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The critical care management of poor-grade subarachnoid haemorrhage

The critical care management of poor-grade subarachnoid haemorrhage Aneurysmal subarachnoid haemorrhage is a neurological syndrome with complex systemic complications. The rupture of an intracranial aneurysm leads to the acute extravasation of arterial blood under high pressure into the subarachnoid space and often into the brain parenchyma and ventricles. The haemorrhage triggers a cascade of complex events, which ultimately can result in early brain injury, delayed cerebral ischaemia, and systemic complications. Although patients with poor-grade subarachnoid haemorrhage (World Federation of Neurosurgical Societies 4 and 5) are at higher risk of early brain injury, delayed cerebral ischaemia, and systemic complications, the early and aggressive treatment of this patient population has decreased overall mortality from more than 50 % to 35 % in the last four decades. These management strategies include (1) transfer to a high-volume centre, (2) neurological and systemic support in a dedicated neurological intensive care unit, (3) early aneurysm repair, (4) use of multimodal neuromonitoring, (5) control of intracranial pressure and the optimisation of cerebral oxygen delivery, (6) prevention and treatment of medical complications, and (7) prevention, monitoring, and aggressive treatment of delayed cerebral ischaemia. The aim of this article is to provide a summary of critical care management strategies applied to the subarachnoid haemorrhage population, especially for patients in poor neurological condition, on the basis of the modern concepts of early brain injury and delayed cerebral ischaemia. Background level of consciousness have higher risk of death and dis- Aneurysmal subarachnoid haemorrhage (SAH) is a com- ability, although improved outcomes have also been plex neurovascular syndrome with profound systemic ef- shown in this group of patients in the last decades. For fects and is associated with high disability and mortality these reasons, patients presenting with a Glasgow Coma [1]. Despite a 17 % decrease in case fatality in the last Scale (GCS) score of less than 13 have traditionally been three decades associated with improved management defined as having poor-grade SAH (classified as grade 4 strategies, 30-day mortality and before-admission death and 5 according to the Hunt and Hess [4] or the World rate unfortunately are still high, around 35 % and 15 %, Federation of Neurosurgical Societies (WFNS) grading respectively [2]. scales [5] or more recently as VASOGRADE-Red [6]). Outcomes after SAH can vary significantly, from full Poor outcomes are usually secondary to early brain in- recovery to severe disability or death, depending on the jury (EBI) or to delayed cerebral ischaemia (DCI). EBI severity of the initial bleed and potential complications refers to the acute consequences of SAH-associated sud- typically happening in the first 2 weeks after the haem- den increase of intracranial pressure (ICP), which can orrhage [3]. The level of consciousness is considered the cause decreased cerebral perfusion and transient global most important early predictor of outcome [4–6]. Pa- cerebral ischaemia. The global cerebral ischaemia can re- tients with a normal level of consciousness have a low sult in transient loss of consciousness or progressive risk of mortality. Patients admitted with a depressed intracranial hypertension. Subarachnoid blood itself can also damage the brain. DCI is a multifactorial entity * Correspondence: airtonleo.manoel@gmail.com often responsible for poor outcome after SAH in pa- St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1 W8, Canada tients who survive the initial haemorrhage. Clinically, it Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 30 is characterised by a change in neurological function Bond Street, Toronto, ON M5B 1 W8, Canada Full list of author information is available at the end of the article © 2016 de Oliveira Manoel et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 2 of 19 that manifests most often between days 3 and 14 after 1. Initial management: medical stabilisation, haemorrhage. Recently, DCI was defined as a change in prevention of re-bleeding, and control of intracra- level of consciousness (decrease of 2 points in the GCS nial pressure or an increase in 2 points in the National Institute of During aneurysmal SAH, extravasation of high-pressure Health Stroke Scale) or development of new focal deficit arterial blood in the subarachnoid space (and often into lasting for at least 1 hour and not explained by other fac- the brain parenchyma and ventricles) is associated with tors (e.g., systemic complications and hydrocephalus) [7]. a sudden ICP increase that, if severe and sustained, may DCI is believed to be due to a combination of factors such compromise cerebral perfusion, causing global cerebral as angiographic vasospasm, cortical spreading ischaemia, ischaemia and EBI (Fig. 1). If the haemorrhage does not microthrombosis, and microcirculation vasoconstriction. stop, acute cardiopulmonary instability associated with In this review, we will discuss the management of patients intracranial hypertension or compromised cerebral with poor-grade SAH on the basis of the current concepts blood flow (CBF) leads to patient death before hospital of EBI and delayed cerebral ischaemia. admission. In patients who survive the initial haemor- rhage, re-bleeding is the most severe early complication; Search strategy the reported incidence is up to 15 % in the first 24 hours, A PubMed search for articles published until May 2015 and the fatality rate is approximately 70 % [11–13]. was performed by using the terms “Subarachnoid Patients with poor-grade SAH are at higher risk of re- Hemorrhage” [Mesh] AND (“poor-grade” [Title/Abstract] bleeding [14]. Initial management therefore should focus OR “high-grade” [Title/Abstract]), which returned 236 on strategies aimed to prevent re-bleeding and to con- articles. Additionally, the reference lists of the most trol ICP. recent guidelines on the management of SAH were Early aneurysm repair is generally considered the most searched [8–10]. Lastly, the authors’ personal databases important strategy to reduce the risk of aneurysm re- were used as an additional source for this review. rupture [15]. However, evidence for optimum timing of Fig. 1 Early pathophysiology of subarachnoid haemorrhage. Acute haemorrhage from an aneurysm can physically damage the brain and lead to acute transient global ischaemia. Transient global ischaemia secondary to increased intracranial pressure can also trigger sympathetic nervous system activation, leading to systemic complications. The contribution of each process to the pathophysiology is unknown, but transient global ischaemia and subarachnoid blood result in early brain injury, characterised by microcirculation constriction, microthrombosis, disruption of the blood–brain barrier, cytotoxic and vasogenic cerebral oedema, and neuronal and endothelial cell death. CBF cerebral blood flow, CPP cerebral perfusion pressure, ECG electrocardiographic, ET-1 endothelin-1, ICH intracranial haemorrhage, ICP intracranial pressure, MMP-9 matrix metalloproteinase-9, NO nitric oxide, TNF-R1 tumour necrosis factor receptor 1. First published in Nature Reviews Neurology [98] de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 3 of 19 treatment is limited, and it is unclear whether ultra-early 160 mm Hg (or both) in the presence of ruptured un- treatment (less than 24 hours) is superior to early secured aneurysm. The European guidelines are less ag- aneurysm repair (within 72 hours). A recently published gressive and suggest keeping the systolic blood pressure retrospective data analysis comparing ultra-early treatment below 180 mm Hg [10]. These parameters should not be with repair performed within 24–72 hours after haemor- used after aneurysm treatment, when spontaneously high rhage suggests that aneurysm occlusion can be performed blood pressure may be beneficial [25]. safely within 72 hours after aneurysm rupture [16]. The Intracranial hypertension (ICP of at least 20 mm Hg) is a American Heart Association/American Stroke Association relatively common complication of SAH, especially in pa- [9] recommend as a Class IB Recommendation that “surgi- tients presenting with poor neurological condition [26–28]. cal clipping or endovascular coiling of the ruptured Multiple factors such as cerebral oedema, intraparench- aneurysm should be performed as early as feasible in the ymal haematoma, acute communicating hydrocephalus, majority of patients to reduce the rate of re-bleeding after intraventricular haemorrhage, aneurysm re-rupture, SAH”. This recommendation for timing of aneurysm complications related to aneurysm treatment, EBI, and intervention is corroborated by the European Stroke DCI can contribute to the development of intracranial Organization Guidelines for the Management of Intracra- hypertension [29]. High ICP is associated with severe nial Aneurysms and Subarachnoid Haemorrhage [10], derangements of cerebral metabolism [30], increased which stated that “aneurysm should be treated as early as risk of neurological deterioration [25], and poor out- logistically and technically possible to reduce the risk of come, especially if refractory to medical treatment [29, re-bleeding; if possible it should be aimed to intervene at 31]. ICP of greater than 20 mm Hg is an independent least within 72 hours after onset of first symptoms”. predictor of severe disability and death in aneurysmal The results from an ongoing trial only enrolling patients SAH [30]. with poor-grade SAH may help answer the question of Principles of management of intracranial hypertension whether early treatment (within 3 days) is associated with after SAH have been traditionally adopted from trau- improved outcome compared with intermediate (days 4–7) matic brain injury (TBI) literature [32] and are not spe- or late (after day 7) treatment [17]. cifically designed for the SAH population. However, The choice of treatment modality between surgical these two entities are different from a pathophysiological clipping and endovascular coiling is a complex endeav- perspective, and the use of therapies tested in patients our, which requires the expertise of an interdisciplinary with TBI in the SAH population is controversial. Cur- team, including neurointensivists, interventional neuro- rently, the role of therapies such as hyperosmolar agents, radiologists and neurovascular surgeons. For aneurysms hypothermia, barbiturates, and decompressive craniect- considered to be equally treatable by both modalities, omy is not well established in SAH patients with intra- the endovascular approach is superior, being associated cranial hypertension refractory to first-line treatments. with better long-term outcomes [18–20]. Randomised The initial approach to raised ICP includes head of trials of clipping versus coiling included mostly good- bed elevation (between 30° and 45°) to optimise cerebral grade patients, leading to controversy as to whether their venous drainage, normoventilation (arterial partial pres- results apply also to poor-grade patients. Retrospective sure of carbon dioxide (PaCO ): 35–40 mm Hg) [33], data on clipping and coiling in poor-grade patients seem use of sedation and analgesia to achieve a calm and quiet to suggest that surgical clipping and endovascular are state (Richmond Agitation Sedation Scale score of −5or equally effective [21]. An early and short course of an Sedation-Agitation Scale score of 1), and surgical inter- anti-fibrinolytic drug such as tranexamic acid, initiated vention in the presence of mass-occupying lesions [34]. as soon as the radiological diagnosis of SAH is estab- The use of neuromuscular blocking agents is sometimes lished and stopped within 24–72 hours, has been associ- applied to prevent ICP surges during tracheal suctioning ated with decreased rate of ultra-early re-bleeding and a and physiotherapy; however, the role of these drugs for non-significant improvement in long-term functional ICP management is not well established, and some au- outcome [22]. This approach remains controversial [23], thors suggest that they may be more deleterious than and short-term administration of tranexamic acid to pre- beneficial [35]. If ICP remains elevated despite these inter- vent re-bleeding is being further studied in a multicentre ventions, a short course (less than 2 hours) of hyperventi- randomised trial (Dutch Trial Registry number NTR3272) lation (PaCO of 30–35 mm Hg) might be considered [24]. Another medical intervention applied to prevent while new brain imaging is obtained and other interven- aneurysm re-rupture is the avoidance of extremes of blood tions are planned and initiated [36–38]. pressure. The American Heart Association/American Cerebrospinal fluid (CSF) drainage is a mainstay in Stroke Association [9] and the Neurocritical Care [8] ICP management of patients with SAH, especially when guidelines suggest keeping the mean arterial blood pres- hydrocephalus is present [39]. Acute hydrocephalus is sure below 110 mm Hg or systolic blood pressure below common in SAH, and approximately 50 % of patients de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 4 of 19 are affected on admission [40]. When hydrocephalus is achieved with decompressive craniectomy, this may be best associated with a decreased level of consciousness, an obtained when the procedure is performed early (within external ventricular drain (EVD) should be inserted to 48 hours from the bleeding) [52] and in the absence of allow CSF drainage and ICP monitoring. EVD insertion radiological signs of cerebral infarction [51]. Finally, in before aneurysm treatment has been shown to be safe poor-grade patients with large intraparenchymal or Sylvian and not associated with increased risk of aneurysm re- fissure haematomas usually from middle cerebral artery an- rupture [40, 41], if accompanied by early aneurysm eurysms, prophylactic decompressive craniectomy should repair. Additionally, when EVD insertion is performed be considered [34]. before aneurysm repair, CSF drainage should be prac- It is important to mention that long-term outcome ticed with caution because rapid and aggressive CFS after acute brain injury is markedly improved when pa- drainage can increase transmural pressure, increasing tients are managed in a dedicated neurologic/neurosur- the risk of aneurysm re-rupture [41, 42]. Interestingly, gical intensive care unit (ICU) [57, 58]. Especially after approximately 30 % of patients with poor-grade SAH SAH, outcome is affected by hospital caseload, and bet- improve neurologically after EVD insertion and CSF ter outcomes happen in high-volume centres (centres drainage. These responders have a functional outcome treating more than 60 patients per year) [59]. Six-month similar to that of good-grade (WFNS I–III) patients [39]. mortality is inversely associated with hospital annual Hyperosmolar agents, such as mannitol and hyper- caseload; there is a 24 % reduction in mortality for each tonic saline, are usually considered when the above strat- 100 patients admitted per year [60]. Regardless of initial egies fail to control ICP, although their role on clinical grade, early transfer to a high-volume centre is safe and outcome in the SAH population is not well established. cost-effective and should be pursued [61–63]. We could not identify any study addressing the role of mannitol in the management of raised ICP in the SAH 2. Prevention, detection, and treatment of population; for hypertonic saline, we found only case delayed cerebral ischaemia series [43–46] and a small placebo-controlled trial in pa- Delayed neurological deterioration occurs frequently in tients with raised but stable ICP [47]. In these studies, the first 2 weeks after SAH. Common causes of this hypertonic saline was effective to control ICP and im- deterioration include neurological events such as pro- proved CBF [43–47] and may improve outcome in the gression of EBI, hydrocephalus, seizures, ischaemia, and poor-grade population [43]. systemic conditions, such as fever and infections, re- The last line of treatment includes the use of barbitu- spiratory failure, and electrolyte abnormalities. Any de- rates, induced hypothermia, and decompressive craniect- layed neurological deterioration presumed to be related omy [38, 48]. Therapeutic hypothermia has been shown to ischaemia that persists for more than 1 hour and can- to be effective to control ICP in SAH but has not been not be explained differently has been defined as DCI [7] associated with improved functional outcome and re- (Table 1). DCI occurs in up to 30 % of SAH patients sur- duced mortality rates in patients with poor-grade SAH viving the initial haemorrhage. It can present as an acute [49]. The association of barbiturate coma and mild or insidious change in the level of consciousness or as a hypothermia (33–34 °C, median treatment of 7 days) focal neurological symptom, such as aphasia or hemipar- was studied in 100 SAH (64 poor-grade) patients with