Accepted Manuscript Pharmacological management of subarachnoid hemorrhage Adam MH. Young, MRCS, Surya K. Karri, MD, MPH, Adel Helmy, MRCS PhD, Karol P. Budohoski, MD, Ramez W. Kirollos, FRCS(SN), Diederik O. Bulters, FRCS(SN), Peter J. Kirkpatrick, FRCS(SN), FMedSci, Christopher S. Ogilvy, MD, Rikin A. Trivedi, PhD, FRCS(SN) PII:
S1878-8750(15)00081-9
DOI:
10.1016/j.wneu.2015.02.004
Reference:
WNEU 2713
To appear in:
World Neurosurgery
Please cite this article as: Young AM, Karri SK, Helmy A, Budohoski KP, Kirollos RW, Bulters DO, Kirkpatrick PJ, Ogilvy CS, Trivedi RA, Pharmacological management of subarachnoid hemorrhage, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.02.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pharmacological management of subarachnoid hemorrhage Adam MH Young, MRCS,1,2 Surya K Karri, MD, MPH,2 Adel Helmy, MRCS PhD,1 Karol P Budohoski, MD,1 Ramez W Kirollos, FRCS(SN),1 Diederik O Bulters, FRCS(SN),1 Peter J Kirkpatrick, FRCS(SN), FMedSci,1 Christopher S. Ogilvy, MD2, & Rikin A Trivedi, PhD, FRCS(SN)1 1
RI PT
Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
2
Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Wang 745Z, Boston, MA 02114
SC
Figures
M AN U
Figure 1: Spider chart of medical therapies used to treat SAH. Currently the majority of medical therapy is aimed at reducing the effects of delayed cerebral ischemia or vasospasm. These eight individual therapies in this area can be compared to only one which works to prevent re-bleeding and currently there are no products available which reduce the harmful effects of SAH blood or ischemia on neurons.
TE D
Abbreviations: SAH: subarachnoid hemorrhage, DCI: delayed cerebral ischemia, CBF: cerebral blood flow
Key words: subarachnoid hemorrhage, outcome, therapy, mortality Word count: 4,448 (excluding references) 6,833 (total)
EP
Disclosure: The authors declare no competing interests. We confirm that the manuscript has not
AC C
been previously published in whole or in part or submitted elsewhere for review. Correspondence: Adam MH Young, School of Clinical Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK Email: [email protected]
ACCEPTED MANUSCRIPT Introduction Subarachnoid hemorrhage Aneurysmal subarachnoid hemorrhage (SAH) is responsible for approximately 5% of all strokes, but due to young age of onset, primarily in the 5th to 6th decade of life, and high mortality, the loss of productive life years is comparable to that of the more common ischemic and hemorrhagic strokes
RI PT
(Johnson et al., 1996). The mortality rate though varies with age, race and region, but is overall about 45% (Johnson et al., 1996). Of the remaining cases, approximately one third of patients are left with permanent neurological deficits (Linn et al., 1996). The incidence of SAH is 6 to 7 per 100,000 per year, in most populations but around 20 per 100,000 per year in Japan and Finland (Linn et al., 1996). At any point in time, approximately 2-3% of the population will be harboring asymptomatic intra-
SC
cranial aneurysms that have the potential to rupture and cause acute SAH (Takao et al., 2008).
Pharmacotherapy has an accepted role in several aspects of SAH and an emerging role in several
M AN U
others. No preventive pharmacological interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events following endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as, statins may prove promising in the prevention of DCI and are being currently evaluated in
TE D
large scale clinical trials. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase II trial. Clazosentane therapy, a potent endothelin receptor antagonist, did not translate into improved functional outcome. Various other agents have been used to prevent DCI, however, the results have been, at best, inconclusive. Prevention of DCI and
EP
improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by
AC C
which DCI is propagated is clearly needed. In this article, we review the current pharmacological approaches that have been evaluated in SAH. Specifically we will discuss three key categories of intervention; 1) treatment to prevent aneurysm rebleed, 2) treatment to reduce the risk of DCI or vasospasm and 3) treatment that may attenuate the harmful effects of subarachnoid blood or ischemia on neurons (Figure 1). As such we hope to highlight the best treatments available and highlight the areas where further research is required. 1. Medical treatment to prevent aneurysm re-bleeding 1.1 Antifibrinolytic therapy Prior to the development of effective methods to secure aneurysms, antifibrinolytics therapies (AF) such as tranexamic acid (TA) and ε-aminocaproic acid (EACA) were used as first line prevention of
ACCEPTED MANUSCRIPT aneurysmal re-bleeding (Gaberel et al., 2012). The 2003 Cochrane Review demonstrated that although there was a clear decrease in re-bleeding, there was also an increased risk of DCI that was associated with an absence of improvement in functional outcome (Roos et al., 2003). As a result there was a sharp decrease in the use of AFs in the majority of the neurosurgical units (Gaberel et al., 2012). Nevertheless, this review included studies using historical management of SAH (i.e., late aneurysm exclusion and no medical prevention of DCI) (Roos et al., 2003). The evolution of treatment has made
RI PT
this a more promising option. Current practice is to secure the aneurysm as soon as possible after ictus and this considerably reduces the overall risk of re-bleeding (Whitfield et al., 1996). Additionally, the development of agents such as calcium antagonists, has significantly reduced the risk of DCI (Feigin et al., 1998). In keeping with this protocol, the addition of AF use in the pre-exclusion period of
SC
ruptured aneurysms treatment demonstrated promising results (Leipzig et al., 1997).
