Year : 2013 | Volume
| Issue : 2 | Page : 187-190
Early brain injury and subarachnoid hemorrhage: Where are we at present?
Tumul Chowdhury1, Hari Hara Dash2, Ronald B Cappellani1, Jayesh Daya1
1 Department of Anesthesiology and Perioperative Medicine, Health Sciences Center, University of Manitoba, Winnipeg, Canada
2 Department of Anesthesiology and Perioperative Medicine, Fortis Hospital, Gurgaon, India
Department of Anesthesia and Perioperative Medicine, HSC, University of Manitoba, Winnipeg
Source of Support: None, Conflict of Interest: None
|Date of Web Publication||26-Jun-2013|
The current era has adopted many new innovations in nearly every aspect of management of subarachnoid hemorrhage (SAH); however, the neurological outcome has still not changed significantly. These major therapeutic advances mainly addressed the two most important sequels of the SAH-vasospasm and re-bleed. Thus, there is a possibility of some different pathophysiological mechanism that would be responsible for causing poor outcome in these patients. In this article, we have tried to compile the current role of this different yet potentially treatable pathophysiological mechanism in post-SAH patients. The main pathophysiological mechanism for the development of early brain injury (EBI) is the apoptotic pathways. The macro-mechanism includes increased intracranial pressure, disruption of the blood-brain barrier, and finally global ischemia. Most of the treatment strategies are still in the experimental phase. Although the role of EBI following SAH is now well established, the treatment modalities for human patients are yet to be testified.
Keywords: Apoptosis, early brain injury, ischemia, subarachnoid hemorrhage
|How to cite this article:|
Chowdhury T, Dash HH, Cappellani RB, Daya J. Early brain injury and subarachnoid hemorrhage: Where are we at present?. Saudi J Anaesth 2013;7:187-90
|How to cite this URL:|
Chowdhury T, Dash HH, Cappellani RB, Daya J. Early brain injury and subarachnoid hemorrhage: Where are we at present?. Saudi J Anaesth [serial online] 2013 [cited 2022 Jan 26];7:187-90. Available from: https://www.saudija.org/text.asp?2013/7/2/187/114047
| Introduction|| |
Spontaneous subarachnoid hemorrhage (SAH) is one of the most dreaded forms of neurological disease that not only causes significant morbidity and mortality but also results in poor socioeconomic outcome.  Although the current era has adopted many new innovations in nearly every aspect of management of this disease, the neurological outcome has still not changed significantly.  However, these major therapeutic advances mainly addressed the two most important sequel of SAH-vasospasm and re-bleed. Thus, there is a possibility of some different pathophysiological mechanism that would be responsible for causing poor outcome in these patients.
In this article, we have tried to compile the current role of this different yet potentially treatable pathophysiological mechanism in post-SAH patients.
| Early Brain Injury Following Spontaneous Subarachnoid Hemorrhage|| |
The pathophysiological mechanism responsible for any type of brain insult during the first 72 h following SAH is termed as EBI.  Vasospasm usually starts after 72 h post-SAH; however, the pathophysiological mechanism of EBI would certainly play some role in either causing vasospasm or at least sharing the common pathways to produce overall bad neurological outcome at the initial period of SAH.  Recently, a study showed increase in neuroinflammatory response (global Tumor necrosis factor TNF-α) following SAH at 2-3 days, but there was no angiographic vasospasm. However, this inflammatory response was associated with poor outcome at 3 months.  The clinical consequences of both the mechanisms are usually similar, including altered consciousness or the sudden onset of new neurological deficit in patients with ruptured aneurysm. The need to elucidate the etiopathogenesis of EBI is currently a matter of great interest and mainly postulated in animal experiments. The current area of interest for EBI is emerging rapidly as many of the pathophysiological process are potentially treatable.
