Spreading depolarization-modulating drugs and delayed cerebral ischemia after subarachnoid hemorrhage: A hypothesis-generating retrospective clinical study.
BACKGROUND
Delayed cerebral ischemia (DCI) occurs in approximately one-third of patients with aneurysmal subarachnoid hemorrhage (aSAH). A proposed underlying mechanism for DCI is spreading depolarization (SD). Our aim was to, retrospectively, investigate the influence of the use of SD-modulating drugs on the occurrence of DCI.


METHODS
We, retrospectively, combined data from four cohorts of aSAH patients with data on the use of home medication prior to hospital admission, occurrence of DCI, and clinical outcome. Home medication was classified as "SD-inhibiting", "SD-facilitating", or "SD-neutral based" on a comprehensive literature review. We defined subgroups "likely", "possibly" and "weak" concerning the amount of evidence in literature. We performed Cox and Poisson regression analysis and calculated hazard ratios (HR) and risk ratios (RR) for the influence of "SD-modulating" drugs on primary outcome measure DCI and secondary outcome measure poor clinical outcome (modified Rankin Scale ≥3) three months after aSAH. We adjusted for age, sex and clinical condition on admission (aHR/aRR).


RESULTS
DCI occurred in 343 (29%) of 1194 patients. Patients using SD-inhibiting home medication had an aHR for DCI of 0.66 (95% CI: 0.42-1.06) and an aRR for poor outcome of 1.13 (95% CI: 0.90-1.41). Patients using SD-facilitating drugs had an aHR for DCI of 1.24 (95% CI: 0.83-1.87) and an aRR for poor outcome of 1.19 (95% CI: 0.95-1.50). When comparing patients using SD-inhibiting drugs with patients using SD-facilitating drugs, the aHR was 0.54 (95% CI: 0.29-0.99) for DCI and the aRR 0.97 (95% CI: 0.71-1.32) for outcome.


CONCLUSIONS
In this exploratory study chronic use of SD-inhibiting drugs tended to reduce DCI but did not result in a better clinical outcome. Additional research is needed to investigate the specific effects of SD-modulation on DCI and outcome and to further explore its effectiveness in preventing DCI after aSAH.
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Arend M
AM
Hamming
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: I.A.Mulder@lumc.nl.
Inge A
IA
Mulder
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Celine S
CS
Gathier
Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Intensive Care, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Walter M
WM
van den Bergh
Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Jan Willem
JW
Dankbaar
Department of Anesthesiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Reinier G
RG
Hoff
Neurosurgical Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
W Peter
WP
Vandertop
Neurosurgical Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Dagmar
D
Verbaan
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Michel D
MD
Ferrari
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Gabriel J E
GJE
Rinkel
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Ale
A
Algra
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Marieke J H
MJH
Wermer
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012196:Review Literature as Topic; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy*; D016896:Treatment Outcome
D018696:Neuroprotective Agents
Cortical spreading depression; Delayed cerebral ischemia; Drugs; Secondary ischemia; Spreading depolarizations; Subarachnoid hemorrhage