The impact of AF therapy in aneurysmal SAH on functional outcome, rebleeding, and delayed ischemic deficits was reviewed in a recent meta-analysis (Gaberel et al., 2012). Specifically focusing
M AN U
on the rate of re-bleeding and DCI, it was demonstrated that the risk was no different to control10. Furthermore, improved functional outcome was demonstrated when AFs were used for short periods and associated with a medical prevention of ischemic deficit (Starke et al., 2008). Aneurysmal SAH presents a 9.6% risk of re-bleeding in the first 24 h after rupture and a 5.7% risk for the first 3 days (Hillman et al., 1988). In summary, the use of AF on a short-term basis just prior to aneurysm
1997).
TE D
exclusion may be re-evaluated as it might play a role in preventing early re-bleeding (Leipzig et al.,
2. Medical therapy to reduce the risk of DCI or vasospasm
EP
2.1 Hemodynamic therapy
Disturbed cerebral auto-regulation is prominent in SAH patients (Vergouwen et al., 2008). In the presence of vasospasm or microthrombosis this may result in decreased cerebral blood flow (CBF) and
AC C
thereby DCI (Vergouwen et al., 2008). When autoregulation is affected, CBF becomes dependent on cerebral perfusion pressure and blood viscosity. To increase CBF different combinations of hemodilution, hypervolemia, and hypertension have been used for many years (Kosnik et al., 1976).
There is a distinct lack of randomized clinical trials on hemodynamic therapy and clinical outcome, as a result hemodynamic therapy has only ever been analysed in this context of supporting CBF. The induction of hypervolaemia (Mori et al., 1995) and hypertension (Touho et al., 1992) in isolation, or in combination (Darby et al., 1994) was demonstrated to improve CBF, though, none of these studies were adequately controlled.
ACCEPTED MANUSCRIPT The main drawbacks from these early studies is sample size (
S1878-8750(15)00081-9
DOI:
10.1016/j.wneu.2015.02.004
Reference:
WNEU 2713
To appear in:
World Neurosurgery
Please cite this article as: Young AM, Karri SK, Helmy A, Budohoski KP, Kirollos RW, Bulters DO, Kirkpatrick PJ, Ogilvy CS, Trivedi RA, Pharmacological management of subarachnoid hemorrhage, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.02.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pharmacological management of subarachnoid hemorrhage Adam MH Young, MRCS,1,2 Surya K Karri, MD, MPH,2 Adel Helmy, MRCS PhD,1 Karol P Budohoski, MD,1 Ramez W Kirollos, FRCS(SN),1 Diederik O Bulters, FRCS(SN),1 Peter J Kirkpatrick, FRCS(SN), FMedSci,1 Christopher S. Ogilvy, MD2, & Rikin A Trivedi, PhD, FRCS(SN)1 1
RI PT
Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
2
Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Wang 745Z, Boston, MA 02114
SC
Figures
M AN U
Figure 1: Spider chart of medical therapies used to treat SAH. Currently the majority of medical therapy is aimed at reducing the effects of delayed cerebral ischemia or vasospasm. These eight individual therapies in this area can be compared to only one which works to prevent re-bleeding and currently there are no products available which reduce the harmful effects of SAH blood or ischemia on neurons.
TE D
Abbreviations: SAH: subarachnoid hemorrhage, DCI: delayed cerebral ischemia, CBF: cerebral blood flow
Key words: subarachnoid hemorrhage, outcome, therapy, mortality Word count: 4,448 (excluding references) 6,833 (total)
EP
Disclosure: The authors declare no competing interests. We confirm that the manuscript has not
AC C
been previously published in whole or in part or submitted elsewhere for review. Correspondence: Adam MH Young, School of Clinical Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK Email: [email protected]
ACCEPTED MANUSCRIPT Introduction Subarachnoid hemorrhage Aneurysmal subarachnoid hemorrhage (SAH) is responsible for approximately 5% of all strokes, but due to young age of onset, primarily in the 5th to 6th decade of life, and high mortality, the loss of productive life years is comparable to that of the more common ischemic and hemorrhagic strokes
RI PT
(Johnson et al., 1996). The mortality rate though varies with age, race and region, but is overall about 45% (Johnson et al., 1996). Of the remaining cases, approximately one third of patients are left with permanent neurological deficits (Linn et al., 1996). The incidence of SAH is 6 to 7 per 100,000 per year, in most populations but around 20 per 100,000 per year in Japan and Finland (Linn et al., 1996). At any point in time, approximately 2-3% of the population will be harboring asymptomatic intra-
SC
cranial aneurysms that have the potential to rupture and cause acute SAH (Takao et al., 2008).