esis, or as both. These symptoms can be reversible if intracranial hypertension refractory to other medical inter- treated promptly and aggressively; otherwise, DCI tends ventions [50]. Approximately 70 % of patients were severely to progress to cerebral infarction, which is associated with disabled or dead at 1 year, and more than 90 % of patients higher rates of disability and mortality. Traditionally, DCI developed medical complications associated with the has been considered to be related to a cerebral vasocon- hypothermia/barbiturate treatment (i.e., electrolyte disor- striction (angiographic vasospasm) that begins approxi- ders, ventilator associated pneumonia, thrombocytopenia, mately 3 days and peaks 1 week after the haemorrhage and septic shock). Decompressive craniectomy is another and starts resolving after 2 weeks [64]. However, recent possible strategy for refractory ICP management in patients evidence suggests that DCI is a complex, multifactorial with SAH. Poor-grade patients are more commonly ex- syndrome, which can include additional pathophysiologic posed to this rescue therapy than patients with good-grade processes beyond angiographic or sonographic vasospasm SAH [51, 52]. Decompressive craniectomy has been associ- (Fig. 2 and Table 2) [65]. DCI may also occur in cerebral ated with decreased mortality [53], significant reduction of territories without evidence of angiographic vasospasm ICP [34], improved cerebral oxygenation [54, 55], and im- [66]. EBI (defined as brain injury developing in the first proved cerebral metabolism [56]. However, most patients 72 hours after haemorrhage) has significant impact on undergoing decompressive craniectomy due to refractory likelihood and severity of subsequent ischaemic changes ICP have poor outcome, with severe disability or death [67, 68]. For example, poor-grade patients, who have [56]. Many authors suggest that, if any benefit can be worse EBI, as well as patients who lose consciousness at de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 5 of 19 Table 1 The current definitions of early brain injury, delayed cortex hypoperfusion secondary to vasoconstriction [71]. cerebral ischaemia, and cerebral infarction The vast majority of cortical spreading depolarisation A. Early brain injury is the acute consequence of subarachnoid waves usually happen in the first 2 weeks after aneurysm haemorrhage (SAH) that leads to transient global cerebral ischaemia rupture, and 75 % of all CSIs recorded occur between the following the aneurysm rupture. During aneurysmal rupture, arterial fifth and seventh day post-bleeding [72]. In a prospective blood leaks under high pressure into the subarachnoid space and often into the brain parenchyma and ventricles. There is an acute and multicentre study, Dreier et al. [73] assessed the incidence sharp increase in the intracranial pressure (ICP) that may rise high and timing of spreading depolarisations and DCI after enough to compromise cerebral perfusion, causing global cerebral SAH. Eighteen SAH patients requiring craniotomy for ischaemia. This acute drop in cerebral perfusion pressure usually produces loss of consciousness. The initial cerebral injury (i.e., early aneurysm treatment were monitored for up to 10 days brain injury) is the combined result of transient global cerebral with subdural electrodes. Cortical spreading depolarisa- ischaemia and the effects of the subarachnoid blood itself. tions were detected in 13 patients (72 %). DCI was de- B. Global cerebral ischaemia: As discussed above, the aneurysm rupture leading to SAH can increase the ICP to cause global cerebral tected in seven patients and was time-locked to a ischaemia. If the haemorrhage does not stop, the patient dies before sequence of recurrent spreading depolarisations in all hospital admission and this is usually due to acute cardiopulmonary seven cases. Additionally, delayed ischaemic strokes changes associated with the high ICP or due to brain death related to the compromised cerebral blood flow. Re-bleeding remains the most verified by serial computed tomography (CT) scans or important complication in the hours following the initial bleed. There- magnetic resonance imaging occurred in the recording fore, the initial management should focus on strategies to prevent area in four patients. In another prospective study, aneurysm re-bleeding and to control ICP. using a novel subdural opto-electrode technology for C. Delayed cerebral ischaemia (DCI) is defined as “the occurrence of focal simultaneous laser-Doppler flowmetry and direct neurological impairment (such as hemiparesis, aphasia, apraxia, hemian- current-electrocorticography, combined with measure- opia, or neglect), or a decrease of at least 2 points on the Glasgow Coma Scale (either on the total score or on one of its individual components, ments of tissue partial pressure of oxygen, Dreier et al. such as eye, motor on either side, or verbal). This should last for at least [71] studied 13 patients with SAH. Isolated spreading 1 hour, is not apparent immediately after aneurysm occlusion, and depolarisations were detected in 12 of those. These cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies” [7]. DCI waves of depolarisations were associated with physio- remains the most significant cause of long-term disability and mortality logical, absent, or inverse regional CBF responses. Normal in patients who survive the initial haemorrhage to reach definitive haemodynamic response was associated with tissue hyper- aneurysm treatment [163]. In those patients who survive the initial bleed to reach medical assistance, the degree of brain injury associated with oxia, whereas inverse response led to tissue hypoxia. Five transient global cerebral ischaemia is variable. However, the main factor patients presented clusters of prolonged spreading depo- associated with the degree of injury and long-term outcome is ultimately larisations with persistent depressions. These clusters of the level of consciousness. Patients with small haemorrhages at the time of aneurysm rupture usually do not develop transient cerebral ischaemia spreading depolarisations were closely associated with and do not lose consciousness; however, they are still at risk of DCI [164]. structural brain damage as observed by neuroimaging. On the other hand, patients who transiently lose consciousness have Similarly, Bosche et al. [72] have reported low cerebral probably had a transient global ischaemic event and are at a higher risk of DCI [67]. measurements of tissue partial pressure of oxygen occur- D. Cerebral infarction caused by DCI is defined as “the presence of cerebral ring during clusters of spreading depolarisations. infarction on computed tomography or magnetic resonance scan of the Microthrombosis is common after SAH [74]. Subarach- brain within 6 weeks after SAH, or on the latest scan made before death within 6 weeks, or proven at autopsy, not present on the computed noid blood and blood products activate inflammatory tomography or magnetic resonance scans between 24 and 48 hours pathways, along with tissue factor in the microcirculation after early aneurysm occlusion, and not attributable to other causes of cerebral vessel wall, leading to endothelial cell activation such as surgical clipping or endovascular treatment. Hypodensities on computed tomography imaging resulting from ventricular catheter and damage, which in turn cause mural thrombus forma- or intraparenchymal haematoma should not be regarded as cerebral in- tion and release of microemboli [75]. Markers of increased farctions from DCI” [7]. activity of the coagulation cascade have been associated CT computed tomography, MRI magnetic resonance imaging with DCI, cerebral infarction, and poor outcome [76]. For example, in a group of 90 patients with SAH, early (within the time of SAH (and therefore have at least a short epi- 3 days of SAH onset) elevated concentrations of von Will- sode of transient global cerebral ischaemia) have increased ebrand factor were associated with poor outcome (crude risk of DCI [67, 68]. odds ratio (OR) = 4.6, 95 % confidence interval (CI) 2.0– Cortical spreading ischaemia (CSI) is a wave of depolar- 10.9; adjusted OR = 3.3, 95 % CI 1.1–9.8), ischaemic events isation in the grey matter that propagates across the brain (crude hazard ratio (HR) = 2.3, 95 % CI 1.1–4.9; adjusted at 2–5 mm/minute [69, 70], leading to depression in HR = 1.8, 95 % CI 0.8–3.9), and occurrence of spontaneous evoked potentials and spontaneous electroencephalogram DCI (crude HR = 3.5, 95 % CI 0.9–13.1; adjusted HR = 2.2, activity. The use of invasive subdural electrocorticographic 95 % CI 0.5–9.8). The hypothesis is that this early elevation monitoring combined with regional CBF measurements in von Willebrand factor levels probably reflects the forma- has shown that CSI can occur isolated or in clusters, and tion of microthrombi in the cerebral circulation [77, 78]. the depolarisation waves are associated with profound Autopsy studies have shown that patients who developed de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 6 of 19 Fig. 2 Pathophysiological processes in delayed cortical ischaemia. Key processes include angiographic vasospasm, microcirculatory constriction and formation of microthrombi, and waves of cortical spreading ischaemia, all of which can contribute to cerebral infarction. Delayed effects of the early brain injury such as neuronal and endothelial cell apoptosis, and systemic complications, can also occur. CPP cerebral perfusion pressure, ICP intracranial pressure, NO nitric oxide, SAH subarachnoid haemorrhage, TRP transient receptor potential. First published in Nature Reviews Neurology [98] DCI-related cerebral infarction had significantly more the liver [80]. It is an acute-phase protein that increases microthrombi compared with SAH patients who died be- in plasma during major stress situations, such as sepsis, cause of re-bleeding or acute hydrocephalus [75, 79]. burns, and major trauma. Some recent studies have sug- Haptoglobin is a complex tetramer glycoprotein, con- gested that the haptoglobin α1-α1 isoform could be pro- sisting of two α and two β chains, synthesised mainly by tective after SAH [81–83]. Haptoglobin binds free extracellular haemoglobin, which reduces free haemo- globin ability to generate oxygen-free radicals and there- Table 2 Facts that challenged the concept of angiographic fore interferes in one of the possible pathophysiological vasospasm as the main factor leading to delayed cerebral ischaemia pathways of angiographic vasospasm (i.e., haemoglobin- mediated oxidative stress) [82]. A. Approximately 70 % of patients with subarachnoid haemorrhage (SAH) will develop some degree of angiographic vasospasm within 2 weeks of Kantor et al. [82] found, in a cohort of 193 patients haemorrhage [64, 165]; however, only 30 % will develop symptoms (i.e., with SAH, that the haptoglobin α2-α2 isoform was asso- delayed cerebral ischaemia, or DCI) [88]. ciated with worse functional outcome at 3 months when B. DCI-associated cerebral infarct is an independent factor for poor outcome after SAH [166]; however, cerebral infarction can happen compared with the α1-α1 genotype. The haptoglobin asymptomatically [88] or in vascular territories not affected by α2-α2 isoform has a lower affinity for binding haemoglo- vasospasm [167]. bin and possibly inhibits haptoglobin-haemoglobin clear- C. Large-vessel angiographic vasospasm detected by modalities such as transcranial Doppler has a poor temporal relationship with the ance because of its larger size [84]. The α2-α2 genotype development of DCI [167]. remained significantly associated with worse functional D. There is no evidence that nimodipine decreases the rate of angiographic outcome (OR 4.138; P = 0.0463) after adjustment for age, vasospasm or promotes cerebral vasodilation; however, it remains the sole pharmacological intervention proven to improve outcomes sex, Fisher grade, and Hunt and Hess grade. A previous from DCI [108, 111]. study had already shown that haptoglobin α2-α2 geno- E. There is an important dissociation between vasospasm-related type was associated with higher rates of angiographic morbidity and functional outcome after SAH [168, 169]. F. The prevention and treatment of angiographic vasospasm do not vasospasm by transcranial Doppler (TCD) and conven- necessarily translate into improved outcome [169]. tional angiography performed between days 3 and 14 de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 7 of 19 after SAH [81]. A recent study by Leclerc et al. [83] events, oedema, and excitotoxicity that can result in de- showed, in a cohort of 74 patients with SAH, that hapto- layed and often progressive secondary brain injury. Un- globin α2-α2 genotype was an independent risk factor like primary injury, this delayed damage is considered, at for the development of focal and global angiographic least partially, preventable or reversible if adequately vasospasm and also predictive of unfavourable functional treated. Its prevention, timely detection, and appropriate outcomes and mortality. management require an early, aggressive, and well- The hypothesis is that patients with haptoglobin α2-α2 structured approach to patient care. This is especially genotype do worse because of reduced CSF clearance of true in patients with poor-grade SAH, where limited haemoglobin, increased reactive oxygen species, and neurological examination and a higher incidence of sys- therefore development of more inflammation. This hy- temic complications make DCI identification a signifi- pothesis is corroborated by an experimental model of cant challenge. SAH, which showed that mice expressing human α2-α2 DCI is often a diagnosis of exclusion; confounding fac- haptogobin developed more severe angiographic vaso- tors such as hypoxia, electrolyte disturbances, infection, spasm and increased macrophage/neutrophil counts in fever, hydrocephalus, convulsive, and non-convulsive sei- the CSF after SAH, when compared with wild-type α1- zures can produce delayed neurological deterioration α1 haptogobin-expressing mice [85]. Although there is similar to that of DCI and should always be considered no clinical intervention directly designed to address this in the differential and treated accordingly. Moreover, in important recent finding on the pathophysiology of the poor-grade SAH population, new neurological defi- SAH, the genetic effect on outcome after SAH may in- cits are clinically difficult to detect because of decreased crease our knowledge of the disease. level of consciousness and the frequent need for sed- ation (usually required for ICP and mechanical ventila- Delayed cerebral ischaemia monitoring. Triggers for tion management), making the detection of acute detection and confirmation of delayed cerebral ischaemia neurological deterioration even more challenging. Pa- in sedated or poor-grade patients tients who require sedation but who are clinically stable Figure 3 summarises a possible approach for the man- (i.e., absence of ICP crisis, cardiopulmonary instability, agement of SAH patients in poor neurological condition. or status epilepticus) should undergo interruption of The key management of patients with acute brain injury, sedation and analgesia (i.e., neurological wake-up tests) including the SAH population, is the minimisation of a that could detect focal neurological deficits. Wake-up complex cascade of ischaemic and apoptotic cellular tests seem to be safe since they are not associated with Fig. 3 Summary of a possible approach for the management of subarachnoid haemorrhage patients in poor neurological condition. ARDS acute respiratory distress syndrome, BP blood pressure, CPP cerebral perfusion pressure, CSF cerebrospinal fluid, CTA/CTP computed tomography angiography/computed tomography perfusion, DCI delayed cerebral ischaemia, DSA doxyl stearic acid, ECG electrocardiogram, GCS Glasgow Coma Scale, Hgb haemoglobin, HOB head of bed, ICH intracerebral haemorrhage, ICP intracranial pressure, IPC intermittent pneumatic compression, iv intravenously, IVH intraventricular haemorrhage, MAP mean arterial pressure, MRI/MRA magnetic resonance imaging/magnetic resonance angiography, NeuroICU neurointensive care unit, NIHSS National Institutes of Health Stroke Scale/Score, PaCO arterial partial pressure of carbon dioxide, SaO arterial 2 2 oxygen saturation, SBP systolic blood pressure, SIADH syndrome of inappropriate secretion of antidiuretic hormone, SPECT single-photon emission computed tomography, T temperature, VTE venous thromboembolism, WFNS World Federation of Neurosurgical Societies de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 8 of 19 changes in cerebral metabolism or oxygenation as mea- use of TCD and multimodal CT [94, 95] for monitoring sured by microdialysis and direct brain tissue oxygen- patients with SAH in accordance with the VASOGRADE ation measurement, respectively [86]. However, the [6]. It is important to mention that, in the poor-grade sensitivity of neurological examination to detect signs of population, if screening CTA or digital subtraction angiog- DCI in the setting of poor-grade SAH is low [87]; ap- raphy has already