Neurosurg Rev DOI 10.1007/s10143-015-0617-3
REVIEW
Diagnosis of cerebral vasospasm and risk of delayed cerebral ischemia related to aneurysmal subarachnoid haemorrhage: an overview of available tools Susanna Bacigaluppi & Gianluigi Zona & Francesca Secci & Gianantonio Spena & Nicola Mavilio & Giulia Brusa & Ronit Agid & Timo Krings & Gianandrea Ottonello & Marco Fontanella
Received: 25 May 2014 / Accepted: 16 November 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract In the first weeks following aneurysmal subarachnoid haemorrhage, cerebrovascular alterations may impact the outcome significantly. Diagnosis of cerebral vasospasm and detection of alterations at risk of delayed cerebral ischemia are key targets to be monitored in the post-acute phase. Available tools include clinical monitoring, as well as studies that can detect possible arterial narrowing, alterations of perfusion, metabolism and neurophysiology. Each technique is able to investigate possible vascular impairment and has different advantages and limits. All available techniques have been described. Among these, the most practical have been selected and compared for their peculiar characteristics. Based on this analysis, a flowchart to monitor these patients is finally proposed.
S. Bacigaluppi (*) : G. Zona : F. Secci Department of Neurosurgery, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy e-mail: [email protected] G. Spena : M. Fontanella Department of Neurosurgery, Spedali Civili di Brescia, Università di Brescia, Brescia, Italy N. Mavilio Department of Neuroradiology, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy G. Brusa : G. Ottonello Department of Neurology and Neurophysiology, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy R. Agid : T. Krings Department of Neuroradiology, Toronto Western Hospital, University Health Network Toronto, Toronto, ON, Canada
Keywords Cerebral blood flow . Cerebral metabolism . Delayed cerebral ischemia . Diagnosis . Subarachnoid haemorrhage . Vasospasm Abbreviations 99 mTc-HMPAO ACA AJDO2 BA BOLD MRI CBF CBV CMRO2 CT CTA CTP CV CVR DCI DSA DWI EEG GADPH GCS HSP7C ICA LI MCA MFV MRA MRI
Technetium 99 m coupled to hexamethylpropyleneamine oxime Anterior cerebral artery Arterio-venous difference of O2 Basilar artery Blood oxygen level-dependent magnetic resonance imaging Cerebral blood flow Cerebral blood volume Cerebral metabolic rate of oxygen Computed tomography Computed tomographic angiography Computed tomographic perfusion Cerebral vasospasm Cerebral vascular reserve Delayed cerebral ischemia Digital subtraction angiography Diffusion weighted image Electroencephalography Glyceraldehyde-3-phosphate dehydrogenase Glasgow Coma Score Heat-Shock Cognate 7 Internal carotid artery Lindegaard index Middle cerebral artery Mean flow velocity Magnetic resonance angiography Magnetic resonance imaging
Neurosurg Rev
MTT NIH-SS NIRS OEF PCA PCO2 PET PI PO2 PWI RI ROI SAH SJO2 SPECT TCD TOF VA WFNS
Mean transit time National Institute of Health Stroke scale Near infrared spectography Oxygen extraction fraction Posterior cerebral artery Partial CO2 pressure Positron emission tomography Pulsatility index Partial oxygen pressure Perfusion-weighted magnetic resonance imaging Resistance index Region of interest Subarachnoidal haemorrhage Jugular venous oxygen saturation Single photon emission computed tomography Transcranial Doppler Time of flight Vertebral artery World Federation of Neurological Surgeons grading scale
