- Email: [email protected]
When in Rome, do as the Romans do?
Perspectives Commentary on: Results of an International Survey on the Investigation and Endovascular Management of Cerebral Vasospasm and Delayed Cerebral Ischemia by Hollingworth et al. World Neurosurg 83: 1120-1126.E1, 2015
When in Rome, do as the Romans do? R. Loch Macdonald
I
n a paper recently published in WORLD NEUROSURGERY, Hollingworth et al. report the results of a survey of 344 neurosurgeons and neuroradiologists from 32 countries that asked 13 questions regarding how they diagnose and treat angiographic vasospasm and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) (8). The goal was to conduct an international survey on the diagnosis and endovascular treatment of DCI to assess the variability in practice. Variability was great, and basically it seems as if doctors use endovascular therapy according to their local institutional practices (hence, the title of this article). This is not surprising because, as the authors note, there is no high-quality evidence on which to base the diagnosis of DCI or on how to treat it. A neurocritical care consensus meeting that reviewed the literature on endovascular treatment of cerebral vasospasm concluded essentially nothing, because all of the data were retrospective analyses of heterogeneous, small sets of patients (10). Publications from different centers show that different methods are used to treat DCI. Publications on intraarterial verapamil are mainly from the United States, the French (in Canada or France) seem to have a preference for milrinone, and intra-arterial nimodipine is used in Europe (there is no parenteral formulation available in North America) (1, 3, 5, 7, 9, 11).
What can we learn from this survey? The authors are correct that documenting variability in practice is one way to generate interest in conducting a clinical trial. It is important for answering some of the concerns about whether clinical equipoise exists for a clinical trial (13). They have designed and begun such a study, which is definitely needed. DCI is a disease in which physicians in different parts of the world or a country or even within a hospital manage a patient with the same disease a different way because they think they know the best way. It follows then that for any of
Key words Angioplasty - Cerebral vasospasm - Delayed cerebral ischemia - Intra-arterial treatment - Subarachnoid hemorrhage - Survey - Transcranial Doppler -
638
Abbreviations and Acronyms DCI: Delayed cerebral ischemia SAH: Subarachnoid hemorrhage
www.SCIENCEDIRECT.com
these specific treatments, they are either equally ineffective or effective, or at least close enough in diagnostic use or efficacy to not be obviously different in day-to-day practice. It is always notable how strongly physicians can believe in various treatments despite a lack of evidence that they are efficacious and safe (for example, milrinone or even therapeutic balloon angioplasty for DCI). Doctors say they use a treatment because it works in their patients, and they treat maybe 30 or so patients with SAH a year. How can they tell that the treatment works? They are presumably comparing how the patients do now with how they did before they used the new treatment. Sometimes this might be reasonable, for example, when the disease uniformly is fatal and a treatment is introduced and the patients survive. Otherwise, this expert opinionetype approach is flawed because it relies on historical controls and very small numbers of patients. In comparison, the only drug approved in the United States for treatment of SAH is nimodipine, and the main pivotal study upon which approval was based included 554 patients. In retrospect, some of the questions might have been worded more clearly and used the recommended terms angiographic vasospasm and DCI (17). I had trouble understanding what the answer b option to question 4 meant. The authors found that screening for “cerebral vasospasm” relied mostly on transcranial Doppler ultrasound. My impression is that this test is being used less often. It has several disadvantages. Although it is safe and noninvasive, a trained consistent operator is needed and even with one, there are numerous sources of variability and it has been difficult to correlate it strongly with angiographic vasospasm and DCI (2). At our hospital, we rely on computed tomographic angiography and perfusion, the disadvantages of
Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department of Surgery, University of Toronto, Ontario, Canada To whom correspondence should be addressed: R. Loch Macdonald, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 84, 3:638-639. http://dx.doi.org/10.1016/j.wneu.2015.05.006
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.05.006
PERSPECTIVES
which include radiation and contrast exposure and that it is technically challenging to get reproducible measurements (12, 14). In contrast, a measure of blood flow like computed tomography perfusion is one step closer than transcranial Doppler ultrasound to what we want to know, which is not the diameter of arteries but delivery of oxygen to the brain. In terms of treatment of DCI, more than half of U.S. practitioners would treat asymptomatic angiographic vasospasm as opposed to a quarter in other countries. This variability fits with the neurocritical care consensus paper by Stocchetti (15) that noted evidence for triggers to treat angiographic vasospasm and DCI was of very low to moderate quality. Any recommendations were based largely on expert opinion, which the current survey shows is like most expert opinion—you can get whatever opinion you want. Indeed, there is an ongoing clinical trial in which investigators are comparing supportive care with induced hypertension for the treatment of DCI (6). This raises the point that the clinical trial the authors are conducting is not the only question surrounding endovascular management of DCI. What the best treatment is a question worth answering but a more fundamental one is whether any endovascular therapy is indicated at all. This relates to the theory that angiographic vasospasm is an epiphenomenon that does not actually cause ischemia, a theory that has been debated already (12, 16). This theory is based on the lack of improvement in outcome that has been achieved despite drug treatments that reduce angiographic
REFERENCES 1. Albanese E, Russo A, Quiroga M, Willis RN Jr, Mericle RA, Ulm AJ: Ultrahigh-dose intraarterial infusion of verapamil through an indwelling microcatheter for medically refractory severe vasospasm: initial experience. Clinical article. J Neurosurg 113:913-922, 2010. 2. Carrera E, Schmidt JM, Oddo M, Fernandez L, Claassen J, Seder D, Lee K, Badjatia N, Connolly ES Jr, Mayer SA: Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Neurosurgery 65: 316-323, 2009. 3. Dehdashti AR, Binaghi S, Uske A, Regli L: Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study. Neurol India 59: 810-816, 2011. 4. Fleckenstein A: History of calcium antagonists. Circ Res 52:I3-16, 1983. 5. Fraticelli AT, Cholley BP, Losser MR, Saint Maurice JP, Payen D: Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 39:893-898, 2008. 6. Gathier CS, van den Bergh WM, Slooter AJ: HIMALAIA (Hypertension Induction in the Management of AneurysmaL subArachnoid haemorrhage with secondary IschaemiA): a randomized single-blind controlled trial of induced hypertension vs. no induced hypertension in the treatment of delayed cerebral ischemia after subarachnoid hemorrhage. Int J Stroke 9:375-380, 2014.
vasospasm. The vasospasm epiphenomenon theory is only one of several possible explanations for this. The variability in endovascular management suggests there is clinical equipoise for the clinical trial the authors mention (13). The clinical trial has 4 arms and will be difficult to analyze but will give some indication as to what the best vasodilator is after SAH. Clinical outcome is being measured quite soon after the hemorrhage and will be unlikely to show any differences between, groups given the small numbers of patients, although at least some information about safety will be able to be gained. Finally, some pharmacology pertains to this survey and the ongoing clinical trial. Verapamil is a phenylalkylamine L-type calcium channel antagonist that is a vasodilator and also has potentially negative cardiac effects. Nimodipine and nicardipine are dihydropyridines that also antagonize calcium entry through L-type calcium channels but that have less cardiac effects. Nimodipine was developed specifically to be a cerebral arterial vasodilator (4). There is no parenteral formulation of nimodipine available in the United States. It is thus interesting that one U.S. respondent said they used nimodipine as a second-line treatment. I hope this was not intra-arterial because there have been fatalities from intravascular injection of nimodipine aspirated from gelatin capsules in the United States. This led to the black box warning on the package insert and to development of the liquid oral formulation, Nymalize (Arbor Pharmaceuticals Inc., Atlanta, Georgia, USA).
