, including intra-arterial administration of nimodipine [2], papaverine (PPV) [3, 4], verapamil [5], and percutaneous transluminal angioplasty (PTA) [6], have been used to treat SVS. However, the mechanism of SVS remains unsolved, and that is why DIND still occurs in 34.3 % of patients with poor-grade aSAH in the recent large Japanese study [7]. Milrinone, a bipyridine phosphodiesterase (PDE) III inhibitor, is classified as an inodilator with both inotropic and vasodilator effects. An experimental study showed that milrinone improved cerebral vasospasm [8], and that intracisternal infusion of milrinone was more effective than intra-arterial infusion of it [9]. In human, two studies reported that intra-arterial injection of milrinone reduced the SVS after SAH [10, 11], and one reported the effectiveness of cisternal irrigation of milrinone, i.e., from a ventricular catheter in the lateral ventricle to a cisternal catheter in the basal cistern, to prevent SVS after SAH [12]. However, cisternal irrigation via ventricular catheter has some disadvantages such as risk of pneumocephalus, requirement for the long-term rest, and risk of catheter infection especially when it placed more than 10 days [13]. From these disadvantages of cisternal irrigation, we needed
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Neurocrit Care
Between 2005 and 2012, 428 consecutive patients diagnosed as SAH due to a ruptured intracranial aneurysm and treated (clipped or coiled) within 48 h after the onset were retrospectively reviewed. Two patients who received intraarterial infusion of milrinone and one with PTA were excluded from this study. In 425 cases, we did not use any intra-arterial infusions or percutaneous transluminal angioplasty (PTA) for the treatment of vasospasm. SAH was confirmed in all the patients by head computed tomographic scans (CT) or lumbar puncture and was rated according to the Fisher scale. World Federation of Neurological Surgeons (WFNS) grade on arrival was used for initial clinical grading. Subsequently, contrast-enhanced head three-dimensional CT angiography (CTA) was performed for detecting a bleeding source such as intracranial aneurysm. This study protocol was approved by institutional review board and local ethical committee.
arteries, according to Consensus 2009 [15]. Delayed cerebral infarction (DCI) was defined as newly developed low density area on postoperative CT scan as a result of DIND. In the CTA, we observed bilateral A1 and A2 segment of the anterior cerebral artery, bilateral M1 and M2 segment of the middle cerebral artery, bilateral P1 and P2 segments of the posterior cerebral artery, and the basilar artery. Each spastic arterial segment was subjectively compared with the same segments in the CTA done at the initial diagnosis. The presence of a vasospasm was assessed using a grading scale as follows: none, mild (75 % reduction) [4]. In patients with the evidence of moderate or severe vasospasm on CTA, normovolemia were initiated together with the milrinone therapy as described below. Milrinone therapy via lumbar subarachnoid catheter. A subarachnoid catheter was placed into lumbar subarachnoid cistern via lower lumber entry point in a standard fashion. Patients received 0.87 mg milrinone (2.6 ml/day) per 7 ml normal physiological saline for 2 h injected into the lumbar subarachnoid cistern through the catheter. The catheter was clamped for subsequent 2 h, and cisternal drainage was performed for following 4 h. This 8-h cycle was repeated until day 14 after the onset of SAH. If the patients had a ventricular catheter, cisternal irrigation basically from the ventricle to the cistern was performed until day 7 after the onset of SAH as previously reported [14], followed by lumbar cisternal injection of milrinone. The contraindication of this milrinone therapy included high-grade scoliosis or other lumbar spinal canal diseases, and bleeding tendency. In this series, we did not experience such patients.
Management of SAH
Outcome Measurement
All patients received intravenous infusion of fasudil hydrochloride (a rho-kinase inhibitor) if no contraindication existed. Cisterns were irrigated via ventricular drainage for 3–5 days if ventricular drain was inserted. The details of cisternal irrigation were previously described [14]. Three-dimensional CTA or distal subtraction angiography was performed between day 5 and 7, around day 10, and after day 14 to confirm the obliteration of the aneurysm and to assess the severity of vasospasm. Plain head CT scans were performed on the day after the surgery to assess the initial damage, and around day 21 to confirm cerebral infarction due to SVS. Delayed ischemic neurological deficit was defined as a worsening of the neurological condition (altered consciousness, aphasia, and hemiplegia or hemiparesis) that could not be attributed to rebleeding, postoperative complications, hydrocephalus, or systemic complications, with luminal narrowing of cerebral
DIND, DCI, and modified Rankin scale (mRS) at 3 months after SAH were used for the assessment of outcome. The outcome of poor-grade (grade IV and V) SAH also showed with that in the previous reports, including historical controls of our department [11, 16–18] and the combined results of the other hospitals in the same division of Japan Neurosurgical Society which was recently published [7].