recognised the presence of severe angio- proximately 20 % of patients who develop DCI, as iden- graphic vasospasm in a setting of acute neurological tified by new infarctions on CT or magnetic resonance, deterioration, it is reasonable to start empiric DCI therapy do not have any evidence of clinical neurological deteri- without additional neurological investigation. Additionally, oration [88, 89]. Interestingly, these patients who devel- when screening CTP demonstrates perfusion deficits oped “asymptomatic” cerebral infarctions were less likely (CBF of less than 25 ml/100 g/minute or MTT of more to receive vasopressor agents and had higher frequency than 6.5 seconds or both) [91], it is reasonable to initiate of death or moderate-to-severe disability than those with therapy for DCI. “symptomatic” DCI [88]. ICP and cerebral perfusion pressure (CPP) monitoring Because neurological examination is less useful in this have been the cornerstone parameters in the manage- setting, a suspicion of DCI will frequently be based on ment of comatose patients with acute brain injury. Crit- changes detected by screening tools. According to the ical levels of CPP (of less than 70 mm Hg) have been Neurocritical Care Guidelines on the management of SAH, significantly associated with cerebral infarction [96] after “in sedated or poor-grade SAH patients, clinical deterior- SAH. Also, CPP of less than 60 mm Hg has been associ- ation may be difficult to assess, and transcranial Doppler ated with higher ICP levels and abnormal levels of P O ti 2 (TCD), continuous electroencephalography (cEEG), brain and LPR [97]. However, recent clinical data suggest that tissue oxygen pressure (P O2) monitoring, and/or cerebral cerebral hypoxia (P O of less than 20 mm Hg) and ti ti 2 microdialysis (CMD) are options for monitoring for vaso- cerebral energy dysfunction (LPR of more than 40) may spasm and DCI”. Changes commonly used to trigger inter- occur despite normal levels of ICP and CPP in the poor- vention include the following [8, 90]: grade SAH population [97]. Chen et al. [97], in a cohort of 19 patients with poor- 1. An increase in either (a) TCD mean flow velocity in grade SAH, demonstrated that ICP and CPP monitoring the middle cerebral artery (FVMCA) of more than may not be sufficient to detect episodes of cerebral com- 50 cm/second over 24 hours or (b) mean FVMCA promise, such as severe brain hypoxia detected by P O ti 2 of at least 200 cm/second or middle cerebral artery/ catheter (P O of not more than 10 mm Hg) or brain ti 2 internal carotid artery ratio of more than 6 or both [8]. energy dysfunction detected by CMD (LPR of at least 2. 2. CT perfusion parameters: CBF of less than 25 ml/ 40). The sensitivities of abnormal ICP or CPP levels for 100 g/minute or mean transit times (MTTs) of more elevated LPR and reduced P O were 21.2 %, and critical ti 2 than 6.5 seconds or both [91]. levels of LPR or P O were found on many occasions ti 2 3. Severe angiographic vasospasm (defined as a when ICP or CPP was normal. Additionally, early brain narrowing of at least 70 % from baseline) [92] tissue hypoxia (i.e., within 24 hours of haemorrhage) is detected by digital subtraction angiography (i.e., gold very prevalent in the poor-grade SAH population [98]. standard) or CT angiography (which is also highly Therefore, the use of multimodal neuromonitoring may specific for angiographic vasospasm). be a good complement to ICP/CPP monitoring, which 4. Electroencephalography (EEG) reduced alpha could detect cerebral oxygen or energy compromise in variability [93]. an early reversible state [93] (Fig. 4). 5. Abnormal levels of brain tissue oxygen (P O of less ti 2 than 20 mm Hg; Fig. 4) or CMD (i.e., lactate/pyruvate Continuous electroencephalography monitoring in patients ratio (LPR) of more than 40 and glucose of less than with poor-grade subarachnoid haemorrhage 0.5 mM and in second line for glutamate of more Continuous EEG (cEEG) has been described as a useful than 40 mM) or both [93]. monitoring tool for the prediction and diagnosis of angiographic vasospasm and DCI. Also, cEEG findings Multimodal neuromonitoring may be a prognostic marker in patients with poor- Modalities capable of monitoring CBF (e.g., CT perfu- grade SAH [99, 100]. Several studies have investigated sion or CTP), cerebral oxygenation (e.g., brain tissue and demonstrated a positive correlation between cEEG oxygen catheter), and cerebral metabolism (e.g., microdi- findings and angiographic vasospasm, DCI, and functional alysis) are theoretically superior to modalities monitor- outcome [99–102], supporting the critical care use of ing exclusively vessel diameter (e.g., TCD, conventional this modality in poor-grade or sedated SAH patients. angiography, and CT angiography, or CTA). We have Commonly described quantitative cEEG findings that previously published a possible approach combining the predict angiographic vasospasm or DCI are (a) decreased de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 9 of 19 Fig. 4 (See legend on next page.) de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 10 of 19 (See figure on previous page.) Fig. 4 Approach to low brain tissue oxygen. Consider the combined used of P O and microdialysis catheter to detect non-hypoxic patterns of ti 2 cellular dysfunction [97]. According to the manufacturer, an equilibrium time as long as 2 hours may be necessary before P O readings are ti 2 stable, because of the presence of the tip surrounding microhaemorrhages. Sensor damage may also occur during insertion. Increase inspired fraction of oxygen (FiO ) to 100 %. If P O increases, it confirms good catheter function. Oxygen challenge to assess tissue oxygen reactivity. FiO 2 ti 2 2 is increased from baseline to 100 % for 5 minutes to evaluate the function and responsiveness of the brain tissue oxygen probe. A positive response happens when P O levels increase in response to higher FiO . A negative response (lack of P O response to higher FiO ) suggests ti 2 2 ti 2 2 probe or system malfunction. Another possibility if there is a negative response is that the probe placement is in a contused or infarcted area. Follow-up computed tomography might be necessary in this situation to ensure appropriate probe position. Mean arterial pressure (MAP) challenge to assess cerebral autoregulation. MAP is increased by 10 mm Hg. Patients with impaired autoregulation demonstrated an elevation in ICP with increased MAP. When the autoregulation is intact, no change or a drop in ICP levels follows the elevation in blood pressure. Another way to assess cerebral autoregulation is the evaluation of the index of P O pressure reactivity. When autoregulation is intact, P O is relatively ti 2 ti 2 unaffected by changes in CPP, so the index of P O pressure reactivity is near zero [170]. The threshold haemoglobin (Hgb) of 9 mg/dl to indicate ti 2 blood transfusion was based on a previously published P O study [171]. CPP cerebral perfusion pressure, CSF cerebrospinal fluid, CT computed ti 2 tomography, ICP intracranial pressure, PaCO arterial partial pressure of carbon dioxide, PaO partial pressure of oxygen in arterial blood, P O brain 2 2 ti 2 tissue oxygen pressure, RASS Richmond Agitation-Sedation Scale, SAH subarachnoid haemorrhage, SBP systolic blood pressure relative alpha variability [101] and (b) decreased alpha/ CMD measures the interstitial levels of several sub- delta ratio [100, 102]. Other cEEG findings such as peri- stances, such as glucose, lactate, pyruvate, glutamate, odic epileptiform discharges, electrographic status epilep- glycerol, and several inflammatory biomarkers. An in- ticus, and the absence of sleep architecture have been creased LPR is the most common and better-studied described as independent prognostic factors in the poor- marker of anaerobic cerebral metabolism and therefore grade SAH population after adjustment for known prog- is an indicator of cerebral ischaemia [93]. Metabolic nostic factors such as age, clinical grade (i.e., Hunt and changes detected by CMD, such as elevated LPR, have Hess grade), and the presence of intraventricular haemor- been shown to predict delayed neurological deterioration rhage [99]. Claassen et al. [99] described, in a cohort of and “symptomatic vasospasm” [105, 106]. Also, extreme 116 patients with SAH, that the absence of sleep architec- microdialysate values of lactate, glutamate, LPR, and gly- ture (80 % versus 47 %; OR 4.3, 95 % CI 1.1–17.2) and the cerol have been associated with cerebral infarction and presence of periodic lateralised epileptiform discharges permanent neurological deficits [107]. (PLEDs) (91 versus 66 %; OR 18.8, 95 % CI 1.6–214.6) were associated with 3-month poor outcome by modified Pharmacological prophylaxis Rankin scale. Additionally, all patients with absent EEG Table 3 summarises drugs investigated and under investi- reactivity, generalised periodic epileptiform discharges, gation for prevention of DCI. According to the American and bilateral independent PLEDs and 92 % of patients (11 Heart Association, the Neurocritical Care Society, and the out of 12) with non-convulsive status epilepticus pro- European guidelines [8–10], nimodipine, an L-type dihy- gressed to have a poor functional outcome at 3 months. dropyridine calcium channel antagonist, is the only medi- cation proven to improve outcomes after SAH [108]. The Monitoring brain tissue partial pressure of oxygen concept that nimodipine decreases the rate of angio- The invasive monitoring of brain tissue oxygenation al- graphic vasospasm has been challenged, and the mecha- lows regional and continuous monitoring of P O , nisms by which it improves patient outcome in a setting ti 2 which may detect early changes in cerebral tissue oxy- of SAH are not completely established. genation that precede ischaemic damage. P O levels of Nimodipine probably has a neuroprotective action by ti 2 below 20 mm Hg require attention and might be a decreasing the influx of calcium after cerebral ischae- warning sign of ischaemia not detected clinically. P O mia due to DCI. Additionally, nimodipine might de- ti 2 levels of below 15 mm Hg require immediate interven- crease the incidence of microthrombi by increasing the tion to optimise cerebral tissue oxygenation (Fig. 4). endogenous fibrinolysis [109] and may antagonise cor- P O levels have been directly correlated with the de- tical spreading ischaemia [110]. Nimodipine seems to ti 2 velopment of ischaemic events [96], angiographic vaso- improve long-term outcome in the poor-grade popula- spasm [103], and outcome [104]. In addition to P O tion as well [111]. A multicentre, randomised placebo- ti 2 monitoring, the use of CMD may be a possible alterna- controlled double-blind trial studied the effect of nimo- tive for monitoring sedated or poor-grade patients at risk dipine in 188 patients with poor-grade SAH (Hunt and of DCI. The combined use of P O and CMD catheter Hess grade 3–5) [111]. The treatment was associated ti 2 can help discriminate two patterns of cellular dysfunction with an improvement in functional outcome at 3 months (i.e., hypoxic and non-hypoxic cellular dysfunction) [97]. (29.2 % in the nimodipine group versus 9.8 % in the de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 11 of 19 Table 3 Evidence review of drugs used in aneurysmal subarachnoid haemorrhage Drug Direct drug action Possible mechanisms of action Status Guidelines [8–10] Nimodipine [82] L-type calcium � Reduction of angiographic Meta-analysis of clinical trials Class I, level A channel antagonist vasospasm found that oral nimodipine Nimodipine should be � Increase in fibrinolytic reduced the risk of DCI and administered enterally activity poor outcome. (60 mg every 4 hours) to � Neuroprotection prevent DCI. � Inhibition of cortical The only drug approved spreading ischaemia for SAH in the USA and Europe. Clazosentan [168] Endothelin A Reduction of angiographic � Four randomised clinical trials Not addressed receptor vasospasm and a meta-analysis However, after the antagonist � Clazosentan reduced angio publication of the graphic vasospasm without a CONSCIOUS trials and significant effect on outcome. following meta-analysis, � Hypotension and pulmonary clazosentan infusion will complications associated with not be recommended the drug use could have for patients with SAH, as a counteracted the beneficial Class I, level A. effects of the drug. Fasudil [172] Rho-kinase Reduces smooth muscle � Eight randomised clinical trials Not addressed inhibitor contraction and inhibits TNF- � Treatment significantly The drug is approved for induced IL-6 release from reduced the incidence of use in patients in Japan C6 glioma cells angiographic vasospasm and and China but not in cerebral infarction and Europe or USA. improved the odds ratio for good recovery compared with placebo or nimodipine and other drugs. Statins [92–94] Inhibit HMG-CoA � Preserve endothelial function � Seven randomised clinical Guidelines published before reductase � Anti-inflammatory effects trials of statins in patients with the STASH trial [92]. � Antioxidant SAH. The recommendations will � Antithrombotic actions � An additional study showing probably remain the same � Vascular protection no benefit of higher dose of to administer statins only if � Neuroprotective and simvastatin (80 mg versus the patient was already neurorestorative action 40 mg) receiving them at time of � One systematic review not SAH, as a Class I, level A. including the STASH trial found no effect of statin treatment on poor outcome. Magnesium [90] Antagonism of � Vasodilation� Increased � Seven randomised clinical Class I, level A calcium channels endothelial cell prostacyclin trials Magnesium is not on vascular � Endothelial protection � Meta-analysis reported no recommended for smooth muscle � Protect the blood–brain barrier effect of magnesium on poor prevention of DCI. � Reduce cerebral oedema outcome � Anticonvulsant (N-methyl-D- aspartate receptor antagonism) Dantrolene [173] Inhibits ryanodine Reduces intracellular calcium � One small dose-escalation Not addressed receptors release in smooth muscle and study Remains experimental may be neuroprotective � Dantrolene in a dose of 2.5 mg/kg, administered over the course of 60 minutes, was associated with reduced cerebral blood-flow velocities measured by transcranial Doppler. Intrathecal thrombolytics Fibrinolytic agents The rapid clearance of � Five RCTs and a meta-analysis Not addressed (i.e., urokinase and subarachnoid clot could reduce � Thrombolysis was associated Further trials are needed. recombinant tissue angiographic vasospasm and with significant reductions in Standardisation plasminogen activator) [174] complications, such as cortical angiographic vasospasm, of techniques and spreading ischaemia and delayed neurological deficits, evaluation in a larger microthrombosis. hydrocephalus, and poor study are required. outcome. Antiplatelet drugs [175] Inhibition of Inhibition of platelet � Seven randomised clinical trials Not addressed � Acetylsalicylic acid platelet aggregation aggregation and a meta-analysis found trends Further trials are needed. � OKY-046 (Cataclot) - toward reduction in poor outcome According to the meta- de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 12 of 19 Table 3 Evidence review of drugs used in aneurysmal subarachnoid haemorrhage (Continued) selective thromboxane but also toward increased analysis results, treatment synthetase inhibitor intracranial haemorrhage. with antiplatelet agents to � Dipyridamole � Only ticlopidine was associated prevent DCI or poor � Ticlopidine with statistically significant fewer outcome cannot be occurrences of a poor outcome recommended. (only one small RCT) Albumin [176] Multiple Neuroprotective � One open-label dose-escalation Not addressed trial Remains experimental � Trend toward improved outcome with 1.25 g/kg per day Erythropoietin [177, 178] Multiple � Prevent loss of autoregulation � Two RCTs Not addressed � Reduce angiographic vasospasm � One negative study Remains experimental � Inhibits apoptosis and stimulates and one showing that patients neurogenesis and angiogenesis who received erythropoietin had fewer cerebral infarcts, shorter duration of autoregulatory dysfunction, and better clinical outcome. Cilostazol [179] Inhibits � Antithrombotic � One small (109 patients) Not addressed phosphodiesterase � Vasodilatory randomised, single-blind study Remains experimental 3 � Anti-smooth muscle proliferation � Cilostazol significantly reduced � Inotropic and chronotropic effects angiographic vasospasm, DCI, and cerebral infarction but had no effect on outcome. CONSCIOUS Clazosentan to Overcome Neurological Ischaemia and Infarction Occurring After Subarachnoid Haemorrhage, DCI delayed cerebral ischaemia, IL-6 interleukin-6, RCT randomised controlled trial, SAH subarachnoid haemorrhage, STASH simvastatin in aneurysmal subarachnoid haemorrhage, TNF tumour necrosis factor placebo), despite similar rates of moderate and severe Statins angiographic vasospasm found in the follow-up angiog- There is great interest in the impact of statins in the raphy (64.3 % in the nimodipine group versus 66.2 % in prevention of DCI. Statins preserve