Introduction Intracranial aneurysms represent a medical challenge: Progress in the understanding of their pathophysiology [56] might improve future diagnosis, rupture prevention and treatment strategies. For ruptured aneurysms, subarachnoid haemorrhage (SAH) still has a significant immediate mortality rate. Acute treatment aims at prevention of rebleeding and at management of intracranial hypertension. Ischemia is another serious threat for these patients. Whereas its occurrence has been demonstrated in the ultra early phase after bleeding [55], its prevention represents a main issue not only during aneurysm treatment [8, 92] but also in the weeks following SAH. Both cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) have to be prevented, carefully monitored and eventually treated [75]. Indeed, since primary brain damage and acute circulatory impairments have a determining role on the evolution towards DCI, very accurate observation and detection of any sign of brain sufferance are pivotal keys for limiting unfavourable consequences. The term ‘acute brain injury’ includes all damages to the brain within the first 3 days: Blood clot, increased ICP and acute insufficiency of autoregulation all contribute to flow impairments which lead in the following days to spreading electrical dysfunctions of neurons that cannot be rebalanced due to insufficient metabolic supply, also known as cortical spreading depression [36]. Furthermore,
extravasated blood together with acutely damaged and metabolically impaired tissues triggers inflammation. Impaired and damaged endothelium may alter the blood brain barrier and also favour the formation of microthrombi that further aggravate microcirculatory conditions (revised in [30, 36, 91]). CV has a multifactorial origin and is a consequence of a complex inflammatory process caused mainly by oxidized haemoglobin degradation products [51]. It occurs generally between days 3 and 14 after aneurysm rupture and is a major cause of delayed clinical deterioration. CV is a dynamic phenomenon with several stages: day 0 (triggering event: SAH), preliminary phase (days 1–3), initial vasospasm (days 3–4), peak (days 6–8), initial resolution of the vasospasm (days 10–14) and end of the spasm (day 21) [10, 11, 94, 138]. While subclinical arterial narrowing is extremely frequent after SAH, CV becomes symptomatic only in about 30 % of patients [108, 51]. Diagnosis of CV is not standardized and neither are the exams to assess related hypoperfusion and ischemia [121]. In a deteriorating patient, clinical diagnosis of CV should be considered after other causes such as hydrocephalus, infection, hypotension and hyponatremia are ruled out [80, 81]. Following acute SAH, brain ischemia is commonly attributed to CV, although it can be secondary to different causes [132]. Actually, in about one third of patients with ischemia, there is no evidence of CV in the corresponding vessel [108], indicating that microcirculation disorders sometimes are more relevant than large vessel vasospasm. The following review deals with monitoring and detection of perfusion alterations once basic parameters (temperature, oxygen saturation, electrolyte balance, etc.) are under proper control and intracranial hypertension, hydrocephalus and inflammatory brain oedema have been addressed. Different causes of clinical deterioration due to vascular impairment should be managed accordingly [15]; for instance, an increase of systemic pressure may not be beneficial during a compromised autoregulation [61, 67] but may be beneficial in true CV. A safe, fast and cost-effective diagnosis of these vascular alterations in the clinical practice may contribute to a better outcome.
General concepts Vascular alterations can involve several levels: morphological alterations of the arteries, abnormal perfusion of the brain as well as metabolic, neurophysiological effects and clinical manifestations. Clinical monitoring Close clinical monitoring has been systematically applied to SAH patients in the pre-CT era and is still of great importance.