7. Hanggi D, Turowski B, Beseoglu K, Yong M, Steiger HJ: Intra-arterial nimodipine for severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and cerebral perfusion. AJNR Am J Neuroradiol 29: 1053-1060, 2008. 8. Hollingworth M, Chen PR, Goddard AJ, Coulthard A, Soderman M, Bulsara KR: Results of an International Survey on the Investigation and Endovascular Management of Cerebral Vasospasm and Delayed Cerebral Ischemia. World Neurosurg 83:1120-1126.e1, 2015. 9. Jun P, Ko NU, English JD, Dowd CF, Halbach VV, Higashida RT, Lawton MT, Hetts SW: Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 31:1911-1916, 2010. 10. Kimball MM, Velat GJ, Hoh BL: Critical care guidelines on the endovascular management of cerebral vasospasm. Neurocrit Care 15:336-341, 2011. 11. Lannes M, Teitelbaum J, Del Pilar CM, Cardoso M, Angle M: Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage: the montreal neurological hospital protocol. Neurocrit Care 16:354-362, 2012. 12. Macdonald RL: Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44-58, 2014.
Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage. Neuroradiology 2015. 15. Stocchetti N: Triggers for aggressive interventions in subarachnoid hemorrhage. Neurocrit Care 15: 324-328, 2011. 16. Vergouwen MD, Vermeulen M, Roos YB: Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: is angiographic vasospasm an epiphenomenon? Stroke 40:e39, 2009. 17. Vergouwen MD, Vermeulen M, van Gijin J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, terBrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:2391-2395, 2010.
Conflict of interest statement: R. L. Macdonald receives grant support from the Physicians Services Incorporated Foundation, Brain Aneurysm Foundation, Canadian Institutes for Health Research, and the Heart and Stroke Foundation of Canada; and is Chief Scientific Officer of Edge Therapeutics, Inc. Citation: World Neurosurg. (2015) 84, 3:638-639. http://dx.doi.org/10.1016/j.wneu.2015.05.006
13. Miller FG, Joffe S: Equipoise and the dilemma of randomized clinical trials. N Engl J Med 364: 476-480, 2011.
Journal homepage: www.WORLDNEUROSURGERY.org
14. Murphy A, de Oliveira Manoel AL, Burgers K, Kouzmina E, Lee T, Macdonald RL, Bharatha A:
1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY 84 [3]: 638-639, SEPTEMBER 2015
Available online: www.sciencedirect.com
www.WORLDNEUROSURGERY.org
639
When in Rome, do as the Romans do? R. Loch Macdonald
I
n a paper recently published in WORLD NEUROSURGERY, Hollingworth et al. report the results of a survey of 344 neurosurgeons and neuroradiologists from 32 countries that asked 13 questions regarding how they diagnose and treat angiographic vasospasm and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) (8). The goal was to conduct an international survey on the diagnosis and endovascular treatment of DCI to assess the variability in practice. Variability was great, and basically it seems as if doctors use endovascular therapy according to their local institutional practices (hence, the title of this article). This is not surprising because, as the authors note, there is no high-quality evidence on which to base the diagnosis of DCI or on how to treat it. A neurocritical care consensus meeting that reviewed the literature on endovascular treatment of cerebral vasospasm concluded essentially nothing, because all of the data were retrospective analyses of heterogeneous, small sets of patients (10). Publications from different centers show that different methods are used to treat DCI. Publications on intraarterial verapamil are mainly from the United States, the French (in Canada or France) seem to have a preference for milrinone, and intra-arterial nimodipine is used in Europe (there is no parenteral formulation available in North America) (1, 3, 5, 7, 9, 11).