endothelial func- the placebo group). However, in the sub-group of grade 5 tion by increasing nitric oxide synthesis while decreas- patients, no difference in functional outcome between ing the synthesis of endothelin-1. Also, there are other nimodipine and placebo groups was found [111]. statin effects that may be interesting in the SAH set- Interestingly, in the poor-grade population, the admin- ting, such as anti-inflammatory, antioxidant, and anti- istration of nimodipine is associated with an acute drop thrombotic effects. Additionally, statins have described in the mean arterial pressure and CPP, which is trans- neuroprotective and neurorestorative action. So far, six lated into a decrease in CBF and brain tissue oxygen- randomised clinical trials [118] of statins in patients ation [112, 113]. However, there is no prospective study with SAH have been published; however, a systematic that evaluates the long-term consequences of these review of these studies found no effect of statin treat- physiological changes on functional outcome. ment on poor outcome; mortality was 10 % in the statin group versus 21 % in controls (relative risk 0.62, 95 % CI 0.36–1.06); DCI was significantly reduced in the sta- tin group. The overall quality of these studies was Magnesium judged to be low to moderate. Recently, two multicen- Magnesium is a calcium channel antagonist with potent tre randomised clinical trials were published. One com- vasodilator and neuroprotective properties. Animal pared two different regimens of simvastatin (80 versus models of SAH have shown reversal of cerebral arterial 40 mg), which showed no effect of higher dose on DCI, vasoconstriction, leading to reduction of the size of is- modified Rankin disability score at 3 months, and an chaemic lesions [114]. Additionally, magnesium may de- analysis of cost-effectiveness [119]. The second study crease the rate and frequency of cortical spreading had previously shown no benefit in the use of 40 mg ischaemia [115]. Unfortunately, a large clinical trial com- simvastatin compared with placebo for long-term out- bined with a meta-analysis [116] showed no clinical come, as measured by modified Rankin score at benefit with the use of magnesium infusion, measured as 6 months [120]. Mortality and favourable outcome were favourable outcome at 6 months, incidence of DCI, or similar in both simvastatin and placebo groups (10 % cerebral infarction. A possible explanation is that high versus 9 % and 58 % versus 62 %, respectively). Serious levels of plasma magnesium are associated with worse adverse events were also similar in both groups (18 %) clinical outcomes [117]. [120]. Therefore, the guidelines will probably keep their de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 13 of 19 recommendation to administer statins only if the pa- Cardiac complications following SAH can range from tient was already receiving them at the time of SAH benign electrocardiogram changes to overt cardiogenic [118]. shock requiring intra-aortic balloon pump [130, 131]. Positive troponin is a good marker of left ventricular dysfunction after SAH [132], which increases the risk of Haemodynamic prophylaxis hypotension, pulmonary oedema, and cerebral infarc- The use of prophylactic hypervolemia, a component of tion [133]. The treatment is mainly supportive, and so-called triple-H therapy (hypervolemia, hypertension, most of the cases will recover spontaneously within and haemodilution), is not recommended [8–10], based 2 weeks [134]. However, aggressive ICU management on lack of evidence that it positively affects functional may be required in the setting of severely impaired left outcome. It also increases the costs and risk of systemic ventricular function and DCI. Thus, the use of ino- complications, such as cardiac dysfunction, pulmonary tropic agents such as dobutamine [135], levosimendan oedema, and infection [121, 122]. [136], milrinone [137], and even intra-aortic balloon pump counterpulsation [138] has been described and Delayed cerebral ischaemia treatment can be considered to optimise the cardiac function in Haemodynamic manipulation, what is known as the order to improve CBF. triple-H therapy, has for decades been the cornerstone Patients with poor-grade SAH are at higher risk of car- of DCI management [94, 95]. However, the literature diac and pulmonary complications [139]. Additionally, supporting its safety and efficacy is scarce [123]. Angio- hypovolemia and pulmonary oedema are common phe- graphic vasospasm, in the absence of DCI, should not nomena in this population, increasing the risk for de- be treated [90, 124]. The development of a new focal layed cerebral ischaemia [140, 141]. Therefore, the poor- deficit or a decrease in level of consciousness, not ex- grade SAH population may benefit from advanced plained by other causes (e.g., hydrocephalus or re- haemodynamic monitoring. Yoneda et al. [139], in a bleeding), should prompt aggressive treatment [90, multicentre prospective cohort study of haemodynamic 124]. A fluid bolus with normal saline might be the first monitoring using a transpulmonary thermodilution sys- step because it increases CBF in areas of cerebral is- tem (PiCCO Plus), which included a group of 138 pa- chaemia [125]. The main goal is to maintain euvolemia tients with poor-grade SAH, showed that extravascular and normal circulating blood volume. Hypervolemia lung water index (P = 0.049), pulmonary vascular perme- and haemodilution do not improve cerebral oxygen de- ability index (P = 0.039), and systemic vascular resistance livery and may be associated with adverse events [121, index (P = 0.038) were significantly higher in the poor- 122]. Patients who fail to completely reverse the new grade group when compared with the good-grade popu- deficit after a fluid challenge may undergo a trial of lation. Additionally, poor-grade patients displayed sig- hypertension unless the blood pressure is elevated at nificantly lower cardiac index on days 1 and 2 (P = 0.027 baseline or in the presence of heart failure [9]. Blood and P = 0.011, respectively) and developed heart failure- pressure is augmented in a step-wise fashion by the use like afterload mismatch at an early stage, and those who of a vasopressor, typically noradrenaline [8, 126]. The developed DCI had haemodynamic measures of hypovol- neurologic examination is repeated frequently in each emia, as shown by a decreased global end-diastolic volume blood pressure step (180 mm Hg/190 mm Hg/200 mm index [139]. The same group described the mean global Hg), and the target should be based on clinical im- end-diastolic volume index (normal range, 680–800 ml/ provement. If the neurological deficit persists after the 2 m ) as an independent factor for the development of DCI induction of hypertension (typically up to a systolic (HR 0.74, 95 % CI 0.60–0.93; P = 0.008). Patients who de- blood pressure of 200 to 220 mm Hg), a rescue therapy veloped DCI had significantly lower global end-diastolic with cerebral angioplasty or intra-arterial infusion of a volume index compared with patients who did not (783 ± vasodilator might be of benefit [127]. The prophylactic 2 2 25 ml/m versus 870 ± 14 ml/m ; P = 0.007). A threshold use of angioplasty is not associated with improved out- 2 of less than 822 ml/m was correlated with DCI develop- come and might be associated with increased risk of arter- ment, whereas a global end-diastolic volume index above ial rupture and is not recommended [128]. 2 921 ml/m was associated with the development of severe pulmonary oedema. These finding suggest that maintain- Medical complications ing global end-diastolic volume index slightly above the It is well described that medical complications after normal range may be effective to prevent hypovolemia SAH have a negative impact on survival and functional and severe pulmonary oedema, which may decrease the outcome. Up to 80 % of patients will develop a serious risk of DCI. medical complication during phase 2, increasing the risk Pulmonary complication, such as hospital-acquired pneu- for secondary brain injury [129]. monia, cardiogenic or neurogenic pulmonary oedema, de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 14 of 19 aspiration pneumonitis, and pulmonary embolism, occur in Anaemia can be easily corrected, but blood transfusion approximately 30 % of patients after SAH [142]. Acute re- has been implicated with worse outcome after SAH [156, spiratory distress syndrome can affect 27 % of cases and is 157], including higher mortality, after adjustment for the independently associated with worse outcomes [143]. In most common clinical indications of transfusion [158]. this clinical scenario, extra caution should be taken to avoid Although there is no clear threshold for transfusion in fluid overload; however, diuretics might be dangerous be- patients with SAH, general ICU thresholds are not applic- cause of the risk of hypovolemia-induced cerebral able for this population [7, 101, 159]. Dhar et al. [160], in ischaemia. an elegant study using positron emission tomography Hyponatremia (serum sodium of less than 135 mEq/ scan, demonstrated that transfusion in patients with dl) is the most common electrolyte derangement after haemoglobin levels of less than 9 g/dl was the only inter- SAH, occurring in up to 50 % of patients. There are two vention capable of increasing global CBF and oxygen de- possible mechanisms responsible for the development of livery, when compared with crystalloid bolus and induced hyponatremia after SAH: (1) cerebral salt wasting (CSW) hypertension. The clinical applicability of these findings and (2) the syndrome of inappropriate secretion of anti- needs to be addressed in a large trial because the study en- diuretic hormone (SIADH) [144]. These entities are fun- rolled a small number of patients (38 in total) and had damentally different in their pathogenesis; however, they only physiological endpoints. are difficult to distinguish in clinical practice and may Patients with poor-grade SAH are at high risk of ven- concur in the same patient [145]. Importantly, CSW ous thromboembolism [161]. Guidelines on manage- courses with intravascular volume contraction, which in- ment of SAH suggest starting mechanical prophylaxis creases the risk of DCI and poor outcome [145]. Like- with intermittent compression devices before aneurysm wise, the treatment of SIADH on the basis of fluid treatment [8–10]. Pharmacologic thromboprophylaxis restriction is not indicated, because of increased risk of seems to be safe if started within 12 to 24 hours after hypovolemia-associated cerebral infarction [146, 147]. aneurysm treatment [162]. Therefore, in clinical practice, the management of hypo- natremia in the setting of SAH is based on the avoidance Conclusions of hypovolemia and the judicious repletion of volume Aneurysmal SAH is a complex neurovascular disease as- and sodium losses [144]. sociated with multiple neurological and systemic compli- In a retrospective study in a single academic centre, cations and requires multidisciplinary specialised care, Wartenberg et al. found that a single occurrence of best provided in high-volume centres. Patients who sur- hyperglycaemia, fever, or anaemia after aneurismal SAH vive the initial bleed can deteriorate within 2 weeks, espe- was independently predictive of poor outcome, even cially because of DCI. DCI is a syndrome with a complex after adjustment for traditional prognostic variables, multifactorial pathophysiology that extends beyond the such as age, clinical grade, aneurysm size, re-bleeding, historic explanation of angiographic vasospasm. and cerebral infarction [129]. Although the risk of death and moderate and severe dis- Fever is the most common medical complication after ability has decreased significantly over the last three de- SAH and is associated with longer ICU and hospital cades, the extent to which the prevalence of cognitive length of stays, worse functional outcomes, and higher deficits, poor quality of life, and daytoday functioning have mortality [148, 149]. Although non-infectious fever is changed over the same period is completely undetermined. common, especially in the presence of intraventricular Further studies should simultaneously tackle multiple haemorrhage and poor-grade patients [150], it is strongly pathophysiological pathways, and long-term functional recommended that frequent temperature checks and outcomes shall be assessed by means of outcome measures careful assessment for possible infectious cause are able to recognise subtle cognitive changes. made. During the time window of vasospasm, it is desir- able to maintain normothermia with antipyretic drugs, Abbreviations followed by advanced fever control with surface cooling CBF: Cerebral blood flow; cEEG: Continuous electroencephalography; CI: Confidence interval; CMD: Cerebral microdialysis; CPP: Cerebral perfusion or intravascular devices [151, 152]. In this situation, espe- pressure; CSF: Cerebrospinal fluid; CSI: Cortical spreading ischaemia; cial attention should be paid to detect and treat shivering. CSW: Cerebral salt wasting; CT: Computed tomography; CTA: Computed The protocol for diagnosis and treatment of shivering has tomography angiography; CTP: Computed tomography perfusion; DCI: Delayed cerebral ischaemia; EBI: Early brain injury; been published elsewhere [153]. EEG: Electroencephalography; EVD: External ventricular drain; FVMCA: Flow Ideally, blood sugar should be kept less than 200 mg/ velocity in the middle cerebral artery; GCS: Glasgow Coma Scale; HR: Hazard dl and hypoglycaemia (less than 80 mg/dl) should be ratio; ICP: Intracranial pressure; ICU: Intensive care unit; LPR: Lactate/pyruvate ratio; MTT: Mean transit time; OR: Odds ratio; PaCO : Arterial partial pressure strictly avoided. Both have been shown in microdialysis of carbon dioxide; PLED: Periodic lateralised epileptiform discharge; studies to be associated with metabolic crisis and worse P O : Brain tissue oxygen pressure; SAH: Subarachnoid haemorrhage; ti 2 neurological outcome [154, 155]. SIADH: Syndrome of inappropriate secretion of antidiuretic hormone; de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 15 of 19 TBI: Traumatic brain injury; TCD: Transcranial Doppler; WFNS: World 9. Connolly Jr ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Federation of Neurosurgical Societies.. Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43: Competing interests 1711–37. RLM receives grant support from the Physicians Services Incorporated 10. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. 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Timing of operation for articles judged to be important for the topic addressed in this review poor-grade aneurysmal subarachnoid hemorrhage: study protocol for a article. All authors contributed to the drafting, revising, and approval of the randomized controlled trial. BMC Neurol. 2013;13:108. final manuscript. 18. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping Acknowledgements versus endovascular coiling in 2143 patients with ruptured intracranial This work was supported by a Personnel Award from the Heart and Stroke aneurysms: a randomised trial. Lancet. 2002;360:1267–74. Foundation of Canada and an Early Researcher Award from the Ontario Ministry 19. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. of Research and Innovation to TAS. The authors would like to thank the Bitove International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus Foundation for generously funding the research. endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, Author details subgroups, and aneurysm occlusion. Lancet. 2005;366:809–17. St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1 W8, Canada. 20. Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RS. The durability of Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 30 endovascular coiling versus neurosurgical clipping of ruptured cerebral Bond Street, Toronto, ON M5B 1 W8, Canada. Toronto Western Hospital aneurysms: 18 year follow-up of the UK cohort of the International MSNICU, 2nd Floor McLaughlin Room 411-H, 399 Bathurst Street, Toronto, Subarachnoid Aneurysm Trial (ISAT). Lancet. 2015;385:691–7. ON M5T 2S8, Canada. 21. 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The critical care management of poor-grade subarachnoid haemorrhage

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Abstract