to refine the technique to infuse milrinone into cerebral arteries for a longer period in a less complicated manner. There is no study that showed the feasibility of milrinone through the lumbar subarachnoid catheter for the DIND after aSAH. We hypothesized that milrinone injection via lumbar subarachnoid catheter would be effective for the prevention of DIND after aSAH. In this study, we assessed the feasibility of milrinone infusion via lumber subarachnoid catheter for prevention of DIND after aSAH, and reviewed the old treatment regimens and the results in the recent clinical reports.
Methods
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Statistical Analysis Data are presented as mean ± standard deviation for continuous variables, and as frequency for categorical variables. Comparisons between groups were performed using unpaired Student’s t test for continuous variables, and Fisher’s exact test or Chi square test for categorical variables. A p value less than .05 was considered significant for all the analyses.
Neurocrit Care Table 1 Baseline characteristics of 425 patients who received clipping or coil embolization of ruptured intracranial aneurysm WFNS I–V (n = 425) Age (mean ± SD)
63.7 ± 13.8
Table 2 Outcome after aneurysmal subarachnoid hemorrhage treated with clipping or coil embolization
WFNS IV, V (n = 145) 66.6 ± 12.2 44:101
WFNS grade I–V
WFNS grade IV,V
DIND
68
16.0 %
26
17.9 %
DCI
30
7.1 %
12
8.3 %
60.0 %
46
31.7 %
Sex(M:F)
126:299
WFNS grade Grade I
0,1,2
255
150
0
3
50
20
Grade II
110
0
4
53
28
Grade III
20
0
Grade IV
71
71
5 6
36 31
Grade V
74
74
Group I
17
0
Group II
59
2
Group III
275
81
Group IV
74
62
Anterior circulation
370
122
Posterior circulation
55
23
319 97
105 37
9
3
Fisher group
Location of aneurysm
mRS at 3 months
27 24
7.2 %
16.0 %
Note that DIND was suppressed even in WFNS grade IV and V patients. DCI delayed cerebral infarction, DIND delayed ischemic neurological deficit, mRS modified Rankin Scale, WFNS World Federation of Neurological Surgeons
Table 3 Postoperative outcome of the poor-grade aneurysmal subarachnoid hemorrhage: review of the literatures Authors and Year
Treatment for SVS
Grade IV and V DIND (n, (n) %)
Treatment Clipping Coil embolization Others Cisternal irrigation
165
70
Milrinone via lumbar drainage
170
76
Note that the number of the aneurysm in posterior circulation and the number of endovascular treatment are more dominant in WFNS grade IV and V patients than in WFNS grade I-III patients. SD standard deviation, WFNS World Federation of Neurological Surgeons
Results Of 425 patients who received clipping or coiling for the ruptured aneurysm, 170 patients (40.0 %) received intrathecal milrinone injection via lumbar catheter. Of these, 105 patients (61.8 %) received ventricular drainage followed by cisternal irrigation. Baseline characteristics were shown in Table 1. The outcomes were shown in Table 2. In the patient with WFNS grade I–V, DIND was observed in 68 patients (16.0 %), DCI in 30 patients (7.1 %), and mortality was 7.2 %. In patients with WFNS grade IV and V (n = 145), 26 patients (17.9 %) were presented with DIND, 12 (8.3 %) with DCI, and mortality was 16.0 %. Patients with WFNS grade IV and V showed a significantly worse outcome (mRS) than those with WFNS grade I-III (p < 0.0001, Chi square test). However, there is no significant difference of the number of DIND and DCI between them. Table 3 showed the incidence of DIND after poor-grade aSAH in the other studies, and the results
Bracard et al. 2002 PTA, [16] Papaverine
80
15 (18.8)
Weir et al. 2003 [18]
PTA, Papaverine
27
7 (26.0)
Goto et al. 2004 [12]
Milrinone
24
7 (29.2)
Shirao et al. 2010 [7]
Not specified
283
97 (34.3)
Taylor et al. 2011 [17]
PTA
47
18 (38.3)
This study
Milrinone
145
26 (17.9)
Postoperative outcome of the poor-grade SAH in the current study and previous reports. DIND delayed ischemic neurological deficit, PTA percutaneous transluminal angioplasty, SVS symptomatic vasospasm
of this study were comparable or superior to those of the other reports. There were 165 patients who received cisternal irrigation. Of these, 75 patients received milrinone through lumbar catheter. Of these, DIND was in 24 and DCI in 11. Of 165 patients with cisternal irrigation, 90 patients were without milrinone through lumbar catheter. DIND was observed in 18, and DCI was observed in 9. There were 260 patients who did not receive cisternal irrigation. Of these, 68 patients were with milrinone through lumbar catheter. DIND was in 17, DCI in 7. 192 were without milrinone through lumbar catheter. DIND was in 9, DCI in 3. There were 143 patients with milrinone through lumbar catheter, and DIND was observed in 41 and DCI in 18.