| Etiopathogenesis of Early Brain Injury|| |
SAH is a complex pathophysiological process, wherein the initial physiological response is increase in intracranial pressure (ICP). Though thought to be a protective mechanism, this rise in ICP usually decreases the cerebral perfusion pressure and further causes cerebral ischemia. The presence of blood and its degraded products in the ventricles produce obstructive hydrocephalus, which again causes increase in ICP. This results in the development of global ischemia, which stimulates many ischemic pathways, usually produces oxidative damage to neural tissue, and finally leads to neuronal death. The ischemic mediators disrupt the blood brain barrier and produce cytotoxic neuronal edema. This sets off the vicious cycle, producing more ischemia and so on. ,
| Molecular Mechanism|| |
Apoptosis is the most common proposed mechanism for the development of EBI.  It is a programmed cell death that is usually devoid of cell inflammatory mediators. In the ischemic cell, mitochondrial dysfunction is the precursor of final neuronal injury. On the other hand, necrotic pathways may occur and usually difficult to differentiate; however, this process is usually followed by inflammatory mediators and often depicts irreversible cell injury. The reversible nature of apoptotic pathways has shown some promising treatment options. In general, post SAH, the ischemic insult of brain stimulates a wide array of complex pathways that finally stimulate the apoptotic mechanism and finally the production of EBI. The proposed different mechanisms to produce EBI include oxidative injury, nitric oxide dysregulation, generation of matrix metalloproteinase 9 (MMP-9), modulation of nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway, activation of c-Jun N-terminal kinase pathway, interleukin-1beta activation, and other factors such as vascular endothelial growth factor and mitogen-activation protein kinase. ,,,,, The role of iron overload that is produced after degradation of hemoglobin following SAH has also been shown to cause EBI.  On the other hand, some processes such as autophagy play a protective role in EBI by removing misfolded proteins and scavenging other dysfunctional proteins as well as organelle.  Understanding these molecular mechanisms will lead to promising treatment options in SAH patients and possibly would open new doors for future treatment strategies.
| Management|| |
The management of EBI is mainly experimental; however, the treatment options are multidisciplinary and involve all the aspects of SAH management.
Management of SAH starts from early resuscitation steps, such as airway control, adequate breathing to maintain normoventilation, avoiding hypoxemia, maintaining adequate perfusion, and identifying other disabilities. Maintenance of cerebral oxygenation and perfusion is the utmost goal. The supportive care should aim to prevent secondary brain injury and involve seizure control, avoid hypoglycemia or hyperglycemia, maintain normothermia, and minimize the increase in ICP.  The role of external ventricular drain to relieve increase in ICP should be discussed with the surgeon and this sometimes remains the only lifesaving maneuver, especially in poor-grade patients.
Most of the patients with SAH are hypovolemic. Maintenance of normovolemia with isotonic fluids is recommended.  Avoidance of glucose-containing solutions and correction of underlying electrolytes abnormalities are important in preventing secondary brain injury. The use of hypervolemia to prevent vasospasm is now not a part of standard care because it can aggravate cerebral edema and hence ischemia and produce other systemic complications including pulmonary edema and congestive heart failure. 
Poor-grade patients often require intubation and elective ventilation. Normocarbia should be maintained. Hypocarbia can cause cerebral vasoconstriction and may worsen the ischemia. However, transient hyperventilation should be used only in the situation of ICP raised ICP due to re-bleed, hydrocephalus, or massive infarct. Early tracheostomy will be beneficial in patients with massive ischemia/infarct, in which prolonged ventilation would be anticipated.
Options include either clipping or coiling of the ruptured aneurysm. Previous studies have shown that outcome (free of disability) at 1 year is significantly better with endovascular coiling and the survival benefit continues for at least 7 years. , Although a small risk, there were more episodes of re-bleed in the coiling group. The current evidence also favors coiling if aneurysm is suitable for both coiling and clipping. 