Aneurysmal subarachnoid haemorrhage is a neurological syndrome with complex systemic complications. The rupture of an intracranial aneurysm leads to the acute extravasation of arterial blood under high pressure into the subarachnoid space and often into the brain parenchyma and ventricles. The haemorrhage triggers a cascade of complex events, which ultimately can result in early brain injury, delayed cerebral ischaemia, and systemic complications. Although patients with poor-grade subarachnoid haemorrhage (World Federation of Neurosurgical Societies 4 and 5) are at higher risk of early brain injury, delayed cerebral ischaemia, and systemic complications, the early and aggressive treatment of this patient population has decreased overall mortality from more than 50 % to 35 % in the last four decades. These management strategies include (1) transfer to a high-volume centre, (2) neurological and systemic support in a dedicated neurological intensive care unit, (3) early aneurysm repair, (4) use of multimodal neuromonitoring, (5) control of intracranial pressure and the optimisation of cerebral oxygen delivery, (6) prevention and treatment of medical complications, and (7) prevention, monitoring, and aggressive treatment of delayed cerebral ischaemia. The aim of this article is to provide a summary of critical care management strategies applied to the subarachnoid haemorrhage population, especially for patients in poor neurological condition, on the basis of the modern concepts of early brain injury and delayed cerebral ischaemia. Background level of consciousness have higher risk of death and dis- Aneurysmal subarachnoid haemorrhage (SAH) is a com- ability, although improved outcomes have also been plex neurovascular syndrome with profound systemic ef- shown in this group of patients in the last decades. For fects and is associated with high disability and mortality these reasons, patients presenting with a Glasgow Coma [1]. Despite a 17 % decrease in case fatality in the last Scale (GCS) score of less than 13 have traditionally been three decades associated with improved management defined as having poor-grade SAH (classified as grade 4 strategies, 30-day mortality and before-admission death and 5 according to the Hunt and Hess [4] or the World rate unfortunately are still high, around 35 % and 15 %, Federation of Neurosurgical Societies (WFNS) grading respectively [2]. scales [5] or more recently as VASOGRADE-Red [6]). Outcomes after SAH can vary significantly, from full Poor outcomes are usually secondary to early brain in- recovery to severe disability or death, depending on the jury (EBI) or to delayed cerebral ischaemia (DCI). EBI severity of the initial bleed and potential complications refers to the acute consequences of SAH-associated sud- typically happening in the first 2 weeks after the haem- den increase of intracranial pressure (ICP), which can orrhage [3]. The level of consciousness is considered the cause decreased cerebral perfusion and transient global most important early predictor of outcome [4–6]. Pa- cerebral ischaemia. The global cerebral ischaemia can re- tients with a normal level of consciousness have a low sult in transient loss of consciousness or progressive risk of mortality. Patients admitted with a depressed intracranial hypertension. Subarachnoid blood itself can also damage the brain. DCI is a multifactorial entity * Correspondence: airtonleo.manoel@gmail.com often responsible for poor outcome after SAH in pa- St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1 W8, Canada tients who survive the initial haemorrhage. Clinically, it Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 30 is characterised by a change in neurological function Bond Street, Toronto, ON M5B 1 W8, Canada Full list of author information is available at the end of the article © 2016 de Oliveira Manoel et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 2 of 19 that manifests most often between days 3 and 14 after 1. Initial management: medical stabilisation, haemorrhage. Recently, DCI was defined as a change in prevention of re-bleeding, and control of intracra- level of consciousness (decrease of 2 points in the GCS nial pressure or an increase in 2 points in the National Institute of During aneurysmal SAH, extravasation of high-pressure Health Stroke Scale) or development of new focal deficit arterial blood in the subarachnoid space (and often into lasting for at least 1 hour and not explained by other fac- the brain parenchyma and ventricles) is associated with tors (e.g., systemic complications and hydrocephalus) [7]. a sudden ICP increase that, if severe and sustained, may DCI is believed to be due to a combination of factors such compromise cerebral perfusion, causing global cerebral as angiographic vasospasm, cortical spreading ischaemia, ischaemia and EBI (Fig. 1). If the haemorrhage does not microthrombosis, and microcirculation vasoconstriction. stop, acute cardiopulmonary instability associated with In this review, we will discuss the management of patients intracranial hypertension or compromised cerebral with poor-grade SAH on the basis of the current concepts blood flow (CBF) leads to patient death before hospital of EBI and delayed cerebral ischaemia. admission. In patients who survive the initial haemor- rhage, re-bleeding is the most severe early complication; Search strategy the reported incidence is up to 15 % in the first 24 hours, A PubMed search for articles published until May 2015 and the fatality rate is approximately 70 % [11–13]. was performed by using the terms “Subarachnoid Patients with poor-grade SAH are at higher risk of re- Hemorrhage” [Mesh] AND (“poor-grade” [Title/Abstract] bleeding [14]. Initial management therefore should focus OR “high-grade” [Title/Abstract]), which returned 236 on strategies aimed to prevent re-bleeding and to con- articles. Additionally, the reference lists of the most trol ICP. recent guidelines on the management of SAH were Early aneurysm repair is generally considered the most searched [8–10]. Lastly, the authors’ personal databases important strategy to reduce the risk of aneurysm re- were used as an additional source for this review. rupture [15]. However, evidence for optimum timing of Fig. 1 Early pathophysiology of subarachnoid haemorrhage. Acute haemorrhage from an aneurysm can physically damage the brain and lead to acute transient global ischaemia. Transient global ischaemia secondary to increased intracranial pressure can also trigger sympathetic nervous system activation, leading to systemic complications. The contribution of each process to the pathophysiology is unknown, but transient global ischaemia and subarachnoid blood result in early brain injury, characterised by microcirculation constriction, microthrombosis, disruption of the blood–brain barrier, cytotoxic and vasogenic cerebral oedema, and neuronal and endothelial cell death. CBF cerebral blood flow, CPP cerebral perfusion pressure, ECG electrocardiographic, ET-1 endothelin-1, ICH intracranial haemorrhage, ICP intracranial pressure, MMP-9 matrix metalloproteinase-9, NO nitric oxide, TNF-R1 tumour necrosis factor receptor 1. First published in Nature Reviews Neurology [98] de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 3 of 19 treatment is limited, and it is unclear whether ultra-early 160 mm Hg (or both) in the presence of ruptured un- treatment (less than 24 hours) is superior to early secured aneurysm. The European guidelines are less ag- aneurysm repair (within 72 hours). A recently published gressive and suggest keeping the systolic blood pressure retrospective data analysis comparing ultra-early treatment below 180 mm Hg [10]. These parameters should not be with repair performed within 24–72 hours after haemor- used after aneurysm treatment, when spontaneously high rhage suggests that aneurysm occlusion can be performed blood pressure may be beneficial [25]. safely within 72 hours after aneurysm rupture [16]. The Intracranial hypertension (ICP of at least 20 mm Hg) is a American Heart Association/American Stroke Association relatively common complication of SAH, especially in pa- [9] recommend as a Class IB Recommendation that “surgi- tients presenting with poor neurological condition [26–28]. cal clipping or endovascular coiling of the ruptured Multiple factors such as cerebral oedema, intraparench- aneurysm should be performed as early as feasible in the ymal haematoma, acute communicating hydrocephalus, majority of patients to reduce the rate of re-bleeding after intraventricular haemorrhage, aneurysm re-rupture, SAH”. This recommendation for timing of aneurysm complications related to aneurysm treatment, EBI, and intervention is corroborated by the European Stroke DCI can contribute to the development of intracranial Organization Guidelines for the Management of Intracra- hypertension [29]. High ICP is associated with severe nial Aneurysms and Subarachnoid Haemorrhage [10], derangements of cerebral metabolism [30], increased which stated that “aneurysm should be treated as early as risk of neurological deterioration [25], and poor out- logistically and technically possible to reduce the risk of come, especially if refractory to medical treatment [29, re-bleeding; if possible it should be aimed to intervene at 31]. ICP of greater than 20 mm Hg is an independent least within 72 hours after onset of first symptoms”. predictor of severe disability and death in aneurysmal The results from an ongoing trial only enrolling patients SAH [30]. with poor-grade SAH may help answer the question of Principles of management of intracranial hypertension whether early treatment (within 3 days) is associated with after SAH have been traditionally adopted from trau- improved outcome compared with intermediate (days 4–7) matic brain injury (TBI) literature [32] and are not spe- or late (after day 7) treatment [17]. cifically designed for the SAH population. However, The choice of treatment modality between surgical these two entities are different from a pathophysiological clipping and endovascular coiling is a complex endeav- perspective, and the use of therapies tested in patients our, which requires the expertise of an interdisciplinary with TBI in the SAH population is controversial. Cur- team, including neurointensivists, interventional neuro- rently, the role of therapies such as hyperosmolar agents, radiologists and neurovascular surgeons. For aneurysms hypothermia, barbiturates, and decompressive craniect- considered to be equally treatable by both modalities, omy is not well established in SAH patients with intra- the endovascular approach is superior, being associated cranial hypertension refractory to first-line treatments. with better long-term outcomes [18–20]. Randomised The initial approach to raised ICP includes head of trials of clipping versus coiling included mostly good- bed elevation (between 30° and 45°) to optimise cerebral grade patients, leading to controversy as to whether their venous drainage, normoventilation (arterial partial pres- results apply also to poor-grade patients. Retrospective sure of carbon dioxide (PaCO ): 35–40 mm Hg) [33], data on clipping and coiling in poor-grade patients seem use of sedation and analgesia to achieve a calm and quiet to suggest that surgical clipping and endovascular are state (Richmond Agitation Sedation Scale score of −5or equally effective [21]. An early and short course of an Sedation-Agitation Scale score of 1), and surgical inter- anti-fibrinolytic drug such as tranexamic acid, initiated vention in the presence of mass-occupying lesions [34]. as soon as the radiological diagnosis of SAH is estab- The use of neuromuscular blocking agents is sometimes lished and stopped within 24–72 hours, has been associ- applied to prevent ICP surges during tracheal suctioning ated with decreased rate of ultra-early re-bleeding and a and physiotherapy; however, the role of these drugs for non-significant improvement in long-term functional ICP management is not well established, and some au- outcome [22]. This approach remains controversial [23], thors suggest that they may be more deleterious than and short-term administration of tranexamic acid to pre- beneficial [35]. If ICP remains elevated despite these inter- vent re-bleeding is being further studied in a multicentre ventions, a short course (less than 2 hours) of hyperventi- randomised trial (Dutch Trial Registry number NTR3272) lation (PaCO of 30–35 mm Hg) might be considered [24]. Another medical intervention applied to prevent while new brain imaging is obtained and other interven- aneurysm re-rupture is the avoidance of extremes of blood tions are planned and initiated [36–38]. pressure. The American Heart Association/American Cerebrospinal fluid (CSF) drainage is a mainstay in Stroke Association [9] and the Neurocritical Care [8] ICP management of patients with SAH, especially when guidelines suggest keeping the mean arterial blood pres- hydrocephalus is present [39]. Acute hydrocephalus is sure below 110 mm Hg or systolic blood pressure below common in SAH, and approximately 50 % of patients de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 4 of 19 are affected on admission [40]. When hydrocephalus is achieved with decompressive craniectomy, this may be best associated with a decreased level of consciousness, an obtained when the procedure is performed early (within external ventricular drain (EVD) should be inserted to 48 hours from the bleeding) [52] and in the absence of allow CSF drainage and ICP monitoring. EVD insertion radiological signs of cerebral infarction [51]. Finally, in before aneurysm treatment has been shown to be safe poor-grade patients with large intraparenchymal or Sylvian and not associated with increased risk of aneurysm re- fissure haematomas usually from middle cerebral artery an- rupture [40, 41], if accompanied by early aneurysm eurysms, prophylactic decompressive craniectomy should repair. Additionally, when EVD insertion is performed be considered [34]. before aneurysm repair, CSF drainage should be prac- It is important to mention that long-term outcome ticed with caution because rapid and aggressive CFS after acute brain injury is markedly improved when pa- drainage can increase transmural pressure, increasing tients are managed in a dedicated neurologic/neurosur- the risk of aneurysm re-rupture [41, 42]. Interestingly, gical intensive care unit (ICU) [57, 58]. Especially after approximately 30 % of patients with poor-grade SAH SAH, outcome is affected by hospital caseload, and bet- improve neurologically after EVD insertion and CSF ter outcomes happen in high-volume centres (centres drainage. These responders have a functional outcome treating more than 60 patients per year) [59]. Six-month similar to that of good-grade (WFNS I–III) patients [39]. mortality is inversely associated with hospital annual Hyperosmolar agents, such as mannitol and hyper- caseload; there is a 24 % reduction in mortality for each tonic saline, are usually considered when the above strat- 100 patients admitted per year [60]. Regardless of initial egies fail to control ICP, although their role on clinical grade, early transfer to a high-volume centre is safe and outcome in the SAH population is not well established. cost-effective and should be pursued [61–63]. We could not identify any study addressing the role of mannitol in the management of raised ICP in the SAH 2. Prevention, detection, and treatment of population; for hypertonic saline, we found only case delayed cerebral ischaemia series [43–46] and a small placebo-controlled trial in pa- Delayed neurological deterioration occurs frequently in tients with raised but stable ICP [47]. In these studies, the first 2 weeks after SAH. Common causes of this hypertonic saline was effective to control ICP and im- deterioration include neurological events such as pro- proved CBF [43–47] and may improve outcome in the gression of EBI, hydrocephalus, seizures, ischaemia, and poor-grade population [43]. systemic conditions, such as fever and infections, re- The last line of treatment includes the use of barbitu- spiratory failure, and electrolyte abnormalities. Any de- rates, induced hypothermia, and decompressive craniect- layed neurological deterioration presumed to be related omy [38, 48]. Therapeutic hypothermia has been shown to ischaemia that persists for more than 1 hour and can- to be effective to control ICP in SAH but has not been not be explained differently has been defined as DCI [7] associated with improved functional outcome and re- (Table 1). DCI occurs in up to 30 % of SAH patients sur- duced mortality rates in patients with poor-grade SAH viving the initial haemorrhage. It can present as an acute [49]. The association of barbiturate coma and mild or insidious change in the level of consciousness or as a hypothermia (33–34 °C, median treatment of 7 days) focal neurological symptom, such as aphasia or hemipar- was studied in 100 SAH (64 poor-grade) patients with esis, or as both. These symptoms can be reversible if intracranial hypertension refractory to other medical inter- treated promptly and aggressively; otherwise, DCI tends ventions [50]. Approximately 70 % of patients were severely to progress to cerebral infarction, which is associated with disabled or dead at 1 year, and more than 90 % of patients higher rates of disability and mortality. Traditionally, DCI developed medical complications associated with the has been considered to be related to a cerebral vasocon- hypothermia/barbiturate treatment (i.e., electrolyte disor- striction (angiographic vasospasm) that begins approxi- ders, ventilator associated pneumonia, thrombocytopenia, mately 3 days and peaks 1 week after the haemorrhage and septic shock). Decompressive craniectomy is another and starts resolving after 2 weeks [64]. However, recent possible strategy for refractory ICP management in patients evidence suggests that DCI is a complex, multifactorial