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There were 282 patients without milrinone through the lumbar catheter, and DIND was in 27 and DCI in 12. Of 30 patients with DCI, 13 patients with CTA-proven vasospasm without DIND resulted in DIND and DCI despite milrinone infusion. Two patients with DIND without DCI resulted in DCI despite milrinone infusion. Both DIND and DCI were observed in the rest (15 patients) before milrinone infusion. Of 26 cases with DIND after poor-grade SAH, 20 cases (76.9 %) received milrinone via lumbar catheter. However, 16 cases (80.0 %) received milrinone after DIND was observed. Four cases (15.3 %) started before manifestation of DIND, but resulted in DIND and DCI. No major complication related to milrinone injection was observed. The patients showed no significant change in systolic (mean 146.0 ± 22.8 vs. 149.4 ± 21.0) and diastolic (mean 73.4 ± 9.4 vs. 74.2 ± 9.1) blood pressure during the treatment. No new arrhythmia related to milrinone was observed. No hemorrhagic complication was observed. Headache after injection of milrinone was infrequently found in the patients, but was tolerable. Leg dysesthesia was also sometimes observed when the lumbar catheter was inserted, but it was relieved after the course of the catheter had changed. Meningitis due to lumbar drainage was observed in 6 patients (3.5 %).
Discussion This is the first report that showed the feasibility of intrathecal milrinone infusion via lumbar catheter for SVS after aSAH. In 1990s, intra-arterial injection of papaverine has been extensively used for the treatment of SVS [12, 16, 17]. The advantage of intra-arterial injection is direct administration to the vessel narrowing using strong vasodilator. Calcium channel blockers, papaverine, fasudil hydrochloride, and milrinone were previously reported, and are now being used for intra-arterial infusion therapy for SVS [2–5, 10, 11, 15, 19]. A recent observational study indicated that endovascular treatment for SVS is performed in the majority of the hospitals in Japan (78.7 %) [15]. However, because the half lives of these drugs are several hours, repeated administration is needed when SVS continues for more than 1 day, and interventional procedures have potential risks that further aggravate the patient’s condition [20]. Moreover, both intra-arterial [10] and intravenous infusion [21] themselves do not escape from reduction of systemic blood pressure because of dilatation of systemic vessels. Because main trunks of cerebral arteries are situated in subarachnoid space, it is apparent that intracisternal administration is one of the most reasonable methods for
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the treatment of SVS. Thus, we changed the standard regimen for vasospasm from the intra-arterial fashion to the intracisternal one in the mid 2000s. The problems were that the management of continuous cisternal irrigation circuit was too difficult to perform in a general ward, and that we could not place intraventricular catheter more than 10 days because the risk of retrograde infection would increase. That was why a more simple method was needed for prevention of SVS. In this paper, we showed that our strategies including intrathecal injection of milrinone via lumbar subarachnoid catheter suppressed the occurrence of DIND. The overall rate of DIND and DCI after aSAH was 16.0 and 7.1 %, respectively, both of which were better than PRESAT study in Japan (DIND 19.1 % and DCI 17.6 % in 534 Japanese population) [22]. The number of the poor-grade patients with DIND in this study was significantly smaller than that after PPV + PTA previously reported. Moreover, the results of this study were comparable to those of cisternal milrinone irrigation via ventricular catheter. Majority of the ineffective cases were those who received intrathecal milrinone after the occurrence of DIND. From these facts, we think that the milrinone therapy via lumbar catheter should be started not after the vasospasm becomes symptomatic but after angiographical vasospasm was detected by the serial CT angiography. The overall outcome of aneurysmal SAH who received clipping/coil embolization in our department was comparable to other reports. The 3-month mortality after aSAH in this study was 7.2 %, better than the data of ISAT in which the 2-month mortality rate was 7.9 % [23]. Recent reports from the Netherlands [24] indicated that the overall risk of death around 1 month was 34 %. Especially in poor-grade SAH, our results were significantly better than the results of the other departments in Chugoku-Shikoku division (DIND 34.3 % and mortality 23.7 %) [7]. These facts showed that our postoperative management using milrinone would not be inferior to that of others using intraarterial fasudil and PTA. The reason why the result of this study was better than the other clinical studies might be multifactorial. Fasudil, milrinone, and lumbar drainage might be effective. We managed the post-SAH patients with normovolemia, not with hypervolemia and induced hypertension. It seems that hypervolemia do not appear to confer additional benefits over normovolemic therapy [25]. In Japan, over the half (60.2 %) of the neurosurgical departments started the treatment for DIND after appearance of SVS, and only 26.1 % of those after angiographic vasospasm in large extraparenchymal arteries was revealed with or without SVS (26.1 %) [15]. We should have in mind that the earlier start of the treatment for DIND would result in the better outcome of the patients.