The prevention of SAH sequel in the form of either EBI or vasospasm would depend on definite management if done at an early phase. The prophylactic use of calcium channel antagonist-nimodipine is the standard care to prevent and treat vasospasm.
| Specific Management of Early Brain Injury|| |
Blocker of apoptotic pathway
Apoptotic pathways play a crucial role in developing EBI following SAH. This apoptotic pathway involves many enzymes including Cytochrome-C, Caspase, and P53. There are many agents that specifically block these different enzymes at different levels and have been shown to attenuate EBI. The noteworthy point is that these enzymatic processes are essential for normal regulation also, so the blockage of these may produce many untoward effects.
Statins (Hydroxymethylglutaryl coenzyme A reductase inhibitors) such as atrovastin has been shown to inhibit Caspase-dependent proapoptotic pathway and found to be neuroprotective.  The role of cyclosporine A in the stabilization of mitochondrial membrane by inhibiting mitochondrial permeability transition pore (mPTP) opening was also found to be one of the antiapoptotic mechanisms to attenuate SAH-induced EBI. 
Recent studies have demonstrated the possible role of volatile anesthetic in the prevention of EBI. In this study, use of isoflurane in post-SAH animals delayed the EBI produced by SAH. Isoflurane is found to be an inhibitor of apoptotic pathway through sphingosine-related activation and this study further concludes that the use of isoflurane in early surgery or intervention might be beneficial.  In another study, use of isoflurane was also associated with decrease in BBI disruption, which has an important role for causing EBI following SAH. 
The other agents found to attenuate or prevent EBI are mainly the inhibitors of other pathways. These agents include desferoxamine (iron overload), minocycline (MMP-9 inhibitor), hydrogen-rich saline (decreases oxidative stress), osteopontin (deactivation of nuclear factor-κB activity and MMP-9 inhibitor), sodium orthovanadate (tyrosine phosphatase inhibitor), melatonin, and recombinant human erythropoietin (activation Nrf2-ARE pathway). ,,,,,,
| Hypothermia|| |
Hypothermia attenuates the mediators of ischemic cascade and confers neuroprotection. The ischemia-induced apoptotic pathways could be blocked by hypothermia; however, the exact therapeutic window is still a matter of investigation. The current literature, however, does not support the use of mild therapeutic hypothermia, especially in good-grade aneurysm patients.  On the other hand, it has shown some promising results in experimental poor-grade aneurysms. There is also a conflict about the timing to institute hypothermia to maximize its beneficial role. , Large, randomized studies are further required to elucidate the role of hypothermia in EBI, especially in poor-grade patients.
| Hyperbaric Oxygen Therapy|| |
Post SAH, there is increased lipid per oxidation and upregulation of Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase (NOX), a major enzymatic source of superoxide anion in the brain. Hyperbaric oxygen has found to blunt these oxidative responses. This therapy has also shown to reverse early ischemia and prolong neuroprotective effects. ,
| Interpretation of Experimental Results|| |
The major researches for therapies to attenuate or to prevent EBI in post-SAH patients are only carried out in animal models. The interpretation of these data to human are not always direct, because some cerebro-physiological differences exist among different species. Thus, it would be interesting to observe the results in human patients in the near future.
In conclusion, the role of EBI following SAH is now well established and its pathogenesis mainly involves the ischemic-apoptotic pathways; however, the management strategies are still in the experimental phase and are yet to be performed on patients. The future therapies would also be more focused toward the role of gene and stem cell therapies in such cases.
