FEATURED ARTICLE

Anesthetic Conditioning in Aneurysmal Subarachnoid Hemorrhage Patients

Umeshkumar Athiraman, MD, MBBS
Department of Anesthesiology
Washington University School of Medicine
St. Louis, Missouri

Umeshkumar Athiraman MD, MBBS

Background:
Aneurysmal subarachnoid hemorrhage (SAH) affects approximately 30,000 people in the US per year and it accounts for approximately 85% of subarachnoid hemorrhage bleed.¹ Morbidity and mortality remains unacceptably high – ~30% of patients die;² 50% of survivors have long-term cognitive deficits that preclude return to work.³ The two most important determinants of outcome after aneurysmal subarachnoid hemorrhage are initial hemorrhage severity and secondary brain injury due to early brain injury (EBI) and delayed cerebral ischemia (DCI). Many strategies to prevent EBI and DCI have been explored and none have proven efficacious, likely due to targeting individual elements of what has proven to be a multifactorial pathophysiological process. New therapies are desperately needed to improve patient outcome after SAH. 

Conditioning:
Conditioning is a strategy where a sub-lethal noxious stimulus presented to any tissue in the body invokes endogenous protective mechanisms so that the organ develops tolerance towards subsequent similar or stronger insult. Several conditioning agents provide protection in a variety of organ systems through conditioning-based mechanisms.^4-9 Conditioning against brain injury can be induced by various conditions and agents such as ischemia⁸, hypoxia⁹, LPS4, thrombin⁵, anesthetics⁶, and other drugs some of which are already approved by FDA. Conditioning is a therapeutic strategy that is not only powerful, but also remarkably pleiotropic with protective effects on all major CNS cell types including neurons, glia, and vascular cells.¹⁰ The pleiotropic protective effect of conditioning, along with the therapeutic window of opportunity between SAH and onset of EBI (typically one-three days) and onset of DCI (typically four-twelve days) makes SAH one form of hemorrhagic stroke particularly amenable to conditioning-based therapy.⁶

Anesthetic conditioning:
Several studies have shown the neuroprotective role of anesthetics in cerebral ischemic injury.^11,12 In addition to its protective effects on ischemic brain injury, anesthetic conditioning was shown to protect against other brain injuries such as intracerebral hemorrhage,^13-16 traumatic brain injury,^17,18 and subarachnoid hemorrhage. Though ample evidence exists related to anesthetic neuroprotection and ischemic stroke, data related to anesthetic neuroprotection in hemorrhagic stroke is limited. Patients with subarachnoid hemorrhage are exposed to anesthetics for initial procedures such as coiling or clipping for obliteration of aneurysms, sedation in the ICU for mechanically ventilated patients and for other subsequent procedures such as decompressive craniectomies, hematoma evacuations and placement of shunts. Appropriate selection of anesthetics during the early period of ictus may substantially reduce the secondary brain injury after SAH which may eventually reduce the overall mortality and morbidity of the SAH patients. Anesthetic conditioning has a great translational potential to the clinic as the commonly used anesthetic drugs are relatively safe, already approved by FDA and used on a regular basis.

Early brain injury (EBI): one-three days after SAH, and is characterized by blood-brain barrier (BBB) disruption, neuro inflammation, and cerebral edema.¹⁹ Evidence showing that treatment of delayed vasospasm post SAH didn’t influence outcomes of these patients led to focus on EBI after SAH.²⁰ Identification of clinical neuroprotective strategies in the initial period of SAH is essential to attenuate EBI which may eventually reduce the incidence and/or severity of DCI and may result in overall improved neurological outcome.

Anesthetics and EBI: Experimental studies have shown neuroprotective effects of inhalational and intravenous anesthetics on EBI post SAH. (Table 1)

Isoflurane: Isoflurane is the most commonly studied anesthetic agent in the cerebral neuroprotection. Isoflurane 2% post conditioning in SAH was shown to attenuate EBI at 24 hours by improving neurological score, reducing brain water content and decreasing neuronal apoptosis, though this protective effect was not seen at 72 hours.²¹ Following studies by same group reported that isoflurane post conditioning with 2% and not 1% prevented blood brain barrier disruption²² and attenuated brain inflammation.²³

Sevoflurane, Desflurane: Currently, there are no experimental studies found in the literature evaluating the effects of sevoflurane and desflurane on EBI post SAH.