Neurocrit Care
The milrinone therapy introduced in this study made the management of the vasospasm easier. Neurosurgeons do not need to concern about angiography room for this milrinone treatment. It might be more cost-effective than frequent endovascular interventions. Although we did not include the patients who received endovascular intervention, the results of this study did not deny the effectiveness of endovascular intervention for the vasospasm after SAH. Systemic side effects of milrinone were not detected in this study, possibly because the excess amount of the drug would be drained out through the catheter. A recent randomized study suggested that lumbar drainage of cerebrospinal fluid after the SAH reduced the prevalence of DIND [26], but not completely. In the LUMAS study [26], the overall rate of DIND after lumbar drainage was 21.0 %, slightly worse than our results (16.0 %). The milrinone treatment via the lumbar catheter would be a simple add-on for lumbar drainage against vasospasm after SAH. Although we could not detect any severe complications using milrinone, this method would have the potential of risk of intraspinal bleeding, spinal cord injury, and wound infection because of lumbar drainage. Milrinone itself has the risk of arrhythmia. This study has some limitations. Lack of control group was the main limitation of this study and it was impossible to obtain reliable conclusions about this drug effectiveness. In Japan, all intra-arterial and intrathecal drugs prescribed for vasospasm after SAH are being used off-label. Fasudil is an available drug for vasospasm in Japan, and a recent meta-analysis about fasudil found a significant reduction in the occurrence of cerebral vasospasm and cerebral infarction as well as an improvement in clinical outcome as assessed by GOS [27]. A survey of 414 hospitals with a neurosurgical department in Japan revealed that 92.5 % of the department used fasudil hydrochloride for the prophylactic therapies for vasospasm [15]. We compared each groups in different time, which would be biased because surgical/endovascular intervention and pre/postoperative management might have been improved throughout the years [28]. Oral nimodipine, an evidence-based proved drug to prevent DCI, is unavailable in Japan. This pilot study showed our experience of intrathecal administration of milrinone via lumbar subarachnoid catheter. This regimen is safe and feasible, and further randomized prospective studies are needed to confirm the effectiveness of this regimen in the patients with SAH. Acknowledgments Conflict of interest of interest.
None. The authors declare that they have no conflict
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ORIGINAL ARTICLE
Milrinone Via Lumbar Subarachnoid Catheter for Vasospasm After Aneurysmal Subarachnoid Hemorrhage Nobutake Sadamasa • Kazumichi Yoshida • Osamu Narumi • Masaki Chin • Sen Yamagata
Ó Springer Science+Business Media New York 2014
Abstract Introduction Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to elucidate the safety and feasibility of intrathecal milrinone infusion via lumber subarachnoid catheter for prevention of DIND after aSAH. Methods We diagnosed 425 consecutive patients with aSAH who received clipping or coil embolization within 48 h after arrival. Patients with the evidence of vasospasm on CT angiography (CTA) received the milrinone therapy via lumbar subarachnoid catheter. DIND, delayed cerebral infarction (DCI), and modified Rankin scale at 3 months after SAH were used for the assessment of outcome. Results Of 425 patients, 170 patients (40.0 %) with CTAproven vasospasm received the milrinone therapy. DIND was observed in 68 patients (16.0 %), DCI in 30 patients (7.1 %), and the overall mortality was 7.2 %. In patients with WFNS grade IV and V aSAH, 26 out of 145 patients (17.9 %) were presented with DIND, 12 (8.3 %) with DCI, and the mortality was 16.0 %. No major complication related to the milrinone injection was observed. Conclusion Intrathecal milrinone injection via lumbar catheter was safe and feasible, and further randomized prospective studies are needed to confirm the effectiveness of this regimen in the patients with SAH.