What can we learn from this survey? The authors are correct that documenting variability in practice is one way to generate interest in conducting a clinical trial. It is important for answering some of the concerns about whether clinical equipoise exists for a clinical trial (13). They have designed and begun such a study, which is definitely needed. DCI is a disease in which physicians in different parts of the world or a country or even within a hospital manage a patient with the same disease a different way because they think they know the best way. It follows then that for any of
Key words Angioplasty - Cerebral vasospasm - Delayed cerebral ischemia - Intra-arterial treatment - Subarachnoid hemorrhage - Survey - Transcranial Doppler -
638
Abbreviations and Acronyms DCI: Delayed cerebral ischemia SAH: Subarachnoid hemorrhage
www.SCIENCEDIRECT.com
these specific treatments, they are either equally ineffective or effective, or at least close enough in diagnostic use or efficacy to not be obviously different in day-to-day practice. It is always notable how strongly physicians can believe in various treatments despite a lack of evidence that they are efficacious and safe (for example, milrinone or even therapeutic balloon angioplasty for DCI). Doctors say they use a treatment because it works in their patients, and they treat maybe 30 or so patients with SAH a year. How can they tell that the treatment works? They are presumably comparing how the patients do now with how they did before they used the new treatment. Sometimes this might be reasonable, for example, when the disease uniformly is fatal and a treatment is introduced and the patients survive. Otherwise, this expert opinionetype approach is flawed because it relies on historical controls and very small numbers of patients. In comparison, the only drug approved in the United States for treatment of SAH is nimodipine, and the main pivotal study upon which approval was based included 554 patients. In retrospect, some of the questions might have been worded more clearly and used the recommended terms angiographic vasospasm and DCI (17). I had trouble understanding what the answer b option to question 4 meant. The authors found that screening for “cerebral vasospasm” relied mostly on transcranial Doppler ultrasound. My impression is that this test is being used less often. It has several disadvantages. Although it is safe and noninvasive, a trained consistent operator is needed and even with one, there are numerous sources of variability and it has been difficult to correlate it strongly with angiographic vasospasm and DCI (2). At our hospital, we rely on computed tomographic angiography and perfusion, the disadvantages of
Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department of Surgery, University of Toronto, Ontario, Canada To whom correspondence should be addressed: R. Loch Macdonald, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 84, 3:638-639. http://dx.doi.org/10.1016/j.wneu.2015.05.006
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.05.006
PERSPECTIVES
which include radiation and contrast exposure and that it is technically challenging to get reproducible measurements (12, 14). In contrast, a measure of blood flow like computed tomography perfusion is one step closer than transcranial Doppler ultrasound to what we want to know, which is not the diameter of arteries but delivery of oxygen to the brain. In terms of treatment of DCI, more than half of U.S. practitioners would treat asymptomatic angiographic vasospasm as opposed to a quarter in other countries. This variability fits with the neurocritical care consensus paper by Stocchetti (15) that noted evidence for triggers to treat angiographic vasospasm and DCI was of very low to moderate quality. Any recommendations were based largely on expert opinion, which the current survey shows is like most expert opinion—you can get whatever opinion you want. Indeed, there is an ongoing clinical trial in which investigators are comparing supportive care with induced hypertension for the treatment of DCI (6). This raises the point that the clinical trial the authors are conducting is not the only question surrounding endovascular management of DCI. What the best treatment is a question worth answering but a more fundamental one is whether any endovascular therapy is indicated at all. This relates to the theory that angiographic vasospasm is an epiphenomenon that does not actually cause ischemia, a theory that has been debated already (12, 16). This theory is based on the lack of improvement in outcome that has been achieved despite drug treatments that reduce angiographic
REFERENCES 1. Albanese E, Russo A, Quiroga M, Willis RN Jr, Mericle RA, Ulm AJ: Ultrahigh-dose intraarterial infusion of verapamil through an indwelling microcatheter for medically refractory severe vasospasm: initial experience. Clinical article. J Neurosurg 113:913-922, 2010. 2. Carrera E, Schmidt JM, Oddo M, Fernandez L, Claassen J, Seder D, Lee K, Badjatia N, Connolly ES Jr, Mayer SA: Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Neurosurgery 65: 316-323, 2009. 3. Dehdashti AR, Binaghi S, Uske A, Regli L: Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study. Neurol India 59: 810-816, 2011. 4. Fleckenstein A: History of calcium antagonists. Circ Res 52:I3-16, 1983. 5. Fraticelli AT, Cholley BP, Losser MR, Saint Maurice JP, Payen D: Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 39:893-898, 2008. 6. Gathier CS, van den Bergh WM, Slooter AJ: HIMALAIA (Hypertension Induction in the Management of AneurysmaL subArachnoid haemorrhage with secondary IschaemiA): a randomized single-blind controlled trial of induced hypertension vs. no induced hypertension in the treatment of delayed cerebral ischemia after subarachnoid hemorrhage. Int J Stroke 9:375-380, 2014.