Argon: Exposure of a noble gas Argon post SAH showed a significant reduction in the mortality of rodents and better functional outcome (as measured by the weight of the animals) compared to the control group, though the neuroscore and cerebral edema did not differ between both groups.²⁴

Xenon: One other noble gas Xenon, exposed post SAH significantly reduced neuronal damage in hippocampal regions and also reduced microglial activity.²⁵ A subsequent study noted that the administration of Xenon through echogenic liposomes (Xe-ELIP) post SAH reduced hematoma volume, prevented neuronal cell death, improved neurological function and decreased mortality and morbidity.²⁶

Propofol: Propofol showed a significant protection against EBI post SAH by reducing cerebral edema, blood brain barrier breakdown and improving neurological score.27 A conflicting result was reported in an invitro study, where embryonic neuronal culture exposed to a clinically relevant dose of propofol attenuated cytotoxicity in oxygen glucose deprivation model but increased cytotoxicity in the hemorrhagic model.²⁸

Delayed cerebral ischemia (DCI):
DCI occurs in ~30% of patients, develops 4-12 days after SAH, and is characterized by large artery vasospasm, distal autoregulatory dysfunction, microvessel thrombosis and cortical spreading depolarization.²⁹ The development of symptomatic vasospasm or DCI is strongly associated with poor outcome and increased mortality in SAH patients30 though some authors argue that EBI plays a critical role in the secondary brain injury post SAH and treatment of EBI is vital.²⁰

Anesthetics and DCI: Experimental studies assessing the effects of anesthetics on DCI post SAH is scarce. (Table 2)

Isoflurane: Isoflurane exposure to the cortical microvessels post SAH attenuated microvascular vasospasm by attenuating endothelin-1 induced vasoconstriction and also didn’t further impair the endothelium dependent vasomotion.³¹ It was also noted that isoflurane post conditioning at clinically relevant time points (15 minutes, one hour, three hours and not at six hours after ictus) significantly improved large artery vasospasm, microvessel thrombosis, autoregulatory dysfunction and neurological outcome.⁶ Subsequent studies showed that isoflurane post conditioning with inotropic support improved cerebral hypo perfusion thus improving the overall recovery from EBI eventually leading to decreased prevalence of DCI and improved neurobehavioral outcome.^32-34

Currently, no experimental studies are found related to other inhalational and intravenous anesthetics on DCI post SAH.

Clinical Studies: (Table 3)
Isoflurane: Isoflurane compared with propofol for ICU sedation in SAH patients noted that isoflurane safely increases regional cerebral blood flow without increasing intracranial pressure in patients with normal ICP.³⁵ Of note, cerebral perfusion pressure (CPP) and PaCo2 was maintained throughout the study in both groups. Another study evaluated the effects of short- and long-term isoflurane use for ICU sedation in cerebrovascular patients concluded that isoflurane may be a safe alternative for ICU sedation provided neuromonitoring is in place and MAP/CPP (MAP= mean arterial pressure) is maintained.³⁶

Sevoflurane: Same group which evaluated isoflurane’s short- and long-term effects evaluated sevoflurane effects for ICU sedation in the cerebrovascular patients. One third of the study population experienced significant adverse events mainly rise in ICP and were switched back to alternative sedation. Authors concluded that use of sevoflurane for ICU sedation may not be safe in this high-risk population.³⁷

Desflurane: A prospective study measured endothelin (ET) and calcitonin gene related peptide levels (CGRP) for patients undergoing late intracranial aneurysm clipping under desflurane anesthesia.³⁸ The study reported a significant reduction of ET-1 levels during anesthesia compared to preinduction levels and concluded that desflurane may reduce the risk of acute cerebral vasospasm given the well-described impact of endothelin-1 on cerebral vasospasm pathophysiology.³⁹ A recent study by Lee et al noted less incidence of transcranial doppler associated vasospasm in desflurane group compared to propofol group but no difference was noted in angiographic vasospasm or the cerebral infarctions.⁴⁰

Barbiturates: Pentobarbital and thiopentone have been used in the treatment of refractory vasospasm not responding to conventional medical measures and noted improved patient outcomes.^41-46 Both the barbiturates have also been noted to reduce cerebral swelling and ICP post SAH.^44,45 Thiopentone used for the treatment of intractable intracranial hypertension and/or refractory vasospasm post SAH have shown to reduce IL-6 and other inflammatory markers.⁴⁷