N. Sadamasa (&) K. Yoshida O. Narumi M. Chin S. Yamagata Department of Neurosurgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki City, Okayama 710-8602, Japan e-mail: [email protected]
Keywords Intracranial aneurysm Milrinone Subarachnoid hemorrhage Vasospasm Treatment Intrathecal injection
Introduction Aneurysmal subarachnoid hemorrhage (aSAH) still remains life-threatening. Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm (SVS) is a major cause of morbidity and mortality after aSAH as well as age, neurological grade, and hematological factors [1]. Various therapeutic strategies, including intra-arterial administration of nimodipine [2], papaverine (PPV) [3, 4], verapamil [5], and percutaneous transluminal angioplasty (PTA) [6], have been used to treat SVS. However, the mechanism of SVS remains unsolved, and that is why DIND still occurs in 34.3 % of patients with poor-grade aSAH in the recent large Japanese study [7]. Milrinone, a bipyridine phosphodiesterase (PDE) III inhibitor, is classified as an inodilator with both inotropic and vasodilator effects. An experimental study showed that milrinone improved cerebral vasospasm [8], and that intracisternal infusion of milrinone was more effective than intra-arterial infusion of it [9]. In human, two studies reported that intra-arterial injection of milrinone reduced the SVS after SAH [10, 11], and one reported the effectiveness of cisternal irrigation of milrinone, i.e., from a ventricular catheter in the lateral ventricle to a cisternal catheter in the basal cistern, to prevent SVS after SAH [12]. However, cisternal irrigation via ventricular catheter has some disadvantages such as risk of pneumocephalus, requirement for the long-term rest, and risk of catheter infection especially when it placed more than 10 days [13]. From these disadvantages of cisternal irrigation, we needed
123
Neurocrit Care
Between 2005 and 2012, 428 consecutive patients diagnosed as SAH due to a ruptured intracranial aneurysm and treated (clipped or coiled) within 48 h after the onset were retrospectively reviewed. Two patients who received intraarterial infusion of milrinone and one with PTA were excluded from this study. In 425 cases, we did not use any intra-arterial infusions or percutaneous transluminal angioplasty (PTA) for the treatment of vasospasm. SAH was confirmed in all the patients by head computed tomographic scans (CT) or lumbar puncture and was rated according to the Fisher scale. World Federation of Neurological Surgeons (WFNS) grade on arrival was used for initial clinical grading. Subsequently, contrast-enhanced head three-dimensional CT angiography (CTA) was performed for detecting a bleeding source such as intracranial aneurysm. This study protocol was approved by institutional review board and local ethical committee.
arteries, according to Consensus 2009 [15]. Delayed cerebral infarction (DCI) was defined as newly developed low density area on postoperative CT scan as a result of DIND. In the CTA, we observed bilateral A1 and A2 segment of the anterior cerebral artery, bilateral M1 and M2 segment of the middle cerebral artery, bilateral P1 and P2 segments of the posterior cerebral artery, and the basilar artery. Each spastic arterial segment was subjectively compared with the same segments in the CTA done at the initial diagnosis. The presence of a vasospasm was assessed using a grading scale as follows: none, mild (75 % reduction) [4]. In patients with the evidence of moderate or severe vasospasm on CTA, normovolemia were initiated together with the milrinone therapy as described below. Milrinone therapy via lumbar subarachnoid catheter. A subarachnoid catheter was placed into lumbar subarachnoid cistern via lower lumber entry point in a standard fashion. Patients received 0.87 mg milrinone (2.6 ml/day) per 7 ml normal physiological saline for 2 h injected into the lumbar subarachnoid cistern through the catheter. The catheter was clamped for subsequent 2 h, and cisternal drainage was performed for following 4 h. This 8-h cycle was repeated until day 14 after the onset of SAH. If the patients had a ventricular catheter, cisternal irrigation basically from the ventricle to the cistern was performed until day 7 after the onset of SAH as previously reported [14], followed by lumbar cisternal injection of milrinone. The contraindication of this milrinone therapy included high-grade scoliosis or other lumbar spinal canal diseases, and bleeding tendency. In this series, we did not experience such patients.