| References|| |
|1.||le Roux AA, Wallace MC. Outcome and cost of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 2010;21:235-46. |
|2.||Ingelmo Ingelmo I, Fàbregas Julià N, Rama-Maceiras P, Hernández-Palazón J, Rubio Romero R, Carmona Aurioles J et al. Subarachnoid hemorrhage: Epidemiology, social impact and a multidisciplinary approach. Rev Esp Anestesiol Reanim 2010;57:S4-15. |
|3.||Cahill J, Calvert JW, Zhang JH. Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 2006;26:1341-53. |
|4.||Nishizawa S. The roles of early brain injury in cerebral vasospasm following subarachnoid hemorrhage: From clinical and scientific aspects. Acta Neurochir Suppl 2013;115:207-11. |
|5.||Chou SH, Feske SK, Atherton J, Konigsberg RG, De Jager PL, Du R, et al. Early elevation of serum tumor necrosis factor-α is associated with poor outcome in subarachnoid hemorrhage. J Investig Med 2012;60:1054-8. |
|6.||Ayer R, Zhang J. Connecting the early brain injury of aneurysmal subarachnoid hemorrhage to clinical practice. Turk Neurosurg 2010;20:159-66. |
|7.||Ayer RE, Zhang JH. The clinical significance of acute brain injury in subarachnoid hemorrhage and opportunity for intervention. Acta Neurochir Suppl 2008;105:179-84. |
|8.||Hasegawa Y, Suzuki H, Sozen T, Altay O, Zhang JH. Apoptotic mechanisms for neuronal cells in early brain injury after subarachnoid hemorrhage. Acta Neurochir Suppl 2011;110:43-8. |
|9.||Sozen T, Tsuchiyama R, Hasegawa Y, Suzuki H, Jadhav V, Nishizawa S, et al. Immunological response in early brain injury after SAH. Acta Neurochir Suppl 2011;110:57-61. |
|10.||Sabri M, Ai J, Macdonald RL. Nitric oxide related pathophysiological changes following subarachnoid haemorrhage. Acta Neurochir Suppl 2011;110:105-9. |
|11.||Guo Z, Sun X, He Z, Jiang Y, Zhang X. Role of matrix metalloproteinase-9 in apoptosis of hippocampal neurons in rats during early brain injury after subarachnoid hemorrhage. Neurol Sci 2010;31:143-9. |
|12.||Yatsushige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH. Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res 2007;85:1436-48. |
|13.||Chen G, Fang Q, Zhang J, Zhou D, Wang Z. Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 2011;89:515-23. |
|14.||Sozen T, Tsuchiyama R, Hasegawa Y, Suzuki H, Jadhav V, Nishizawa S, et al. Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice. Stroke 2009;40:2519-25. |
|15.||Lee JY, Keep RF, He Y, Sagher O, Hua Y, Xi G. Hemoglobin and iron handling in brain after subarachnoid hemorrhage and the effect of deferoxamine on early brain injury. J Cereb Blood Flow Metab 2010;30:1793-803. |
|16.||Jing CH, Wang L, Liu PP, Wu C, Ruan D, Chen G. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 2012;213:144-53. |
|17.||Fugate JE, Rabinstein AA. Intensive care unit management of aneurysmal subarachnoid hemorrhage. Curr Neurol Neurosci Rep 2012;12:1-9. |
|18.||Hoff RG, van Dijk GW, Algra A, Kalkman CJ, Rinkel GJ. Fluid balance and blood volume measurement after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2008;8:391-7. |
|19.||Rinkel GJ, Feigin VL, Algra A, van Gijn J. Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2004;4:CD000483. |
|20.||Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised trial. Lancet 2002;360:1267-74. |
|21.||Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005;366:809-17 |
|22.||van der Schaaf I, Algra A, Wermer M, Molyneux A, Clarke M, van Gijn J, et al. Endovascular coiling versus neurosurgical clipping for patients with aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2005;4:CD003085. |