Propofol: A prospective study using propofol anesthesia for late intracranial aneurysm clipping reported significant decrease in CGRP levels during surgery which led the authors to conclude that propofol anesthesia might potentiate the risk of acute cerebral vasospasm during surgery given the potential vasodilating effect of CGRP.⁴⁸ A poor Glasgow outcome scale at six months was reported with the use of GABAergic sedation in the mechanically ventilated SAH ICU patients.⁴⁹ Propofol sedation in acutely brain injured mechanically ventilated patients was compared with dexmedetomidine and noted that both drugs have comparable effects on cerebral and cardiovascular physiology at the given doses.⁵⁰

Ketamine: Ketamine sedation in acute brain injured patients didn’t increase intracranial pressure^51-53 and also patients in the ketamine group needed less vasopressors to maintain the cerebral perfusion pressure.^51,52 Ketamine was also shown to inhibit spreading depolarization’s in severe brain injury patients^52-55 and also to reduce non-procedural related infarctions.⁵²

Conclusion:
Literature is limited related to this topic. Available work shows that inhalational anesthetics may provide neuroprotection against secondary brain injury post SAH but at this point it is difficult to recommend any particular anesthetic for neuroprotection in SAH patients. Future studies to assess the neuroprotective role of anesthetics on secondary brain injury post subarachnoid hemorrhage are warranted on the following 1) more studies exploring the effects of the commonly used anesthetics on both the EBI and DCI 2) finding the therapeutic window of anesthetics for maximum neuroprotection 3) anesthetic effects on long-term neuroprotection such as cognitive dysfunction post SAH 4) examination of anesthetic effects on different ages and gender 5) cross examination of anesthetic effects in different animal models and species and 6) finding the molecular pathways associated with anesthetic neuroprotection for a druggable target.

Table 1: Inhalational and Intravenous Anesthetics in Early Brain Injury (EBI) after SAH - Experimental Studies

↑= Activation/Increase/elevation, ↓= Inhibition/blockade/decrease, EBI= early brain injury, BBB= blood brain barrier, OGD= oxygen glucose deprivation, SphK = Sphingosine kinase, S1P1 = Sphingosine-1-phosphate receptor, HIF-1= hypoxia inducible factor, HO-1= hemeoxygenase, NMDA= N-methyl-D-aspartate, Nrf2= Nuclear factor erythroid-related factor 2, NF-kB = Nuclear factor-kappa B, AQP4= aquaporin, MMP-9= matrix metalloproteinase. Superscript numbers correspond with the reference list.

Table 2: Inhalational and Intravenous Anesthetics in Delayed Cerebral Ischemia (DCI) Post SAH - Experimental Studies

↑= Activation/Increase/elevation, ↓= Inhibition/blockade/decrease, DCI= delayed cerebral ischemia, ET-1= endothelin-1, HIF-1= hypoxia inducible factor-1. Superscript numbers correspond with the reference list.

Table 3: Inhalational and Intravenous Anesthetics in EBI/DCI Post SAH – Clinical Studies

↑= Activation/Increase/elevation, ↓= Inhibition/blockade/decrease, ET-1= endothelin, TCD= transcranial Doppler, rCBF= regional cerebral blood flow ,  CMRO2= cerebral metabolic rate of oxygen, Sjvo2= jugular vein oxygen saturation, ICP= intracranial pressure, MAP= mean arterial pressure, CPP= cerebral perfusion pressure, FTOE= fraction of tissue oxygen extraction, CGRP= calcitonin gene- related peptide, GOS= Glasgow outcome scale, IL-6= interleukin 6, GABA= Gamma- aminobutyric acid,  NMDA= N-methyl- D- Aspartate. SAH=subarachnoid hemorrhage, ICH= intracerebral hemorrhage, IS= ischemic stroke, TBI= traumatic brain injury, MHS= malignant hemispheric stroke. Superscript numbers correspond with the reference list. (Following references have mixed patients, 36(SAH/ICH/IS), 37(SAH/ICH/IS), 50(SAH/ICH/TBI), 51(SAH/TBI), 53(SAH/TBI), 54(SAH/IVH/TBI), 55(SAH/ICH/TBI/MHS) 