Management of SAH
Outcome Measurement
All patients received intravenous infusion of fasudil hydrochloride (a rho-kinase inhibitor) if no contraindication existed. Cisterns were irrigated via ventricular drainage for 3–5 days if ventricular drain was inserted. The details of cisternal irrigation were previously described [14]. Three-dimensional CTA or distal subtraction angiography was performed between day 5 and 7, around day 10, and after day 14 to confirm the obliteration of the aneurysm and to assess the severity of vasospasm. Plain head CT scans were performed on the day after the surgery to assess the initial damage, and around day 21 to confirm cerebral infarction due to SVS. Delayed ischemic neurological deficit was defined as a worsening of the neurological condition (altered consciousness, aphasia, and hemiplegia or hemiparesis) that could not be attributed to rebleeding, postoperative complications, hydrocephalus, or systemic complications, with luminal narrowing of cerebral
DIND, DCI, and modified Rankin scale (mRS) at 3 months after SAH were used for the assessment of outcome. The outcome of poor-grade (grade IV and V) SAH also showed with that in the previous reports, including historical controls of our department [11, 16–18] and the combined results of the other hospitals in the same division of Japan Neurosurgical Society which was recently published [7].
to refine the technique to infuse milrinone into cerebral arteries for a longer period in a less complicated manner. There is no study that showed the feasibility of milrinone through the lumbar subarachnoid catheter for the DIND after aSAH. We hypothesized that milrinone injection via lumbar subarachnoid catheter would be effective for the prevention of DIND after aSAH. In this study, we assessed the feasibility of milrinone infusion via lumber subarachnoid catheter for prevention of DIND after aSAH, and reviewed the old treatment regimens and the results in the recent clinical reports.
Methods
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Statistical Analysis Data are presented as mean ± standard deviation for continuous variables, and as frequency for categorical variables. Comparisons between groups were performed using unpaired Student’s t test for continuous variables, and Fisher’s exact test or Chi square test for categorical variables. A p value less than .05 was considered significant for all the analyses.
Neurocrit Care Table 1 Baseline characteristics of 425 patients who received clipping or coil embolization of ruptured intracranial aneurysm WFNS I–V (n = 425) Age (mean ± SD)
63.7 ± 13.8
Table 2 Outcome after aneurysmal subarachnoid hemorrhage treated with clipping or coil embolization
WFNS IV, V (n = 145) 66.6 ± 12.2 44:101
WFNS grade I–V
WFNS grade IV,V
DIND
68
16.0 %
26
17.9 %
DCI
30
7.1 %
12
8.3 %
60.0 %
46
31.7 %
Sex(M:F)
126:299
WFNS grade Grade I
0,1,2
255
150
0
3
50
20
Grade II
110
0
4
53
28
Grade III
20
0
Grade IV
71
71
5 6
36 31
Grade V
74
74
Group I
17
0
Group II
59
2
Group III
275
81
Group IV
74
62
Anterior circulation
370
122
Posterior circulation
55
23
319 97
105 37
9
3
Fisher group
Location of aneurysm
mRS at 3 months
27 24
7.2 %
16.0 %
Note that DIND was suppressed even in WFNS grade IV and V patients. DCI delayed cerebral infarction, DIND delayed ischemic neurological deficit, mRS modified Rankin Scale, WFNS World Federation of Neurological Surgeons
Table 3 Postoperative outcome of the poor-grade aneurysmal subarachnoid hemorrhage: review of the literatures Authors and Year
Treatment for SVS
Grade IV and V DIND (n, (n) %)
Treatment Clipping Coil embolization Others Cisternal irrigation
165
70
Milrinone via lumbar drainage
170
76