Pharmacotherapy has an accepted role in several aspects of SAH and an emerging role in several
M AN U
others. No preventive pharmacological interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events following endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as, statins may prove promising in the prevention of DCI and are being currently evaluated in
TE D
large scale clinical trials. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase II trial. Clazosentane therapy, a potent endothelin receptor antagonist, did not translate into improved functional outcome. Various other agents have been used to prevent DCI, however, the results have been, at best, inconclusive. Prevention of DCI and
EP
improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by
AC C
which DCI is propagated is clearly needed. In this article, we review the current pharmacological approaches that have been evaluated in SAH. Specifically we will discuss three key categories of intervention; 1) treatment to prevent aneurysm rebleed, 2) treatment to reduce the risk of DCI or vasospasm and 3) treatment that may attenuate the harmful effects of subarachnoid blood or ischemia on neurons (Figure 1). As such we hope to highlight the best treatments available and highlight the areas where further research is required. 1. Medical treatment to prevent aneurysm re-bleeding 1.1 Antifibrinolytic therapy Prior to the development of effective methods to secure aneurysms, antifibrinolytics therapies (AF) such as tranexamic acid (TA) and ε-aminocaproic acid (EACA) were used as first line prevention of
ACCEPTED MANUSCRIPT aneurysmal re-bleeding (Gaberel et al., 2012). The 2003 Cochrane Review demonstrated that although there was a clear decrease in re-bleeding, there was also an increased risk of DCI that was associated with an absence of improvement in functional outcome (Roos et al., 2003). As a result there was a sharp decrease in the use of AFs in the majority of the neurosurgical units (Gaberel et al., 2012). Nevertheless, this review included studies using historical management of SAH (i.e., late aneurysm exclusion and no medical prevention of DCI) (Roos et al., 2003). The evolution of treatment has made
RI PT
this a more promising option. Current practice is to secure the aneurysm as soon as possible after ictus and this considerably reduces the overall risk of re-bleeding (Whitfield et al., 1996). Additionally, the development of agents such as calcium antagonists, has significantly reduced the risk of DCI (Feigin et al., 1998). In keeping with this protocol, the addition of AF use in the pre-exclusion period of
SC
ruptured aneurysms treatment demonstrated promising results (Leipzig et al., 1997).
The impact of AF therapy in aneurysmal SAH on functional outcome, rebleeding, and delayed ischemic deficits was reviewed in a recent meta-analysis (Gaberel et al., 2012). Specifically focusing
M AN U
on the rate of re-bleeding and DCI, it was demonstrated that the risk was no different to control10. Furthermore, improved functional outcome was demonstrated when AFs were used for short periods and associated with a medical prevention of ischemic deficit (Starke et al., 2008). Aneurysmal SAH presents a 9.6% risk of re-bleeding in the first 24 h after rupture and a 5.7% risk for the first 3 days (Hillman et al., 1988). In summary, the use of AF on a short-term basis just prior to aneurysm
1997).
TE D
exclusion may be re-evaluated as it might play a role in preventing early re-bleeding (Leipzig et al.,
2. Medical therapy to reduce the risk of DCI or vasospasm
EP
2.1 Hemodynamic therapy
Disturbed cerebral auto-regulation is prominent in SAH patients (Vergouwen et al., 2008). In the presence of vasospasm or microthrombosis this may result in decreased cerebral blood flow (CBF) and
AC C
thereby DCI (Vergouwen et al., 2008). When autoregulation is affected, CBF becomes dependent on cerebral perfusion pressure and blood viscosity. To increase CBF different combinations of hemodilution, hypervolemia, and hypertension have been used for many years (Kosnik et al., 1976).
There is a distinct lack of randomized clinical trials on hemodynamic therapy and clinical outcome, as a result hemodynamic therapy has only ever been analysed in this context of supporting CBF. The induction of hypervolaemia (Mori et al., 1995) and hypertension (Touho et al., 1992) in isolation, or in combination (Darby et al., 1994) was demonstrated to improve CBF, though, none of these studies were adequately controlled.
ACCEPTED MANUSCRIPT The main drawbacks from these early studies is sample size (