References:

1. Sudlow CLM and Warlow CP. Comparable studies of the incidence of stroke and its pathological types. Results from an international collaboration. Stroke 28, 491-499. 1997.
2. Mayer SA, et al. Global and domain specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002; 59:1750- 1758.
3. Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project. Stroke. 1993; 24:796–800.      
4. Zimmermann C, Ginis I, Furuya K, Klimanis D, Ruetzler C, Spatz M, et al. Lipopolysaccharide-induced ischemic tolerance is associated with increased levels of ceramide in brain and in plasma. Brain Res. 2001; 895:59-65.
5. Hua Y, Keep RF, Hoff JT, Xi G. Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron. J Cereb Blood Flow Metab. 2003; 23:1448-1454.
6. Milner E, Johnson AW, Nelson JW, Harries MD, Gidday JM, Han BH, et al. Isoflurane post conditioning-induced vascular protection in subarachnoid hemorrhage is mediated via hypoxia-inducible factor 1alpha. Ann Clin Transl Neurol. 2015 Apr;2(4):325-37.
7. Lim SY and DJH: Remote ischemic conditioning: from bench to bedside. Front Physiol 3:27, 2012.
8. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009 Apr;8(4):398-412.
9. Baillieul S, Chacaroun S, Doutreleau S, Detante O, Pépin JL, Verges S. Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries? Exp Biol Med (Maywood). 2017 Jun;242(11):1198-1206.
10. McLaughlin B, Gidday JM. Poised for success: implementation of sound conditioning strategies to promote endogenous protective responses to stroke in patients. Transl Stroke Res. 2013 Feb;4(1):104-13.
11. Wang H, Li P, Xu N, Zhu L, Cai M, Yu W, Gao Y. Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke. Med Gas Res. 2016 Dec 30;6(4):194-205.
12. Jiang M, Sun L, Feng DX, Yu ZQ, Gao R, Sun YZ, Chen G. Neuroprotection provided by isoflurane pre-conditioning and post-conditioning. Med Gas Res. 2017 Mar 30;7(1):48-55.
13. Gigante PR, Appelboom G, Hwang BY, Haque RM, Yeh ML, Ducruet AF, Kellner CP, Gorski J, Keesecker SE, Connolly ES Jr. Isoflurane preconditioning affords functional neuroprotection in a murine model of intracerebral hemorrhage. Acta Neurochir Suppl. 2011; 111:141-4.
14. Khatibi NH, Ma Q, Rolland W, Ostrowski R, Fathali N, Martin R, Applegate R, Stier G, Tang J, Zhang JH. Isoflurane posttreatment reduces brain injury after an intracerebral hemorrhagic stroke in mice. Anesth Analg. 2011 Aug; 113(2):343-8.
15. Karwacki Z, Kowiański P, Dziewiatkowski J, Domaradzka-Pytel B, Ludkiewicz B, Wójcik S, Narkiewicz O, Moryś J. The influence of sevoflurane on the reactivity of astrocytes in the course of the experimental intracerebral haemorrhage in rat. J Physiol Pharmacol. 2005 Sep; 56(3):455-69.
16. Karwacki Z, Kowiański P, Dziewiatkowski J, Domaradzka-Pytel B, Ludkiewicz B, Wójcik S, Narkiewicz O, Moryś J. Quantitative analysis of influence of sevoflurane on the reactivity of microglial cells in the course of the experimental model of intracerebral haemorrhage. Eur J Anaesthesiol. 2006 Oct; 23(10):874-81. Epub 2006 May 24.
17. He H, Liu W, Zhou Y, Liu Y, Weng P, Li Y, Fu H. Sevoflurane post-conditioning attenuates traumatic brain injury-induced neuronal apoptosis by promoting autophagy via the PI3K/AKT signaling pathway. Drug Des Devel Ther. 2018 Mar 23;12:629-638.
18. Harris K, Armstrong SP, Campos-Pires R, Kiru L, Franks NP, Dickinson R. Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site. Anesthesiology. 2013 Nov;119(5):1137-48.
19. Connolly ES Jr, et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association." Stroke 43, no. 6 (2012): 1711-1737.
20. Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol. 2012 Apr; 97(1):14-37.