Neurosurg Rev
As stated above, other causes for clinical deterioration have to be always ruled out: aneurysm rebleeding, hydrocephalus, electrolyte imbalance, hypoxia, seizures, cardiopulmonary dysfunction and/or infection. CV symptoms include exacerbating headache, neck stiffness, insidious onset of confusion, disorientation or drowsiness and focal deficits, which are often fluctuating [80, 81]. The proper choice of clinical grading scales for SAH patients is not trivial, and this issue has been critically revised a few years ago (see [112]). We here briefly mention only those scales commonly used to monitor patients clinically over time, such as the Glasgow Coma Scale (GCS). On the contrary, we do not discuss scales used for prognostic purposes for patients at admission only such as the Hunt Hess Scale and the World Federation of Neurological Surgeons grading scale (WFNS) scale. The most widely used scale, the GCS, is divided into 12 grades obtained by considering three axes: eye opening, verbal response and best motor response, whereas a clinical worsening is defined as a decrease in a minimum of two scores [128]: It was initially developed as a simple tool to grade consciousness in brain trauma in order to overpass the interobserver variability of neurological assessment. Actually, for SAH, this scale used initially to evaluate patients at presentation for prognostic purposes and has been used as well to follow them clinically. However, some limits have to be taken into account: The scale considers the verbal response (not possible in intubated patients), and further, the scale scores the ‘best’ motor response, thus failing to detect a side deficit. On this latter purpose, the GCS scale for SAH patients was integrated in the WFNS scale that acknowledges the presence of a motor deficit [35], but only in the initial setting. Since CV may result in ischemic sufferance, the use of the National Institute of Health Stroke Scale (NIH-SS) could as well be a useful clinical evaluation system. This scale grossly covers most vascular territories [5, 14]; it well correlates with infarct volumes at CT and MRI [14, 69, 88] and with other scales [69, 89], presenting a strong predictive value at 7 days and at 3 months for stroke patients [3, 69]. However, the NIHSS does not provide a detailed assessment of cranial nerves, nor does it confer enough weight to the brainstem or cerebellar ischemia [69]. Again, this scale is obviously impossible to use in intubated and/or sedated patients. Instrumental detection of cerebral vasospasm In order to attribute a clinical worsening to CV, an actual arterial narrowing has to be demonstrated. The golden standard for diagnosis of CV is cerebral catheter arteriography. However, recently, CT angiography (CTA) has been recognized as a valid, less invasive alternative [119]. A significant flow velocity increase at transcranial Doppler (TCD) allows an indirect detection of CV, given that the
velocity of blood flow in a vessel is inversely proportional to its diameter. Colour-coded duplex sonography may additionally permit assessment of the middle cerebral artery diameter [102]. Cerebral perfusion measurement SAH patients developing CV may present early alterations of cerebral perfusion [31, 59, 114]. There are several techniques available, including perfusion computed tomography (CTP), perfusion-weighted MRI (PWI), positron emission tomography (PET), Xenon computed tomography and single photon emission computed tomography (SPECT) [58]. These functional studies are aimed at differentiating ischemic tissues and penumbra, which represent a potentially salvageable tissue that should be targeted by proper therapies [56]. Thresholds for cerebral blood flow (CBF) are time dependent and vary with different specificity and sensitivity in terms of a probabilistic evolution following reperfusion, besides the fact that reported thresholds also vary between studies according to the imaging technique and the methods used for measurement: For an infarcted core, with a higher risk of necrosis, the upper threshold is about 12– 14 mL/100 g/min, and for ischemic penumbra CBF is comprised between 12–14 and 18–22 mL/100 g/min; hypoperfusion is defined for CBF above 22 mL/100 g/min and below 55 mL/100 g/min [56]. The latter is characterized by hypoperfusion without significant impairment of basal metabolism, membrane polarization and thus cellular integrity [8, 34, 60]. This condition entails several adaptive reactions as increased oxygen extraction [32] related to acidosis [13], anaerobic glucose metabolism, glutamate release, decreased neurotransmission [45] and protein synthesis inhibition. Arteriolar vasodilatation is one of the initial responses to hypoxia and hypoglycaemia [60]. In the presence of an intact autoregulation, vasodilatation increases cerebral blood volume (CBV) in relation to the degree of CV to maintain a normal CBF. Thus, cerebral autoregulation, when present, compensates the reduced perfusion pressure of a narrowed artery. Average CBV decreases with increasing degree of CV, while regional CBV increases in case of intact autoregulation and in the absence of exhausted hemodynamic reserve capacity. Angiographically visible arterial CV not always correlates with decreased CBF, as reduced CBF during CV exceeds the area of CV of the major proximal arteries. In contrast, a cerebral perfusion study is capable of evidencing microcirculatory CV as reduced CBF and CBV, even in the absence of angiographically visible narrowing, especially in territories not provided with collateral supplies as the basal ganglia [54] or watershed territories [137]. Mean transit time (MTT) is defined as the mean time required for blood to perfuse a region of tissue (MTT=CBV/ CBF; [125]) and is highly sensitive to hemodynamic
Neurosurg Rev
disturbance [59], providing the possibility to identify progressing CV (MTT greater than 20 % of the average) up to infarcted territories (MTT greater than 47 % of the average) [68]. Cerebral vascular reserve (CVR) can be assessed with a tolerance test with acetazolamide or CO2 [129, 148]. A decreased vascular response indicates a pre-existing parenchymal vasodilatation and loss of CVR [146].