with SAH. Poor-grade patients are more commonly ex- syndrome, which can include additional pathophysiologic posed to this rescue therapy than patients with good-grade processes beyond angiographic or sonographic vasospasm SAH [51, 52]. Decompressive craniectomy has been associ- (Fig. 2 and Table 2) [65]. DCI may also occur in cerebral ated with decreased mortality [53], significant reduction of territories without evidence of angiographic vasospasm ICP [34], improved cerebral oxygenation [54, 55], and im- [66]. EBI (defined as brain injury developing in the first proved cerebral metabolism [56]. However, most patients 72 hours after haemorrhage) has significant impact on undergoing decompressive craniectomy due to refractory likelihood and severity of subsequent ischaemic changes ICP have poor outcome, with severe disability or death [67, 68]. For example, poor-grade patients, who have [56]. Many authors suggest that, if any benefit can be worse EBI, as well as patients who lose consciousness at de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 5 of 19 Table 1 The current definitions of early brain injury, delayed cortex hypoperfusion secondary to vasoconstriction [71]. cerebral ischaemia, and cerebral infarction The vast majority of cortical spreading depolarisation A. Early brain injury is the acute consequence of subarachnoid waves usually happen in the first 2 weeks after aneurysm haemorrhage (SAH) that leads to transient global cerebral ischaemia rupture, and 75 % of all CSIs recorded occur between the following the aneurysm rupture. During aneurysmal rupture, arterial fifth and seventh day post-bleeding [72]. In a prospective blood leaks under high pressure into the subarachnoid space and often into the brain parenchyma and ventricles. There is an acute and multicentre study, Dreier et al. [73] assessed the incidence sharp increase in the intracranial pressure (ICP) that may rise high and timing of spreading depolarisations and DCI after enough to compromise cerebral perfusion, causing global cerebral SAH. Eighteen SAH patients requiring craniotomy for ischaemia. This acute drop in cerebral perfusion pressure usually produces loss of consciousness. The initial cerebral injury (i.e., early aneurysm treatment were monitored for up to 10 days brain injury) is the combined result of transient global cerebral with subdural electrodes. Cortical spreading depolarisa- ischaemia and the effects of the subarachnoid blood itself. tions were detected in 13 patients (72 %). DCI was de- B. Global cerebral ischaemia: As discussed above, the aneurysm rupture leading to SAH can increase the ICP to cause global cerebral tected in seven patients and was time-locked to a ischaemia. If the haemorrhage does not stop, the patient dies before sequence of recurrent spreading depolarisations in all hospital admission and this is usually due to acute cardiopulmonary seven cases. Additionally, delayed ischaemic strokes changes associated with the high ICP or due to brain death related to the compromised cerebral blood flow. Re-bleeding remains the most verified by serial computed tomography (CT) scans or important complication in the hours following the initial bleed. There- magnetic resonance imaging occurred in the recording fore, the initial management should focus on strategies to prevent area in four patients. In another prospective study, aneurysm re-bleeding and to control ICP. using a novel subdural opto-electrode technology for C. Delayed cerebral ischaemia (DCI) is defined as “the occurrence of focal simultaneous laser-Doppler flowmetry and direct neurological impairment (such as hemiparesis, aphasia, apraxia, hemian- current-electrocorticography, combined with measure- opia, or neglect), or a decrease of at least 2 points on the Glasgow Coma Scale (either on the total score or on one of its individual components, ments of tissue partial pressure of oxygen, Dreier et al. such as eye, motor on either side, or verbal). This should last for at least [71] studied 13 patients with SAH. Isolated spreading 1 hour, is not apparent immediately after aneurysm occlusion, and depolarisations were detected in 12 of those. These cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies” [7]. DCI waves of depolarisations were associated with physio- remains the most significant cause of long-term disability and mortality logical, absent, or inverse regional CBF responses. Normal in patients who survive the initial haemorrhage to reach definitive haemodynamic response was associated with tissue hyper- aneurysm treatment [163]. In those patients who survive the initial bleed to reach medical assistance, the degree of brain injury associated with oxia, whereas inverse response led to tissue hypoxia. Five transient global cerebral ischaemia is variable. However, the main factor patients presented clusters of prolonged spreading depo- associated with the degree of injury and long-term outcome is ultimately larisations with persistent depressions. These clusters of the level of consciousness. Patients with small haemorrhages at the time of aneurysm rupture usually do not develop transient cerebral ischaemia spreading depolarisations were closely associated with and do not lose consciousness; however, they are still at risk of DCI [164]. structural brain damage as observed by neuroimaging. On the other hand, patients who transiently lose consciousness have Similarly, Bosche et al. [72] have reported low cerebral probably had a transient global ischaemic event and are at a higher risk of DCI [67]. measurements of tissue partial pressure of oxygen occur- D. Cerebral infarction caused by DCI is defined as “the presence of cerebral ring during clusters of spreading depolarisations. infarction on computed tomography or magnetic resonance scan of the Microthrombosis is common after SAH [74]. Subarach- brain within 6 weeks after SAH, or on the latest scan made before death within 6 weeks, or proven at autopsy, not present on the computed noid blood and blood products activate inflammatory tomography or magnetic resonance scans between 24 and 48 hours pathways, along with tissue factor in the microcirculation after early aneurysm occlusion, and not attributable to other causes of cerebral vessel wall, leading to endothelial cell activation such as surgical clipping or endovascular treatment. Hypodensities on computed tomography imaging resulting from ventricular catheter and damage, which in turn cause mural thrombus forma- or intraparenchymal haematoma should not be regarded as cerebral in- tion and release of microemboli [75]. Markers of increased farctions from DCI” [7]. activity of the coagulation cascade have been associated CT computed tomography, MRI magnetic resonance imaging with DCI, cerebral infarction, and poor outcome [76]. For example, in a group of 90 patients with SAH, early (within the time of SAH (and therefore have at least a short epi- 3 days of SAH onset) elevated concentrations of von Will- sode of transient global cerebral ischaemia) have increased ebrand factor were associated with poor outcome (crude risk of DCI [67, 68]. odds ratio (OR) = 4.6, 95 % confidence interval (CI) 2.0– Cortical spreading ischaemia (CSI) is a wave of depolar- 10.9; adjusted OR = 3.3, 95 % CI 1.1–9.8), ischaemic events isation in the grey matter that propagates across the brain (crude hazard ratio (HR) = 2.3, 95 % CI 1.1–4.9; adjusted at 2–5 mm/minute [69, 70], leading to depression in HR = 1.8, 95 % CI 0.8–3.9), and occurrence of spontaneous evoked potentials and spontaneous electroencephalogram DCI (crude HR = 3.5, 95 % CI 0.9–13.1; adjusted HR = 2.2, activity. The use of invasive subdural electrocorticographic 95 % CI 0.5–9.8). The hypothesis is that this early elevation monitoring combined with regional CBF measurements in von Willebrand factor levels probably reflects the forma- has shown that CSI can occur isolated or in clusters, and tion of microthrombi in the cerebral circulation [77, 78]. the depolarisation waves are associated with profound Autopsy studies have shown that patients who developed de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 6 of 19 Fig. 2 Pathophysiological processes in delayed cortical ischaemia. Key processes include angiographic vasospasm, microcirculatory constriction and formation of microthrombi, and waves of cortical spreading ischaemia, all of which can contribute to cerebral infarction. Delayed effects of the early brain injury such as neuronal and endothelial cell apoptosis, and systemic complications, can also occur. CPP cerebral perfusion pressure, ICP intracranial pressure, NO nitric oxide, SAH subarachnoid haemorrhage, TRP transient receptor potential. First published in Nature Reviews Neurology [98] DCI-related cerebral infarction had significantly more the liver [80]. It is an acute-phase protein that increases microthrombi compared with SAH patients who died be- in plasma during major stress situations, such as sepsis, cause of re-bleeding or acute hydrocephalus [75, 79]. burns, and major trauma. Some recent studies have sug- Haptoglobin is a complex tetramer glycoprotein, con- gested that the haptoglobin α1-α1 isoform could be pro- sisting of two α and two β chains, synthesised mainly by tective after SAH [81–83]. Haptoglobin binds free extracellular haemoglobin, which reduces free haemo- globin ability to generate oxygen-free radicals and there- Table 2 Facts that challenged the concept of angiographic fore interferes in one of the possible pathophysiological vasospasm as the main factor leading to delayed cerebral ischaemia pathways of angiographic vasospasm (i.e., haemoglobin- mediated oxidative stress) [82]. A. Approximately 70 % of patients with subarachnoid haemorrhage (SAH) will develop some degree of angiographic vasospasm within 2 weeks of Kantor et al. [82] found, in a cohort of 193 patients haemorrhage [64, 165]; however, only 30 % will develop symptoms (i.e., with SAH, that the haptoglobin α2-α2 isoform was asso- delayed cerebral ischaemia, or DCI) [88]. ciated with worse functional outcome at 3 months when B. DCI-associated cerebral infarct is an independent factor for poor outcome after SAH [166]; however, cerebral infarction can happen compared with the α1-α1 genotype. The haptoglobin asymptomatically [88] or in vascular territories not affected by α2-α2 isoform has a lower affinity for binding haemoglo- vasospasm [167]. bin and possibly inhibits haptoglobin-haemoglobin clear- C. Large-vessel angiographic vasospasm detected by modalities such as transcranial Doppler has a poor temporal relationship with the ance because of its larger size [84]. The α2-α2 genotype development of DCI [167]. remained significantly associated with worse functional D. There is no evidence that nimodipine decreases the rate of angiographic outcome (OR 4.138; P = 0.0463) after adjustment for age, vasospasm or promotes cerebral vasodilation; however, it remains the sole pharmacological intervention proven to improve outcomes sex, Fisher grade, and Hunt and Hess grade. A previous from DCI [108, 111]. study had already shown that haptoglobin α2-α2 geno- E. There is an important dissociation between vasospasm-related type was associated with higher rates of angiographic morbidity and functional outcome after SAH [168, 169]. F. The prevention and treatment of angiographic vasospasm do not vasospasm by transcranial Doppler (TCD) and conven- necessarily translate into improved outcome [169]. tional angiography performed between days 3 and 14 de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 7 of 19 after SAH [81]. A recent study by Leclerc et al. [83] events, oedema, and excitotoxicity that can result in de- showed, in a cohort of 74 patients with SAH, that hapto- layed and often progressive secondary brain injury. Un- globin α2-α2 genotype was an independent risk factor like primary injury, this delayed damage is considered, at for the development of focal and global angiographic least partially, preventable or reversible if adequately vasospasm and also predictive of unfavourable functional treated. Its prevention, timely detection, and appropriate outcomes and mortality. management require an early, aggressive, and well- The hypothesis is that patients with haptoglobin α2-α2 structured approach to patient care. This is especially genotype do worse because of reduced CSF clearance of true in patients with poor-grade SAH, where limited haemoglobin, increased reactive oxygen species, and neurological examination and a higher incidence of sys- therefore development of more inflammation. This hy- temic complications make DCI identification a signifi- pothesis is corroborated by an experimental model of cant challenge. SAH, which showed that mice expressing human α2-α2 DCI is often a diagnosis of exclusion; confounding fac- haptogobin developed more severe angiographic vaso- tors such as hypoxia, electrolyte disturbances, infection, spasm and increased macrophage/neutrophil counts in fever, hydrocephalus, convulsive, and non-convulsive sei- the CSF after SAH, when compared with wild-type α1- zures can produce delayed neurological deterioration α1 haptogobin-expressing mice [85]. Although there is similar to that of DCI and should always be considered no clinical intervention directly designed to address this in the differential and treated accordingly. Moreover, in important recent finding on the pathophysiology of the poor-grade SAH population, new neurological defi- SAH, the genetic effect on outcome after SAH may in- cits are clinically difficult to detect because of decreased crease our knowledge of the disease. level of consciousness and the frequent need for sed- ation (usually required for ICP and mechanical ventila- Delayed cerebral ischaemia monitoring. Triggers for tion management), making the detection of acute detection and confirmation of delayed cerebral ischaemia neurological deterioration even more challenging. Pa- in sedated or poor-grade patients tients who require sedation but who are clinically stable Figure 3 summarises a possible approach for the man- (i.e., absence of ICP crisis, cardiopulmonary instability, agement of SAH patients in poor neurological condition. or status epilepticus) should undergo interruption of The key management of patients with acute brain injury, sedation and analgesia (i.e., neurological wake-up tests) including the SAH population, is the minimisation of a that could detect focal neurological deficits. Wake-up complex cascade of ischaemic and apoptotic cellular tests seem to be safe since they are not associated with Fig. 3 Summary of a possible approach for the management of subarachnoid haemorrhage patients in poor neurological condition. ARDS acute respiratory distress syndrome, BP blood pressure, CPP cerebral perfusion pressure, CSF cerebrospinal fluid, CTA/CTP computed tomography angiography/computed tomography perfusion, DCI delayed cerebral ischaemia, DSA doxyl stearic acid, ECG electrocardiogram, GCS Glasgow Coma Scale, Hgb haemoglobin, HOB head of bed, ICH intracerebral haemorrhage, ICP intracranial pressure, IPC intermittent pneumatic compression, iv intravenously, IVH intraventricular haemorrhage, MAP mean arterial pressure, MRI/MRA magnetic resonance imaging/magnetic resonance angiography, NeuroICU neurointensive care unit, NIHSS National Institutes of Health Stroke Scale/Score, PaCO arterial partial pressure of carbon dioxide, SaO arterial 2 2 oxygen saturation, SBP systolic blood pressure, SIADH syndrome of inappropriate secretion of antidiuretic hormone, SPECT single-photon emission computed tomography, T temperature, VTE venous thromboembolism, WFNS World Federation of Neurosurgical Societies de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 8 of 19 changes in cerebral metabolism or oxygenation as mea- use of TCD and multimodal CT [94, 95] for monitoring sured by microdialysis and direct brain tissue oxygen- patients with SAH in accordance with the VASOGRADE ation measurement, respectively [86]. However, the [6]. It is important to mention that, in the poor-grade sensitivity of neurological examination to detect signs of population, if screening CTA or digital subtraction angiog- DCI in the setting of poor-grade SAH is low [87]; ap- raphy has already recognised the presence of severe angio- proximately 20 % of patients who develop DCI, as iden- graphic vasospasm in a setting of acute neurological tified by new infarctions on CT or magnetic resonance, deterioration, it is reasonable to start empiric DCI therapy do not have any evidence of clinical neurological deteri- without additional neurological investigation. Additionally, oration [88, 89]. Interestingly, these patients who devel- when screening CTP demonstrates perfusion deficits oped “asymptomatic” cerebral infarctions were less likely (CBF of less than 25 ml/100 g/minute or MTT of more to receive vasopressor agents and had higher frequency than 6.5 seconds or both) [91], it is reasonable to initiate of death or moderate-to-severe disability than those with therapy for DCI. “symptomatic” DCI [88]. ICP and cerebral perfusion pressure (CPP) monitoring Because neurological examination is less useful in this have been the cornerstone parameters in the manage- setting, a suspicion of DCI will frequently be based on ment of comatose patients with acute brain injury. Crit- changes detected by screening tools. According to the ical levels of CPP (of less than 70 mm Hg) have been Neurocritical Care Guidelines on the management of SAH, significantly associated with cerebral infarction [96] after “in sedated or poor-grade SAH patients, clinical deterior- SAH. Also, CPP of less than 60 mm Hg has been associ- ation may be difficult to assess, and transcranial Doppler ated with higher ICP levels and abnormal levels of P O ti 2 (TCD), continuous electroencephalography (cEEG), brain and LPR [97]. However, recent clinical data suggest that tissue oxygen pressure (P O2) monitoring, and/or cerebral cerebral hypoxia (P O of less than 20 mm Hg) and ti ti 2 microdialysis (CMD) are options for monitoring for vaso- cerebral energy dysfunction (LPR of more than 40) may spasm and DCI”. Changes commonly used to trigger inter- occur despite normal levels of ICP and CPP in the poor- vention include the following [8, 90]: grade SAH population [97]. Chen et al. [97], in a cohort of 19 patients with poor- 1. An increase in either (a) TCD mean flow velocity in grade SAH, demonstrated that ICP and CPP monitoring the middle cerebral artery (FVMCA) of more than may not be sufficient to detect episodes of cerebral com- 50 cm/second over 24 hours or (b) mean FVMCA promise, such as severe brain hypoxia detected by P O ti 2 of at least 200 cm/second or middle cerebral artery/ catheter (P O of not more than 10 mm Hg) or brain ti 2 internal carotid artery ratio of more than 6 or both [8]. energy dysfunction detected by CMD (LPR of at least 2. 