21. Altay O, Hasegawa Y, Sherchan P, Suzuki H, Khatibi NH, Tang J, Zhang JH. Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice. Critical care medicine. 2012; 40:1908-1913.
22. Altay O, Suzuki H, Hasegawa Y, Caner B, Krafft PR, Fujii M, Tang J, Zhang JH. Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice. Stroke. 2012 Sep;43(9):2513-6.
23. Altay O, Suzuki H, Hasegawa Y, Ostrowski RP, Tang J, Zhang JH. Isoflurane on brain inflammation. Neurobiol Dis. 2014 Feb; 62:365-71.
24. Höllig A, Weinandy A, Liu J, Clusmann H, Rossaint R, Coburn M. Beneficial Properties of Argon After Experimental Subarachnoid Hemorrhage: Early Treatment Reduces Mortality and Influences Hippocampal Protein Expression. Crit Care Med. 2016 Jul;44(7):e520-9.
25. Veldeman M, Coburn M, Rossaint R, Clusmann H, Nolte K, Kremer B, Höllig A. Xenon Reduces Neuronal Hippocampal Damage and Alters the Pattern of Microglial Activation after Experimental Subarachnoid Hemorrhage: A Randomized Controlled Animal Trial. Front Neurol. 2017 Sep 27;8:511.
26. Miao YF, Peng T, Moody MR, Klegerman ME, Aronowski J, Grotta J, McPherson DD, Kim H, Huang SL. Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage. Sci Rep. 2018 Jan 11;8(1):450.
27. Shi SS, Zhang HB, Wang CH, Yang WZ, Liang RS, Chen Y, Tu XK. Propofol Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats. J Mol Neurosci. 2015 Dec; 57(4):538-45.
28. Yuan J, Cui G, Li W, Zhang X, Wang X, Zheng H, Zhang J, Xiang S, Xie Z. Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons. Anesth Analg. 2016 Apr;122(4):1024-30.
29. Brathwaite S, et al. "Current management of delayed cerebral ischemia: update from results of recent clinical trials." Translational stroke research 5, no. 2 (2014): 207-226.
30. Kassell N, Torner J, Haley E Jr. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 1990; 73:18–36.
31. Park KW, Dai HB, Metais C, Comunale ME, Sellke FW. Isoflurane does not further impair microvascular vasomotion in a rat model of subarachnoid hemorrhage. Can J Anaesth. 2002 Apr;49(4):427-33.
32. Mutoh T, Mutoh T, Sasaki K, Yamamoto Y, Tsuru Y, Tsubone H, Ishikawa T, Taki Y. Isoflurane postconditioning with cardiac support promotes recovery from early brain injury in mice after severe subarachnoid hemorrhage. Life Sci. 2016 May 15; 153:35-40.
33. Mutoh T, Mutoh T, Nakamura K, Yamamoto Y, Tsuru Y, Tsubone H, Ishikawa T, Taki Y. Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage. Clin Exp Pharmacol Physiol. 2017 Apr;44(4):463-469.
34. Mutoh T, Mutoh T, Nakamura K, Sasaki K, Tatewaki Y, Ishikawa T, Taki Y. Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage. Brain Res Bull. 2017 Apr;130:18-26.
35. Villa F, Iacca C, Molinari AF, Giussani C, Aletti G, Pesenti A, Citerio G. Inhalation versus endovenous sedation in subarachnoid hemorrhage patients: effects on regional cerebral blood flow. Crit Care Med. 2012 Oct; 40(10):2797-804.
36. Bösel J, Purrucker JC, Nowak F, Renzland J, Schiller P, Pérez EB, Poli S, Brunn B, Hacke W, Steiner T. Volatile isoflurane sedation in cerebrovascular intensive care patients using AnaConDa(®): effects on cerebral oxygenation, circulation, and pressure. Intensive Care Med. 2012 Dec; 38(12):1955-64.
37. Purrucker JC, Renzland J, Uhlmann L, Bruckner T, Hacke W, Steiner T, Bösel J. Volatile sedation with sevoflurane in intensive care patients with acute stroke or subarachnoid haemorrhage using AnaConDa®: an observational study. Br J Anaesth. 2015 Jun;114(6):934-43.
38. Wang T, Luo F, Shan R, Zhen Y, Zhao J, Zhang S. Changes of endothelin and calcitonin gene-related peptide during desflurane anesthesia in patients undergoing intracranial aneurysm clipping. J Neurosurg Anesthesiol. 2004 Jul; 16(3):236-9.