1.3–2.4 % of patients, and in about 0.5 %, these deficits can be permanent [84, 140]. Due to its invasiveness and possible complications, it is important to limit angiography only to selected cases to confirm diagnosis and treat resistance to medical therapy (Tables 1, 2 and 3).
Transcranial Doppler Cerebral metabolism assessment Parenchymal pH, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), deoxyhaemoglobin and oxyhaemoglobin and other metabolites are markers of adequacy of cerebral perfusion. They can be measured with PET, SPECT, near-infrared spectroscopy (NIRS) and microdialysis. During early vasospasm, CBF decreases but CMRO2 is maintained by a compensatory increase of OEF [20]. As arterial constriction progresses, the extraction of oxygen decreases and CMRO2 is reduced as well [71, 118]. In severe CV, there is an uncoupling between flow and metabolism [134].
Diagnostic techniques for the study of cerebral blood flow alterations The following sections recall the basic principles of several diagnostic tools that have been used on a routine basis as well as for research purposes. Three tables complete the overview for the techniques we consider more suitable in clinical practice to detect and monitor vascular impairment in SAH patients. The first table analyses the capability of detecting flow and metabolic alterations of each selected technique and its timely application. The second table displays diagnostic criteria, sensitivity and specificity. Finally, the third table aims at summarizing their advantages, complications, limits and possible radiation dose. Cerebral digital subtraction angiography Two-dimensional digital subtraction angiography (2D-DSA) is the gold standard for diagnosing CV [28, 87]. It provides a dynamic idea of circulation time and allows the study of all vascular compartments (arterial, arteriolar, capillary, venular and venous). After selective catheterization of the vertebral and carotid arteries, different bidimensional projections of the contrast-enhanced vessel tree are obtained. Rotational angiography (RA) and three-dimensional DSA (3D-DSA) are not generally used for this purpose. Clinical complications of DSA are not much described in the medical literature, though awareness of their existence is widely shared. Neurological complications related to angiography occur in about
Transcranial Doppler utilizes low-frequency pulsed insonation (2 MHz) to measure blood flow velocity within proximal cerebral arteries, obtaining systolic and diastolic peaks and mean flow velocities (MFV). The latter is defined as (systolic+diastolic)/3+diastolic velocities. Further, TCD data to be considered include the pulsatility index ((systolic−diastolic)/mean flow velocity) [9] and the resistance index ((systolic−diastolic)/systolic flow velocity) [106], which correlate well with intracranial pressure and cerebral perfusion [29]. A pulsatility index or a resistance index higher than 0.8 and 0.57, respectively, seems to correlate with poorer outcomes [122, 126]. Acoustic cranial bone windows are defined as sites where the cranial bone is particularly thin as the temporal window or even absent, such as the orbital window. They are essential to perform TCD. The temporal window allows the study of the major supratentorial vessels. Middle and anterior cerebral arteries can be both examined in their more proximal and distal tracts at 36–60 and 60–70 mm depth, respectively [12], while the internal carotid artery siphon and the posterior cerebral artery at a depth of 58–65 and 55–75 mm, respectively [4]. The vertebral arteries and the basilar artery can be monitored as well through the occipital foramen posteriorly at a depth range of approximately 40–75 and 80–105 mm [4], but it is generally more difficult. The middle cerebral artery (MCA) is certainly the easiest artery to monitor with TCD and the most described. CV is diagnosed when the mean flow velocity is above normal thresholds (see Table 2). Ultrasonography alterations occur even 60 h before the onset of symptoms in nearly 70 % of patients [52, 98, 124, 135]. If mean flow velocity is increased, the Lindegaard Index (LI) improves the specificity of TCD for CV [105]. This index can be calculated dividing the highest MFV in a given intracranial vessel by the highest MFV in the ipsilateral extracranial carotid artery [86]. It helps discriminating between velocity increase related to increased blood flow (as in increased systolic pressure or in decreased distal resistances for lost CVR) and increased velocity related to arterial narrowing. In a study plotting cerebral blood flow velocities with arterial blood pressure in different timeframes after SAH, loss of CVR could be followed: CVR impairment may precede CV and CV can in turn also worsen CVR [78].