|23.||Dhar R, Diringer M. Statins and anti-inflammatory therapies for subarachnoid hemorrhage. Curr Treat Options Neurol 2012;14:164-74. |
|24.||Xie Z, Lei B, Huang Q, Deng J, Wu M, Shen W, et al. Neuroprotective effect of Cyclosporin A on the development of early brain injury in a subarachnoid hemorrhage model: A pilot study. Brain Res 2012;1472:113-23. |
|25.||Altay O, Hasegawa Y, Sherchan P, Suzuki H, Khatibi NH, Tang J, et al. Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice. Crit Care Med 2012;40:1908-13. |
|26.||Altay O, Suzuki H, Hasegawa Y, Caner B, Krafft PR, Fujii M, et al. Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice. Stroke 2012;43:2513-6. |
|27.||Lee JY, Keep RF, Hua Y, Ernestus RI, Xi G. Deferoxamine reduces early brain injury following subarachnoid hemorrhage. Acta Neurochir Suppl 2011;112:101-6. |
|28.||Guo ZD, Wu HT, Sun XC, Zhang XD, Zhang JH. Protection of minocycline on early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir Suppl 2011;110:71-4. |
|29.||Zhuang Z, Zhou ML, You WC, Zhu L, Ma CY, Sun XJ, et al. Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci 2012;13:47. |
|30.||Suzuki H, Ayer R, Sugawara T, Chen W, Sozen T, Hasegawa Y, et al. Role of osteopontin in early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir Suppl 2011;110:75-9. |
|31.||Hasegawa Y, Suzuki H, Altay O, Zhang JH. Preservation of tropomyosin-related kinase B (TrkB) signaling by sodium orthovanadate attenuates early brain injury after subarachnoid hemorrhage in rats. Stroke 2011;42:477-83. |
|32.||Wang Z, Ma C, Meng CJ, Zhu GQ, Sun XB, Huo L, et al. Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res 2012;53:129-37. |
|33.||Zhang J, Zhu Y, Zhou D, Wang Z, Chen G. Recombinant human erythropoietin (rhEPO) alleviates early brain injury following subarachnoid hemorrhage in rats: Possible involvement of Nrf2-ARE pathway. Cytokine 2010;52:252-7. |
|34.||Todd MM, Hindman BJ, Clarke WR, Torner JC, Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005;352:135-45. |
|35.||Kawamura Y, Yamada K, Masago A, Katano H, Matsumoto T, Mase M. Hypothermia modulates induction of hsp70 and c-jun mRNA in the rat brain after subarachnoid hemorrhage. J Neurotrauma 2000;17:243-50. |
|36.||Török E, Klopotowski M, Trabold R, Thal SC, Plesnila N, Schöller K. Mild hypothermia (33 degrees C) reduces intracranial hypertension and improves functional outcome after subarachnoid hemorrhage in rats. Neurosurg 2009;65:352-9. |
|37.||Ostrowski RP, Colohan AR, Zhang JH. Neuroprotective effect of hyperbaric oxygen in a rat model of subarachnoid hemorrhage. Acta Neurochir Suppl 2006;96:188-93. |
|38.||Matchett GA, Martin RD, Zhang JH. Hyperbaric oxygen therapy and cerebral ischemia: Neuroprotective mechanisms. Neurol Res 2009;31:114-21. |
|This article has been cited by|
||Neuroprotective Effects of Early Brain Injury after Subarachnoid Hemorrhage in Rats by Calcium Channel Mediating Hydrogen Sulfide
| ||Hong-Zhou Duan, Chong-Wei Wu, Sheng-Li Shen, Jia-Yong Zhang, Liang Li |
| ||Cellular and Molecular Neurobiology. 2021; 41(8): 1707 |
|[Pubmed] | [DOI]|
||Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage
| ||Wentao Qi, Demao Cao, Yucheng Li, Aijun Peng, Youwei Wang, Kai Gao, Cunshan Tao, Yongkang Wu |
| ||Bioscience Reports. 2018; 38(3) |
|[Pubmed] | [DOI]|
||Neopterin plasma concentrations in patients with aneurysmal subarachnoid hemorrhage: correlation with infection and long-term outcome
| ||Leire Azurmendi,Vincent Degos,Natalia Tiberti,Natacha Kapandji,Paola Sanchez-Peña,Asita Sarrafzadeh,Louis Puybasset,Natacha Turck,Jean-Charles Sanchez |
| ||Journal of Neurosurgery. 2015; : 1 |
|[Pubmed] | [DOI]|