39. Kolias AG, Sen J, Belli A. Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches. J Neurosci Res. 2009 Jan;87(1):1-11.
40. Lee JW, Woo JH, Baik HJ, Kim DY, Chae JS, Yang NR, Seo EK. The effect of anesthetic agents on cerebral vasospasms after subarachnoid hemorrhage: A retrospective study. Medicine (Baltimore). 2018 Aug;97(31):e11666.
41. Kassell NF, Peerless SJ, Drake CG, Boarini DJ, Adams HP. Treatment of ischemic deficits from cerebral vasospasm with high dose barbiturate therapy. Neurosurgery. 1980 Dec;7(6):593-7.
42. Armonda RA, Thomas JE, Rosenwasser RH. Early and aggressive treatment of medically intractable cerebral vasospasm with pentobarbital coma, cerebral angioplasty and ICP reduction. Neurosurg Focus. 1998 Oct 15;5(4):e7.
43. Finfer SR, Ferch R, Morgan MK. Barbiturate coma for severe, refractory vasospasm following subarachnoid haemorrhage. Intensive Care Med. 1999 Apr;25(4):406-9.
44. Woodcock J, Ropper AH, Kennedy SK. High dose barbiturates in non-traumatic brain swelling: ICP reduction and effect on outcome. Stroke. 1982 Nov-Dec;13(6):785-7.
45. Niikawa S, Kitajima H, Ohe N, Miwa Y, Ohkuma A. Significance of acute cerebral swelling in patients with sylvian hematoma due to ruptured middle cerebral artery aneurysm, and its management. Neurol Med Chir (Tokyo). 1998 Dec;38(12):844-8; discussion 849-50.
46. Gasser S, Khan N, Yonekawa Y, Imhof HG, Keller E. Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications. J Neurosurg Anesthesiol. 2003 Jul;15(3):240-8.
47. Muroi C, Frei K, El Beltagy M, Cesnulis E, Yonekawa Y, Keller E. Combined therapeutic hypothermia and barbiturate coma reduces interleukin-6 in the cerebrospinal fluid after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2008 Jul;20(3):193-8.
48. Luo F, Ji N, Zhang S, Zhao J, Wang T. Changes of endothelin and calcitonin gene-related peptide concentrations in plasma during propofol anesthesia. J Neurosurg Anesthesiol. 2009 Jan; 21(1):47-50.
49. Hertle DN, Beynon C, Neumann JO, Santos E, Sánchez-Porras R, Unterberg AW, Sakowitz OW. Use of GABAergic sedatives after subarachnoid hemorrhage is associated with worse outcome-preliminary findings. J Clin Anesth. 2016 Dec;35:118-122.
50. James ML, Olson DM, Graffagnino C. A pilot study of cerebral and haemodynamic physiological changes during sedation with dexmedetomidine or propofol in patients with acute brain injury. Anaesth Intensive Care. 2012 Nov;40(6):949-57.
51. Schmittner MD, Vajkoczy SL, Horn P, Bertsch T, Quintel M, Vajkoczy P, Muench E. Effects of fentanyl and S(+)-ketamine on cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with intracranial pathologies: a pilot study. J Neurosurg Anesthesiol. 2007 Oct;19(4):257-62.
52. Von der Brelie C, Seifert M, Rot S, Tittel A, Sanft C, Meier U, Lemcke J. Sedation of Patients with Acute Aneurysmal Subarachnoid Hemorrhage with Ketamine Is Safe and Might Influence the Occurrence of Cerebral Infarctions Associated with Delayed Cerebral Ischemia. World Neurosurg. 2017 Jan; 97:374-382.
53. Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW. Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg. 2018 May 1:1-7.
54. Sakowitz OW, Kiening KL, Krajewski KL, Sarrafzadeh AS, Fabricius M, Strong AJ, Unterberg AW, Dreier JP. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke. 2009 Aug; 40(8):e519-22.
55. Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; Cooperative Study of Brain Injury Depolarizations (COSBID).  Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain. 2012 Aug;135(Pt 8):2390-8.