Neurosurg Rev Table 1
Selected diagnostic techniques for detection of flow and metabolic alterations: chronological characteristics and suggested timing Vasospasm
Parenchymal alterations
Continuous
Timing
Until day 14 (facultative) Baseline exam within 72 h after SAH Repeat daily up to day 14 [103, 136] (or until discharge) Clinical suspicion and/or positive TCD, or suspected false negative TCD
Proximal
Distal
Blood flow
Metabolic
NIRS TCD
No Yes
No No
No No
Yes No
Yes Possible
CTA CTP DSA
Yes No Yes
No No Yes
No Yes Yes
No No No
No No No
PWI
No
No
Yes
No
No
CVR can also be measured as flow changes detected under careful and brief CO2 modulation based on the fact that the effect
Table 2
NIRS Cortical oxygen saturation reduction TCD MCA
ACA PCA
CTP
ICA VA BA Arterial diameter VS of proximal segments VS of the distal segments (A2, A3 of ACA, M2, M3 of MCA, P2, P3 of PCA) CBF MTT
DSA
PWI
a
of moderate blood-gas alterations (hypercapnia and hypoxia) can be detected as flow velocity alterations on cerebral vessels [139].
Selected diagnostic techniques for detection of flow and metabolic alterations: diagnostic criteria, sensitivity and specificity Diagnostic criteria
CTA
Clinical suspicion and/or other positive tests for CV and insufficient response to medical treatment (see flow chart) If iodinated contrast medium counterindicated For DCI quantification
Overall Arterial diameter Parenchymal blush Flow dynamics a TTP DWI 50 %
Angiographic vasospasm
b
Clinical vasospasm
c
Unspecified vasospasm
Sensitivity
Specificity
Ref.
100 %a (very small sample size) 38–100 %a, 69 %b [43] 77 %b, 78a [43]
85.7 %a
[147]
70–100 %a, 84 %b [43] 87 %b, 85a [43]
13–35 %a 48–75 %a
65–68a 69–70 %a
[1, 16, 72, 79, 85, 90, 122] [1, 105], [2, 72], [39, 50] [90, 144] [90, 144]
MFV >130 cm/s MFV >80 cm/s MFV >95 cm/s Arterial diameter decrease
100 %c 27–43 %a 39–76.9 %a 80 %a 90–91 %a 82–90 %a
100 %c 88–100 %a 79–100 %a 73–93 %a 73–93 %a 50–92 %a
[16] [90, 123] [90, 123] [49] [49, 119] [49, 119]
Decreased, but no standards [49], e.g. 6.4 s [141]
83 %a
95 %a
[141]
92 %a
81 %a
[141]
3.9–6.4 % MFV >120 cm/s LI >3 MFV increase 25–35 cm/s/day MFV increase 50 cm/s/day MFV >130 cm/s MFV >110 cm/s
Slow and poor flow might indicate also brain edemaa
93 %a [49] 74 %a 100 % 84 % (3D volume [74] (3D volume rendering DSA) rendering DSA)
endovascular treatment of VS if at N.A. MR: TTP delay >2 s and DWI decrease
REVIEW
Diagnosis of cerebral vasospasm and risk of delayed cerebral ischemia related to aneurysmal subarachnoid haemorrhage: an overview of available tools Susanna Bacigaluppi & Gianluigi Zona & Francesca Secci & Gianantonio Spena & Nicola Mavilio & Giulia Brusa & Ronit Agid & Timo Krings & Gianandrea Ottonello & Marco Fontanella
Received: 25 May 2014 / Accepted: 16 November 2014 # Springer-Verlag Berlin Heidelberg 2015
Abstract In the first weeks following aneurysmal subarachnoid haemorrhage, cerebrovascular alterations may impact the outcome significantly. Diagnosis of cerebral vasospasm and detection of alterations at risk of delayed cerebral ischemia are key targets to be monitored in the post-acute phase. Available tools include clinical monitoring, as well as studies that can detect possible arterial narrowing, alterations of perfusion, metabolism and neurophysiology. Each technique is able to investigate possible vascular impairment and has different advantages and limits. All available techniques have been described. Among these, the most practical have been selected and compared for their peculiar characteristics. Based on this analysis, a flowchart to monitor these patients is finally proposed.