2. CT perfusion parameters: CBF of less than 25 ml/ 40). The sensitivities of abnormal ICP or CPP levels for 100 g/minute or mean transit times (MTTs) of more elevated LPR and reduced P O were 21.2 %, and critical ti 2 than 6.5 seconds or both [91]. levels of LPR or P O were found on many occasions ti 2 3. Severe angiographic vasospasm (defined as a when ICP or CPP was normal. Additionally, early brain narrowing of at least 70 % from baseline) [92] tissue hypoxia (i.e., within 24 hours of haemorrhage) is detected by digital subtraction angiography (i.e., gold very prevalent in the poor-grade SAH population [98]. standard) or CT angiography (which is also highly Therefore, the use of multimodal neuromonitoring may specific for angiographic vasospasm). be a good complement to ICP/CPP monitoring, which 4. Electroencephalography (EEG) reduced alpha could detect cerebral oxygen or energy compromise in variability [93]. an early reversible state [93] (Fig. 4). 5. Abnormal levels of brain tissue oxygen (P O of less ti 2 than 20 mm Hg; Fig. 4) or CMD (i.e., lactate/pyruvate Continuous electroencephalography monitoring in patients ratio (LPR) of more than 40 and glucose of less than with poor-grade subarachnoid haemorrhage 0.5 mM and in second line for glutamate of more Continuous EEG (cEEG) has been described as a useful than 40 mM) or both [93]. monitoring tool for the prediction and diagnosis of angiographic vasospasm and DCI. Also, cEEG findings Multimodal neuromonitoring may be a prognostic marker in patients with poor- Modalities capable of monitoring CBF (e.g., CT perfu- grade SAH [99, 100]. Several studies have investigated sion or CTP), cerebral oxygenation (e.g., brain tissue and demonstrated a positive correlation between cEEG oxygen catheter), and cerebral metabolism (e.g., microdi- findings and angiographic vasospasm, DCI, and functional alysis) are theoretically superior to modalities monitor- outcome [99–102], supporting the critical care use of ing exclusively vessel diameter (e.g., TCD, conventional this modality in poor-grade or sedated SAH patients. angiography, and CT angiography, or CTA). We have Commonly described quantitative cEEG findings that previously published a possible approach combining the predict angiographic vasospasm or DCI are (a) decreased de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 9 of 19 Fig. 4 (See legend on next page.) de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 10 of 19 (See figure on previous page.) Fig. 4 Approach to low brain tissue oxygen. Consider the combined used of P O and microdialysis catheter to detect non-hypoxic patterns of ti 2 cellular dysfunction [97]. According to the manufacturer, an equilibrium time as long as 2 hours may be necessary before P O readings are ti 2 stable, because of the presence of the tip surrounding microhaemorrhages. Sensor damage may also occur during insertion. Increase inspired fraction of oxygen (FiO ) to 100 %. If P O increases, it confirms good catheter function. Oxygen challenge to assess tissue oxygen reactivity. FiO 2 ti 2 2 is increased from baseline to 100 % for 5 minutes to evaluate the function and responsiveness of the brain tissue oxygen probe. A positive response happens when P O levels increase in response to higher FiO . A negative response (lack of P O response to higher FiO ) suggests ti 2 2 ti 2 2 probe or system malfunction. Another possibility if there is a negative response is that the probe placement is in a contused or infarcted area. Follow-up computed tomography might be necessary in this situation to ensure appropriate probe position. Mean arterial pressure (MAP) challenge to assess cerebral autoregulation. MAP is increased by 10 mm Hg. Patients with impaired autoregulation demonstrated an elevation in ICP with increased MAP. When the autoregulation is intact, no change or a drop in ICP levels follows the elevation in blood pressure. Another way to assess cerebral autoregulation is the evaluation of the index of P O pressure reactivity. When autoregulation is intact, P O is relatively ti 2 ti 2 unaffected by changes in CPP, so the index of P O pressure reactivity is near zero [170]. The threshold haemoglobin (Hgb) of 9 mg/dl to indicate ti 2 blood transfusion was based on a previously published P O study [171]. CPP cerebral perfusion pressure, CSF cerebrospinal fluid, CT computed ti 2 tomography, ICP intracranial pressure, PaCO arterial partial pressure of carbon dioxide, PaO partial pressure of oxygen in arterial blood, P O brain 2 2 ti 2 tissue oxygen pressure, RASS Richmond Agitation-Sedation Scale, SAH subarachnoid haemorrhage, SBP systolic blood pressure relative alpha variability [101] and (b) decreased alpha/ CMD measures the interstitial levels of several sub- delta ratio [100, 102]. Other cEEG findings such as peri- stances, such as glucose, lactate, pyruvate, glutamate, odic epileptiform discharges, electrographic status epilep- glycerol, and several inflammatory biomarkers. An in- ticus, and the absence of sleep architecture have been creased LPR is the most common and better-studied described as independent prognostic factors in the poor- marker of anaerobic cerebral metabolism and therefore grade SAH population after adjustment for known prog- is an indicator of cerebral ischaemia [93]. Metabolic nostic factors such as age, clinical grade (i.e., Hunt and changes detected by CMD, such as elevated LPR, have Hess grade), and the presence of intraventricular haemor- been shown to predict delayed neurological deterioration rhage [99]. Claassen et al. [99] described, in a cohort of and “symptomatic vasospasm” [105, 106]. Also, extreme 116 patients with SAH, that the absence of sleep architec- microdialysate values of lactate, glutamate, LPR, and gly- ture (80 % versus 47 %; OR 4.3, 95 % CI 1.1–17.2) and the cerol have been associated with cerebral infarction and presence of periodic lateralised epileptiform discharges permanent neurological deficits [107]. (PLEDs) (91 versus 66 %; OR 18.8, 95 % CI 1.6–214.6) were associated with 3-month poor outcome by modified Pharmacological prophylaxis Rankin scale. Additionally, all patients with absent EEG Table 3 summarises drugs investigated and under investi- reactivity, generalised periodic epileptiform discharges, gation for prevention of DCI. According to the American and bilateral independent PLEDs and 92 % of patients (11 Heart Association, the Neurocritical Care Society, and the out of 12) with non-convulsive status epilepticus pro- European guidelines [8–10], nimodipine, an L-type dihy- gressed to have a poor functional outcome at 3 months. dropyridine calcium channel antagonist, is the only medi- cation proven to improve outcomes after SAH [108]. The Monitoring brain tissue partial pressure of oxygen concept that nimodipine decreases the rate of angio- The invasive monitoring of brain tissue oxygenation al- graphic vasospasm has been challenged, and the mecha- lows regional and continuous monitoring of P O , nisms by which it improves patient outcome in a setting ti 2 which may detect early changes in cerebral tissue oxy- of SAH are not completely established. genation that precede ischaemic damage. P O levels of Nimodipine probably has a neuroprotective action by ti 2 below 20 mm Hg require attention and might be a decreasing the influx of calcium after cerebral ischae- warning sign of ischaemia not detected clinically. P O mia due to DCI. Additionally, nimodipine might de- ti 2 levels of below 15 mm Hg require immediate interven- crease the incidence of microthrombi by increasing the tion to optimise cerebral tissue oxygenation (Fig. 4). endogenous fibrinolysis [109] and may antagonise cor- P O levels have been directly correlated with the de- tical spreading ischaemia [110]. Nimodipine seems to ti 2 velopment of ischaemic events [96], angiographic vaso- improve long-term outcome in the poor-grade popula- spasm [103], and outcome [104]. In addition to P O tion as well [111]. A multicentre, randomised placebo- ti 2 monitoring, the use of CMD may be a possible alterna- controlled double-blind trial studied the effect of nimo- tive for monitoring sedated or poor-grade patients at risk dipine in 188 patients with poor-grade SAH (Hunt and of DCI. The combined use of P O and CMD catheter Hess grade 3–5) [111]. The treatment was associated ti 2 can help discriminate two patterns of cellular dysfunction with an improvement in functional outcome at 3 months (i.e., hypoxic and non-hypoxic cellular dysfunction) [97]. (29.2 % in the nimodipine group versus 9.8 % in the de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 11 of 19 Table 3 Evidence review of drugs used in aneurysmal subarachnoid haemorrhage Drug Direct drug action Possible mechanisms of action Status Guidelines [8–10] Nimodipine [82] L-type calcium � Reduction of angiographic Meta-analysis of clinical trials Class I, level A channel antagonist vasospasm found that oral nimodipine Nimodipine should be � Increase in fibrinolytic reduced the risk of DCI and administered enterally activity poor outcome. (60 mg every 4 hours) to � Neuroprotection prevent DCI. � Inhibition of cortical The only drug approved spreading ischaemia for SAH in the USA and Europe. Clazosentan [168] Endothelin A Reduction of angiographic � Four randomised clinical trials Not addressed receptor vasospasm and a meta-analysis However, after the antagonist � Clazosentan reduced angio publication of the graphic vasospasm without a CONSCIOUS trials and significant effect on outcome. following meta-analysis, � Hypotension and pulmonary clazosentan infusion will complications associated with not be recommended the drug use could have for patients with SAH, as a counteracted the beneficial Class I, level A. effects of the drug. Fasudil [172] Rho-kinase Reduces smooth muscle � Eight randomised clinical trials Not addressed inhibitor contraction and inhibits TNF- � Treatment significantly The drug is approved for induced IL-6 release from reduced the incidence of use in patients in Japan C6 glioma cells angiographic vasospasm and and China but not in cerebral infarction and Europe or USA. improved the odds ratio for good recovery compared with placebo or nimodipine and other drugs. Statins [92–94] Inhibit HMG-CoA � Preserve endothelial function � Seven randomised clinical Guidelines published before reductase � Anti-inflammatory effects trials of statins in patients with the STASH trial [92]. � Antioxidant SAH. The recommendations will � Antithrombotic actions � An additional study showing probably remain the same � Vascular protection no benefit of higher dose of to administer statins only if � Neuroprotective and simvastatin (80 mg versus the patient was already neurorestorative action 40 mg) receiving them at time of � One systematic review not SAH, as a Class I, level A. including the STASH trial found no effect of statin treatment on poor outcome. Magnesium [90] Antagonism of � Vasodilation� Increased � Seven randomised clinical Class I, level A calcium channels endothelial cell prostacyclin trials Magnesium is not on vascular � Endothelial protection � Meta-analysis reported no recommended for smooth muscle � Protect the blood–brain barrier effect of magnesium on poor prevention of DCI. � Reduce cerebral oedema outcome � Anticonvulsant (N-methyl-D- aspartate receptor antagonism) Dantrolene [173] Inhibits ryanodine Reduces intracellular calcium � One small dose-escalation Not addressed receptors release in smooth muscle and study Remains experimental may be neuroprotective � Dantrolene in a dose of 2.5 mg/kg, administered over the course of 60 minutes, was associated with reduced cerebral blood-flow velocities measured by transcranial Doppler. Intrathecal thrombolytics Fibrinolytic agents The rapid clearance of � Five RCTs and a meta-analysis Not addressed (i.e., urokinase and subarachnoid clot could reduce � Thrombolysis was associated Further trials are needed. recombinant tissue angiographic vasospasm and with significant reductions in Standardisation plasminogen activator) [174] complications, such as cortical angiographic vasospasm, of techniques and spreading ischaemia and delayed neurological deficits, evaluation in a larger microthrombosis. hydrocephalus, and poor study are required. outcome. Antiplatelet drugs [175] Inhibition of Inhibition of platelet � Seven randomised clinical trials Not addressed � Acetylsalicylic acid platelet aggregation aggregation and a meta-analysis found trends Further trials are needed. � OKY-046 (Cataclot) - toward reduction in poor outcome According to the meta- de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 12 of 19 Table 3 Evidence review of drugs used in aneurysmal subarachnoid haemorrhage (Continued) selective thromboxane but also toward increased analysis results, treatment synthetase inhibitor intracranial haemorrhage. with antiplatelet agents to � Dipyridamole � Only ticlopidine was associated prevent DCI or poor � Ticlopidine with statistically significant fewer outcome cannot be occurrences of a poor outcome recommended. (only one small RCT) Albumin [176] Multiple Neuroprotective � One open-label dose-escalation Not addressed trial Remains experimental � Trend toward improved outcome with 1.25 g/kg per day Erythropoietin [177, 178] Multiple � Prevent loss of autoregulation � Two RCTs Not addressed � Reduce angiographic vasospasm � One negative study Remains experimental � Inhibits apoptosis and stimulates and one showing that patients neurogenesis and angiogenesis who received erythropoietin had fewer cerebral infarcts, shorter duration of autoregulatory dysfunction, and better clinical outcome. Cilostazol [179] Inhibits � Antithrombotic � One small (109 patients) Not addressed phosphodiesterase � Vasodilatory randomised, single-blind study Remains experimental 3 � Anti-smooth muscle proliferation � Cilostazol significantly reduced � Inotropic and chronotropic effects angiographic vasospasm, DCI, and cerebral infarction but had no effect on outcome. CONSCIOUS Clazosentan to Overcome Neurological Ischaemia and Infarction Occurring After Subarachnoid Haemorrhage, DCI delayed cerebral ischaemia, IL-6 interleukin-6, RCT randomised controlled trial, SAH subarachnoid haemorrhage, STASH simvastatin in aneurysmal subarachnoid haemorrhage, TNF tumour necrosis factor placebo), despite similar rates of moderate and severe Statins angiographic vasospasm found in the follow-up angiog- There is great interest in the impact of statins in the raphy (64.3 % in the nimodipine group versus 66.2 % in prevention of DCI. Statins preserve endothelial func- the placebo group). However, in the sub-group of grade 5 tion by increasing nitric oxide synthesis while decreas- patients, no difference in functional outcome between ing the synthesis of endothelin-1. Also, there are other nimodipine and placebo groups was found [111]. statin effects that may be interesting in the SAH set- Interestingly, in the poor-grade population, the admin- ting, such as anti-inflammatory, antioxidant, and anti- istration of nimodipine is associated with an acute drop thrombotic effects. Additionally, statins have described in the mean arterial pressure and CPP, which is trans- neuroprotective and neurorestorative action. So far, six lated into a decrease in CBF and brain tissue oxygen- randomised clinical trials [118] of statins in patients ation [112, 113]. However, there is no prospective study with SAH have been published; however, a systematic that evaluates the long-term consequences of these review of these