Note that the number of the aneurysm in posterior circulation and the number of endovascular treatment are more dominant in WFNS grade IV and V patients than in WFNS grade I-III patients. SD standard deviation, WFNS World Federation of Neurological Surgeons
Results Of 425 patients who received clipping or coiling for the ruptured aneurysm, 170 patients (40.0 %) received intrathecal milrinone injection via lumbar catheter. Of these, 105 patients (61.8 %) received ventricular drainage followed by cisternal irrigation. Baseline characteristics were shown in Table 1. The outcomes were shown in Table 2. In the patient with WFNS grade I–V, DIND was observed in 68 patients (16.0 %), DCI in 30 patients (7.1 %), and mortality was 7.2 %. In patients with WFNS grade IV and V (n = 145), 26 patients (17.9 %) were presented with DIND, 12 (8.3 %) with DCI, and mortality was 16.0 %. Patients with WFNS grade IV and V showed a significantly worse outcome (mRS) than those with WFNS grade I-III (p < 0.0001, Chi square test). However, there is no significant difference of the number of DIND and DCI between them. Table 3 showed the incidence of DIND after poor-grade aSAH in the other studies, and the results
Bracard et al. 2002 PTA, [16] Papaverine
80
15 (18.8)
Weir et al. 2003 [18]
PTA, Papaverine
27
7 (26.0)
Goto et al. 2004 [12]
Milrinone
24
7 (29.2)
Shirao et al. 2010 [7]
Not specified
283
97 (34.3)
Taylor et al. 2011 [17]
PTA
47
18 (38.3)
This study
Milrinone
145
26 (17.9)
Postoperative outcome of the poor-grade SAH in the current study and previous reports. DIND delayed ischemic neurological deficit, PTA percutaneous transluminal angioplasty, SVS symptomatic vasospasm
of this study were comparable or superior to those of the other reports. There were 165 patients who received cisternal irrigation. Of these, 75 patients received milrinone through lumbar catheter. Of these, DIND was in 24 and DCI in 11. Of 165 patients with cisternal irrigation, 90 patients were without milrinone through lumbar catheter. DIND was observed in 18, and DCI was observed in 9. There were 260 patients who did not receive cisternal irrigation. Of these, 68 patients were with milrinone through lumbar catheter. DIND was in 17, DCI in 7. 192 were without milrinone through lumbar catheter. DIND was in 9, DCI in 3. There were 143 patients with milrinone through lumbar catheter, and DIND was observed in 41 and DCI in 18.
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Neurocrit Care
There were 282 patients without milrinone through the lumbar catheter, and DIND was in 27 and DCI in 12. Of 30 patients with DCI, 13 patients with CTA-proven vasospasm without DIND resulted in DIND and DCI despite milrinone infusion. Two patients with DIND without DCI resulted in DCI despite milrinone infusion. Both DIND and DCI were observed in the rest (15 patients) before milrinone infusion. Of 26 cases with DIND after poor-grade SAH, 20 cases (76.9 %) received milrinone via lumbar catheter. However, 16 cases (80.0 %) received milrinone after DIND was observed. Four cases (15.3 %) started before manifestation of DIND, but resulted in DIND and DCI. No major complication related to milrinone injection was observed. The patients showed no significant change in systolic (mean 146.0 ± 22.8 vs. 149.4 ± 21.0) and diastolic (mean 73.4 ± 9.4 vs. 74.2 ± 9.1) blood pressure during the treatment. No new arrhythmia related to milrinone was observed. No hemorrhagic complication was observed. Headache after injection of milrinone was infrequently found in the patients, but was tolerable. Leg dysesthesia was also sometimes observed when the lumbar catheter was inserted, but it was relieved after the course of the catheter had changed. Meningitis due to lumbar drainage was observed in 6 patients (3.5 %).