S. Bacigaluppi (*) : G. Zona : F. Secci Department of Neurosurgery, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy e-mail: [email protected] G. Spena : M. Fontanella Department of Neurosurgery, Spedali Civili di Brescia, Università di Brescia, Brescia, Italy N. Mavilio Department of Neuroradiology, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy G. Brusa : G. Ottonello Department of Neurology and Neurophysiology, IRCCS Azienda Ospedaliero Universitaria San Martino-IST, Genova, Italy R. Agid : T. Krings Department of Neuroradiology, Toronto Western Hospital, University Health Network Toronto, Toronto, ON, Canada
Keywords Cerebral blood flow . Cerebral metabolism . Delayed cerebral ischemia . Diagnosis . Subarachnoid haemorrhage . Vasospasm Abbreviations 99 mTc-HMPAO ACA AJDO2 BA BOLD MRI CBF CBV CMRO2 CT CTA CTP CV CVR DCI DSA DWI EEG GADPH GCS HSP7C ICA LI MCA MFV MRA MRI
Technetium 99 m coupled to hexamethylpropyleneamine oxime Anterior cerebral artery Arterio-venous difference of O2 Basilar artery Blood oxygen level-dependent magnetic resonance imaging Cerebral blood flow Cerebral blood volume Cerebral metabolic rate of oxygen Computed tomography Computed tomographic angiography Computed tomographic perfusion Cerebral vasospasm Cerebral vascular reserve Delayed cerebral ischemia Digital subtraction angiography Diffusion weighted image Electroencephalography Glyceraldehyde-3-phosphate dehydrogenase Glasgow Coma Score Heat-Shock Cognate 7 Internal carotid artery Lindegaard index Middle cerebral artery Mean flow velocity Magnetic resonance angiography Magnetic resonance imaging
Neurosurg Rev
MTT NIH-SS NIRS OEF PCA PCO2 PET PI PO2 PWI RI ROI SAH SJO2 SPECT TCD TOF VA WFNS
Mean transit time National Institute of Health Stroke scale Near infrared spectography Oxygen extraction fraction Posterior cerebral artery Partial CO2 pressure Positron emission tomography Pulsatility index Partial oxygen pressure Perfusion-weighted magnetic resonance imaging Resistance index Region of interest Subarachnoidal haemorrhage Jugular venous oxygen saturation Single photon emission computed tomography Transcranial Doppler Time of flight Vertebral artery World Federation of Neurological Surgeons grading scale
Introduction Intracranial aneurysms represent a medical challenge: Progress in the understanding of their pathophysiology [56] might improve future diagnosis, rupture prevention and treatment strategies. For ruptured aneurysms, subarachnoid haemorrhage (SAH) still has a significant immediate mortality rate. Acute treatment aims at prevention of rebleeding and at management of intracranial hypertension. Ischemia is another serious threat for these patients. Whereas its occurrence has been demonstrated in the ultra early phase after bleeding [55], its prevention represents a main issue not only during aneurysm treatment [8, 92] but also in the weeks following SAH. Both cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) have to be prevented, carefully monitored and eventually treated [75]. Indeed, since primary brain damage and acute circulatory impairments have a determining role on the evolution towards DCI, very accurate observation and detection of any sign of brain sufferance are pivotal keys for limiting unfavourable consequences. The term ‘acute brain injury’ includes all damages to the brain within the first 3 days: Blood clot, increased ICP and acute insufficiency of autoregulation all contribute to flow impairments which lead in the following days to spreading electrical dysfunctions of neurons that cannot be rebalanced due to insufficient metabolic supply, also known as cortical spreading depression [36]. Furthermore,