vasospasm. The vasospasm epiphenomenon theory is only one of several possible explanations for this. The variability in endovascular management suggests there is clinical equipoise for the clinical trial the authors mention (13). The clinical trial has 4 arms and will be difficult to analyze but will give some indication as to what the best vasodilator is after SAH. Clinical outcome is being measured quite soon after the hemorrhage and will be unlikely to show any differences between, groups given the small numbers of patients, although at least some information about safety will be able to be gained. Finally, some pharmacology pertains to this survey and the ongoing clinical trial. Verapamil is a phenylalkylamine L-type calcium channel antagonist that is a vasodilator and also has potentially negative cardiac effects. Nimodipine and nicardipine are dihydropyridines that also antagonize calcium entry through L-type calcium channels but that have less cardiac effects. Nimodipine was developed specifically to be a cerebral arterial vasodilator (4). There is no parenteral formulation of nimodipine available in the United States. It is thus interesting that one U.S. respondent said they used nimodipine as a second-line treatment. I hope this was not intra-arterial because there have been fatalities from intravascular injection of nimodipine aspirated from gelatin capsules in the United States. This led to the black box warning on the package insert and to development of the liquid oral formulation, Nymalize (Arbor Pharmaceuticals Inc., Atlanta, Georgia, USA).
7. Hanggi D, Turowski B, Beseoglu K, Yong M, Steiger HJ: Intra-arterial nimodipine for severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and cerebral perfusion. AJNR Am J Neuroradiol 29: 1053-1060, 2008. 8. Hollingworth M, Chen PR, Goddard AJ, Coulthard A, Soderman M, Bulsara KR: Results of an International Survey on the Investigation and Endovascular Management of Cerebral Vasospasm and Delayed Cerebral Ischemia. World Neurosurg 83:1120-1126.e1, 2015. 9. Jun P, Ko NU, English JD, Dowd CF, Halbach VV, Higashida RT, Lawton MT, Hetts SW: Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 31:1911-1916, 2010. 10. Kimball MM, Velat GJ, Hoh BL: Critical care guidelines on the endovascular management of cerebral vasospasm. Neurocrit Care 15:336-341, 2011. 11. Lannes M, Teitelbaum J, Del Pilar CM, Cardoso M, Angle M: Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage: the montreal neurological hospital protocol. Neurocrit Care 16:354-362, 2012. 12. Macdonald RL: Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44-58, 2014.
Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage. Neuroradiology 2015. 15. Stocchetti N: Triggers for aggressive interventions in subarachnoid hemorrhage. Neurocrit Care 15: 324-328, 2011. 16. Vergouwen MD, Vermeulen M, Roos YB: Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: is angiographic vasospasm an epiphenomenon? Stroke 40:e39, 2009. 17. Vergouwen MD, Vermeulen M, van Gijin J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, terBrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:2391-2395, 2010.
Conflict of interest statement: R. L. Macdonald receives grant support from the Physicians Services Incorporated Foundation, Brain Aneurysm Foundation, Canadian Institutes for Health Research, and the Heart and Stroke Foundation of Canada; and is Chief Scientific Officer of Edge Therapeutics, Inc. Citation: World Neurosurg. (2015) 84, 3:638-639. http://dx.doi.org/10.1016/j.wneu.2015.05.006
13. Miller FG, Joffe S: Equipoise and the dilemma of randomized clinical trials. N Engl J Med 364: 476-480, 2011.
Journal homepage: www.WORLDNEUROSURGERY.org
14. Murphy A, de Oliveira Manoel AL, Burgers K, Kouzmina E, Lee T, Macdonald RL, Bharatha A:
1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY 84 [3]: 638-639, SEPTEMBER 2015
Available online: www.sciencedirect.com
www.WORLDNEUROSURGERY.org
639