Discussion This is the first report that showed the feasibility of intrathecal milrinone infusion via lumbar catheter for SVS after aSAH. In 1990s, intra-arterial injection of papaverine has been extensively used for the treatment of SVS [12, 16, 17]. The advantage of intra-arterial injection is direct administration to the vessel narrowing using strong vasodilator. Calcium channel blockers, papaverine, fasudil hydrochloride, and milrinone were previously reported, and are now being used for intra-arterial infusion therapy for SVS [2–5, 10, 11, 15, 19]. A recent observational study indicated that endovascular treatment for SVS is performed in the majority of the hospitals in Japan (78.7 %) [15]. However, because the half lives of these drugs are several hours, repeated administration is needed when SVS continues for more than 1 day, and interventional procedures have potential risks that further aggravate the patient’s condition [20]. Moreover, both intra-arterial [10] and intravenous infusion [21] themselves do not escape from reduction of systemic blood pressure because of dilatation of systemic vessels. Because main trunks of cerebral arteries are situated in subarachnoid space, it is apparent that intracisternal administration is one of the most reasonable methods for
123
the treatment of SVS. Thus, we changed the standard regimen for vasospasm from the intra-arterial fashion to the intracisternal one in the mid 2000s. The problems were that the management of continuous cisternal irrigation circuit was too difficult to perform in a general ward, and that we could not place intraventricular catheter more than 10 days because the risk of retrograde infection would increase. That was why a more simple method was needed for prevention of SVS. In this paper, we showed that our strategies including intrathecal injection of milrinone via lumbar subarachnoid catheter suppressed the occurrence of DIND. The overall rate of DIND and DCI after aSAH was 16.0 and 7.1 %, respectively, both of which were better than PRESAT study in Japan (DIND 19.1 % and DCI 17.6 % in 534 Japanese population) [22]. The number of the poor-grade patients with DIND in this study was significantly smaller than that after PPV + PTA previously reported. Moreover, the results of this study were comparable to those of cisternal milrinone irrigation via ventricular catheter. Majority of the ineffective cases were those who received intrathecal milrinone after the occurrence of DIND. From these facts, we think that the milrinone therapy via lumbar catheter should be started not after the vasospasm becomes symptomatic but after angiographical vasospasm was detected by the serial CT angiography. The overall outcome of aneurysmal SAH who received clipping/coil embolization in our department was comparable to other reports. The 3-month mortality after aSAH in this study was 7.2 %, better than the data of ISAT in which the 2-month mortality rate was 7.9 % [23]. Recent reports from the Netherlands [24] indicated that the overall risk of death around 1 month was 34 %. Especially in poor-grade SAH, our results were significantly better than the results of the other departments in Chugoku-Shikoku division (DIND 34.3 % and mortality 23.7 %) [7]. These facts showed that our postoperative management using milrinone would not be inferior to that of others using intraarterial fasudil and PTA. The reason why the result of this study was better than the other clinical studies might be multifactorial. Fasudil, milrinone, and lumbar drainage might be effective. We managed the post-SAH patients with normovolemia, not with hypervolemia and induced hypertension. It seems that hypervolemia do not appear to confer additional benefits over normovolemic therapy [25]. In Japan, over the half (60.2 %) of the neurosurgical departments started the treatment for DIND after appearance of SVS, and only 26.1 % of those after angiographic vasospasm in large extraparenchymal arteries was revealed with or without SVS (26.1 %) [15]. We should have in mind that the earlier start of the treatment for DIND would result in the better outcome of the patients.
Neurocrit Care
The milrinone therapy introduced in this study made the management of the vasospasm easier. Neurosurgeons do not need to concern about angiography room for this milrinone treatment. It might be more cost-effective than frequent endovascular interventions. Although we did not include the patients who received endovascular intervention, the results of this study did not deny the effectiveness of endovascular intervention for the vasospasm after SAH. Systemic side effects of milrinone were not detected in this study, possibly because the excess amount of the drug would be drained out through the catheter. A recent randomized study suggested that lumbar drainage of cerebrospinal fluid after the SAH reduced the prevalence of DIND [26], but not completely. In the LUMAS study [26], the overall rate of DIND after lumbar drainage was 21.0 %, slightly worse than our results (16.0 %). The milrinone treatment via the lumbar catheter would be a simple add-on for lumbar drainage against vasospasm after SAH. Although we could not detect any severe complications using milrinone, this method would have the potential of risk of intraspinal bleeding, spinal cord injury, and wound infection because of lumbar drainage. Milrinone itself has the risk of arrhythmia. This study has some limitations. Lack of control group was the main limitation of this study and it was impossible to obtain reliable conclusions about this drug effectiveness. In Japan, all intra-arterial and intrathecal drugs prescribed for vasospasm after SAH are being used off-label. Fasudil is an available drug for vasospasm in Japan, and a recent meta-analysis about fasudil found a significant reduction in the occurrence of cerebral vasospasm and cerebral infarction as well as an improvement in clinical outcome as assessed by GOS [27]. A survey of 414 hospitals with a neurosurgical department in Japan revealed that 92.5 % of the department used fasudil hydrochloride for the prophylactic therapies for vasospasm [15]. We compared each groups in different time, which would be biased because surgical/endovascular intervention and pre/postoperative management might have been improved throughout the years [28]. Oral nimodipine, an evidence-based proved drug to prevent DCI, is unavailable in Japan. This pilot study showed our experience of intrathecal administration of milrinone via lumbar subarachnoid catheter. This regimen is safe and feasible, and further randomized prospective studies are needed to confirm the effectiveness of this regimen in the patients with SAH. Acknowledgments Conflict of interest of interest.
None. The authors declare that they have no conflict
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