studies found no effect of statin treat- physiological changes on functional outcome. ment on poor outcome; mortality was 10 % in the statin group versus 21 % in controls (relative risk 0.62, 95 % CI 0.36–1.06); DCI was significantly reduced in the sta- tin group. The overall quality of these studies was Magnesium judged to be low to moderate. Recently, two multicen- Magnesium is a calcium channel antagonist with potent tre randomised clinical trials were published. One com- vasodilator and neuroprotective properties. Animal pared two different regimens of simvastatin (80 versus models of SAH have shown reversal of cerebral arterial 40 mg), which showed no effect of higher dose on DCI, vasoconstriction, leading to reduction of the size of is- modified Rankin disability score at 3 months, and an chaemic lesions [114]. Additionally, magnesium may de- analysis of cost-effectiveness [119]. The second study crease the rate and frequency of cortical spreading had previously shown no benefit in the use of 40 mg ischaemia [115]. Unfortunately, a large clinical trial com- simvastatin compared with placebo for long-term out- bined with a meta-analysis [116] showed no clinical come, as measured by modified Rankin score at benefit with the use of magnesium infusion, measured as 6 months [120]. Mortality and favourable outcome were favourable outcome at 6 months, incidence of DCI, or similar in both simvastatin and placebo groups (10 % cerebral infarction. A possible explanation is that high versus 9 % and 58 % versus 62 %, respectively). Serious levels of plasma magnesium are associated with worse adverse events were also similar in both groups (18 %) clinical outcomes [117]. [120]. Therefore, the guidelines will probably keep their de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 13 of 19 recommendation to administer statins only if the pa- Cardiac complications following SAH can range from tient was already receiving them at the time of SAH benign electrocardiogram changes to overt cardiogenic [118]. shock requiring intra-aortic balloon pump [130, 131]. Positive troponin is a good marker of left ventricular dysfunction after SAH [132], which increases the risk of Haemodynamic prophylaxis hypotension, pulmonary oedema, and cerebral infarc- The use of prophylactic hypervolemia, a component of tion [133]. The treatment is mainly supportive, and so-called triple-H therapy (hypervolemia, hypertension, most of the cases will recover spontaneously within and haemodilution), is not recommended [8–10], based 2 weeks [134]. However, aggressive ICU management on lack of evidence that it positively affects functional may be required in the setting of severely impaired left outcome. It also increases the costs and risk of systemic ventricular function and DCI. Thus, the use of ino- complications, such as cardiac dysfunction, pulmonary tropic agents such as dobutamine [135], levosimendan oedema, and infection [121, 122]. [136], milrinone [137], and even intra-aortic balloon pump counterpulsation [138] has been described and Delayed cerebral ischaemia treatment can be considered to optimise the cardiac function in Haemodynamic manipulation, what is known as the order to improve CBF. triple-H therapy, has for decades been the cornerstone Patients with poor-grade SAH are at higher risk of car- of DCI management [94, 95]. However, the literature diac and pulmonary complications [139]. Additionally, supporting its safety and efficacy is scarce [123]. Angio- hypovolemia and pulmonary oedema are common phe- graphic vasospasm, in the absence of DCI, should not nomena in this population, increasing the risk for de- be treated [90, 124]. The development of a new focal layed cerebral ischaemia [140, 141]. Therefore, the poor- deficit or a decrease in level of consciousness, not ex- grade SAH population may benefit from advanced plained by other causes (e.g., hydrocephalus or re- haemodynamic monitoring. Yoneda et al. [139], in a bleeding), should prompt aggressive treatment [90, multicentre prospective cohort study of haemodynamic 124]. A fluid bolus with normal saline might be the first monitoring using a transpulmonary thermodilution sys- step because it increases CBF in areas of cerebral is- tem (PiCCO Plus), which included a group of 138 pa- chaemia [125]. The main goal is to maintain euvolemia tients with poor-grade SAH, showed that extravascular and normal circulating blood volume. Hypervolemia lung water index (P = 0.049), pulmonary vascular perme- and haemodilution do not improve cerebral oxygen de- ability index (P = 0.039), and systemic vascular resistance livery and may be associated with adverse events [121, index (P = 0.038) were significantly higher in the poor- 122]. Patients who fail to completely reverse the new grade group when compared with the good-grade popu- deficit after a fluid challenge may undergo a trial of lation. Additionally, poor-grade patients displayed sig- hypertension unless the blood pressure is elevated at nificantly lower cardiac index on days 1 and 2 (P = 0.027 baseline or in the presence of heart failure [9]. Blood and P = 0.011, respectively) and developed heart failure- pressure is augmented in a step-wise fashion by the use like afterload mismatch at an early stage, and those who of a vasopressor, typically noradrenaline [8, 126]. The developed DCI had haemodynamic measures of hypovol- neurologic examination is repeated frequently in each emia, as shown by a decreased global end-diastolic volume blood pressure step (180 mm Hg/190 mm Hg/200 mm index [139]. The same group described the mean global Hg), and the target should be based on clinical im- end-diastolic volume index (normal range, 680–800 ml/ provement. If the neurological deficit persists after the 2 m ) as an independent factor for the development of DCI induction of hypertension (typically up to a systolic (HR 0.74, 95 % CI 0.60–0.93; P = 0.008). Patients who de- blood pressure of 200 to 220 mm Hg), a rescue therapy veloped DCI had significantly lower global end-diastolic with cerebral angioplasty or intra-arterial infusion of a volume index compared with patients who did not (783 ± vasodilator might be of benefit [127]. The prophylactic 2 2 25 ml/m versus 870 ± 14 ml/m ; P = 0.007). A threshold use of angioplasty is not associated with improved out- 2 of less than 822 ml/m was correlated with DCI develop- come and might be associated with increased risk of arter- ment, whereas a global end-diastolic volume index above ial rupture and is not recommended [128]. 2 921 ml/m was associated with the development of severe pulmonary oedema. These finding suggest that maintain- Medical complications ing global end-diastolic volume index slightly above the It is well described that medical complications after normal range may be effective to prevent hypovolemia SAH have a negative impact on survival and functional and severe pulmonary oedema, which may decrease the outcome. Up to 80 % of patients will develop a serious risk of DCI. medical complication during phase 2, increasing the risk Pulmonary complication, such as hospital-acquired pneu- for secondary brain injury [129]. monia, cardiogenic or neurogenic pulmonary oedema, de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 14 of 19 aspiration pneumonitis, and pulmonary embolism, occur in Anaemia can be easily corrected, but blood transfusion approximately 30 % of patients after SAH [142]. Acute re- has been implicated with worse outcome after SAH [156, spiratory distress syndrome can affect 27 % of cases and is 157], including higher mortality, after adjustment for the independently associated with worse outcomes [143]. In most common clinical indications of transfusion [158]. this clinical scenario, extra caution should be taken to avoid Although there is no clear threshold for transfusion in fluid overload; however, diuretics might be dangerous be- patients with SAH, general ICU thresholds are not applic- cause of the risk of hypovolemia-induced cerebral able for this population [7, 101, 159]. Dhar et al. [160], in ischaemia. an elegant study using positron emission tomography Hyponatremia (serum sodium of less than 135 mEq/ scan, demonstrated that transfusion in patients with dl) is the most common electrolyte derangement after haemoglobin levels of less than 9 g/dl was the only inter- SAH, occurring in up to 50 % of patients. There are two vention capable of increasing global CBF and oxygen de- possible mechanisms responsible for the development of livery, when compared with crystalloid bolus and induced hyponatremia after SAH: (1) cerebral salt wasting (CSW) hypertension. The clinical applicability of these findings and (2) the syndrome of inappropriate secretion of anti- needs to be addressed in a large trial because the study en- diuretic hormone (SIADH) [144]. These entities are fun- rolled a small number of patients (38 in total) and had damentally different in their pathogenesis; however, they only physiological endpoints. are difficult to distinguish in clinical practice and may Patients with poor-grade SAH are at high risk of ven- concur in the same patient [145]. Importantly, CSW ous thromboembolism [161]. Guidelines on manage- courses with intravascular volume contraction, which in- ment of SAH suggest starting mechanical prophylaxis creases the risk of DCI and poor outcome [145]. Like- with intermittent compression devices before aneurysm wise, the treatment of SIADH on the basis of fluid treatment [8–10]. Pharmacologic thromboprophylaxis restriction is not indicated, because of increased risk of seems to be safe if started within 12 to 24 hours after hypovolemia-associated cerebral infarction [146, 147]. aneurysm treatment [162]. Therefore, in clinical practice, the management of hypo- natremia in the setting of SAH is based on the avoidance Conclusions of hypovolemia and the judicious repletion of volume Aneurysmal SAH is a complex neurovascular disease as- and sodium losses [144]. sociated with multiple neurological and systemic compli- In a retrospective study in a single academic centre, cations and requires multidisciplinary specialised care, Wartenberg et al. found that a single occurrence of best provided in high-volume centres. Patients who sur- hyperglycaemia, fever, or anaemia after aneurismal SAH vive the initial bleed can deteriorate within 2 weeks, espe- was independently predictive of poor outcome, even cially because of DCI. DCI is a syndrome with a complex after adjustment for traditional prognostic variables, multifactorial pathophysiology that extends beyond the such as age, clinical grade, aneurysm size, re-bleeding, historic explanation of angiographic vasospasm. and cerebral infarction [129]. Although the risk of death and moderate and severe dis- Fever is the most common medical complication after ability has decreased significantly over the last three de- SAH and is associated with longer ICU and hospital cades, the extent to which the prevalence of cognitive length of stays, worse functional outcomes, and higher deficits, poor quality of life, and daytoday functioning have mortality [148, 149]. Although non-infectious fever is changed over the same period is completely undetermined. common, especially in the presence of intraventricular Further studies should simultaneously tackle multiple haemorrhage and poor-grade patients [150], it is strongly pathophysiological pathways, and long-term functional recommended that frequent temperature checks and outcomes shall be assessed by means of outcome measures careful assessment for possible infectious cause are able to recognise subtle cognitive changes. made. During the time window of vasospasm, it is desir- able to maintain normothermia with antipyretic drugs, Abbreviations followed by advanced fever control with surface cooling CBF: Cerebral blood flow; cEEG: Continuous electroencephalography; CI: Confidence interval; CMD: Cerebral microdialysis; CPP: Cerebral perfusion or intravascular devices [151, 152]. In this situation, espe- pressure; CSF: Cerebrospinal fluid; CSI: Cortical spreading ischaemia; cial attention should be paid to detect and treat shivering. CSW: Cerebral salt wasting; CT: Computed tomography; CTA: Computed The protocol for diagnosis and treatment of shivering has tomography angiography; CTP: Computed tomography perfusion; DCI: Delayed cerebral ischaemia; EBI: Early brain injury; been published elsewhere [153]. EEG: Electroencephalography; EVD: External ventricular drain; FVMCA: Flow Ideally, blood sugar should be kept less than 200 mg/ velocity in the middle cerebral artery; GCS: Glasgow Coma Scale; HR: Hazard dl and hypoglycaemia (less than 80 mg/dl) should be ratio; ICP: Intracranial pressure; ICU: Intensive care unit; LPR: Lactate/pyruvate ratio; MTT: Mean transit time; OR: Odds ratio; PaCO : Arterial partial pressure strictly avoided. Both have been shown in microdialysis of carbon dioxide; PLED: Periodic lateralised epileptiform discharge; studies to be associated with metabolic crisis and worse P O : Brain tissue oxygen pressure; SAH: Subarachnoid haemorrhage; ti 2 neurological outcome [154, 155]. SIADH: Syndrome of inappropriate secretion of antidiuretic hormone; de Oliveira Manoel et al. Critical Care (2016) 20:21 Page 15 of 19 TBI: Traumatic brain injury; TCD: Transcranial Doppler; WFNS: World 9. Connolly Jr ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Federation of Neurosurgical Societies.. Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43: Competing interests 1711–37. RLM receives grant support from the Physicians Services Incorporated 10. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. 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Starke RM, Connolly ES, Participants in the International Multi-disciplinary conduct the literature search, and to provide evaluations of the clinical Consensus Conference on the Critical Care Management of Subarachnoid significance of the screened articles and to provide additional articles Hemorrhage. Rebleeding after aneurysmal subarachnoid hemorrhage. judged to be important for the topic addressed in this review article and Neurocrit Care. 2011;15:241–6. shared responsibility for the tables. AG helped to form the conceptual 14. van den Berg R, Foumani M, Schröder RD, Peerdeman SM, Horn J, Bipat S, framework for this article and to conduct the literature search and shared et al. Predictors of outcome in World Federation of Neurologic Surgeons responsibility for the tables. SA helped to form the conceptual framework grade V aneurysmal subarachnoid hemorrhage patients. Crit Care Med. for this article and to conduct the literature search. RLM helped to form 2011;39:2722–7. the conceptual framework for this article and to provide evaluations of the 15. Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurysmal subarachnoid clinical significance of the screened articles and to provide additional haemorrhage. Cochrane Database Syst Rev. 2001;8:CD001697. articles judged to be important for the topic addressed in this review 16. Oudshoorn SC, Rinkel GJ, Molyneux AJ, Kerr RS, Dorhout Mees SM, Backes article and was responsible for the figures that were first published in D, et al. Aneurysm treatment <24 versus 24-72 h after subarachnoid Nature Reviews Neurology. TAS and TRM helped to provide evaluations of hemorrhage. Neurocrit Care. 2014;21:4–13. the clinical significance of the screened articles and to provide additional 17. Zhang Q, Ma L, Liu Y, He M, Sun H, Wang X, et al. Timing of operation for articles judged to be important for the topic addressed in this review poor-grade aneurysmal subarachnoid hemorrhage: study protocol for a article. All authors contributed to the drafting, revising, and approval of the randomized controlled trial. BMC Neurol. 2013;13:108. final manuscript. 18. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping Acknowledgements versus endovascular coiling in 2143 patients with ruptured intracranial This work was supported by a Personnel Award from the Heart and Stroke aneurysms: a randomised trial. Lancet. 2002;360:1267–74. Foundation of Canada and an Early Researcher Award from the Ontario Ministry 19. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. of Research and Innovation to TAS. The authors would like to thank the Bitove International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus Foundation for generously funding the research. endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, Author details subgroups, and aneurysm occlusion. Lancet. 2005;366:809–17. St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1 W8, Canada. 20. Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RS. The durability of Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, 30 endovascular coiling versus neurosurgical clipping of ruptured cerebral Bond Street, Toronto, ON M5B 1 W8, Canada. Toronto Western Hospital aneurysms: 18 year follow-up of the UK cohort of the International MSNICU, 2nd Floor McLaughlin Room 411-H, 399 Bathurst Street, Toronto, Subarachnoid Aneurysm Trial (ISAT). Lancet. 2015;385:691–7. ON M5T 2S8, Canada. 21. 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Published: Jan 23, 2016

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