extravasated blood together with acutely damaged and metabolically impaired tissues triggers inflammation. Impaired and damaged endothelium may alter the blood brain barrier and also favour the formation of microthrombi that further aggravate microcirculatory conditions (revised in [30, 36, 91]). CV has a multifactorial origin and is a consequence of a complex inflammatory process caused mainly by oxidized haemoglobin degradation products [51]. It occurs generally between days 3 and 14 after aneurysm rupture and is a major cause of delayed clinical deterioration. CV is a dynamic phenomenon with several stages: day 0 (triggering event: SAH), preliminary phase (days 1–3), initial vasospasm (days 3–4), peak (days 6–8), initial resolution of the vasospasm (days 10–14) and end of the spasm (day 21) [10, 11, 94, 138]. While subclinical arterial narrowing is extremely frequent after SAH, CV becomes symptomatic only in about 30 % of patients [108, 51]. Diagnosis of CV is not standardized and neither are the exams to assess related hypoperfusion and ischemia [121]. In a deteriorating patient, clinical diagnosis of CV should be considered after other causes such as hydrocephalus, infection, hypotension and hyponatremia are ruled out [80, 81]. Following acute SAH, brain ischemia is commonly attributed to CV, although it can be secondary to different causes [132]. Actually, in about one third of patients with ischemia, there is no evidence of CV in the corresponding vessel [108], indicating that microcirculation disorders sometimes are more relevant than large vessel vasospasm. The following review deals with monitoring and detection of perfusion alterations once basic parameters (temperature, oxygen saturation, electrolyte balance, etc.) are under proper control and intracranial hypertension, hydrocephalus and inflammatory brain oedema have been addressed. Different causes of clinical deterioration due to vascular impairment should be managed accordingly [15]; for instance, an increase of systemic pressure may not be beneficial during a compromised autoregulation [61, 67] but may be beneficial in true CV. A safe, fast and cost-effective diagnosis of these vascular alterations in the clinical practice may contribute to a better outcome.
General concepts Vascular alterations can involve several levels: morphological alterations of the arteries, abnormal perfusion of the brain as well as metabolic, neurophysiological effects and clinical manifestations. Clinical monitoring Close clinical monitoring has been systematically applied to SAH patients in the pre-CT era and is still of great importance.
Neurosurg Rev
As stated above, other causes for clinical deterioration have to be always ruled out: aneurysm rebleeding, hydrocephalus, electrolyte imbalance, hypoxia, seizures, cardiopulmonary dysfunction and/or infection. CV symptoms include exacerbating headache, neck stiffness, insidious onset of confusion, disorientation or drowsiness and focal deficits, which are often fluctuating [80, 81]. The proper choice of clinical grading scales for SAH patients is not trivial, and this issue has been critically revised a few years ago (see [112]). We here briefly mention only those scales commonly used to monitor patients clinically over time, such as the Glasgow Coma Scale (GCS). On the contrary, we do not discuss scales used for prognostic purposes for patients at admission only such as the Hunt Hess Scale and the World Federation of Neurological Surgeons grading scale (WFNS) scale. The most widely used scale, the GCS, is divided into 12 grades obtained by considering three axes: eye opening, verbal response and best motor response, whereas a clinical worsening is defined as a decrease in a minimum of two scores [128]: It was initially developed as a simple tool to grade consciousness in brain trauma in order to overpass the interobserver variability of neurological assessment. Actually, for SAH, this scale used initially to evaluate patients at presentation for prognostic purposes and has been used as well to follow them clinically. However, some limits have to be taken into account: The scale considers the verbal response (not possible in intubated patients), and further, the scale scores the ‘best’ motor response, thus failing to detect a side deficit. On this latter purpose, the GCS scale for SAH patients was integrated in the WFNS scale that acknowledges the presence of a motor deficit [35], but only in the initial setting. Since CV may result in ischemic sufferance, the use of the National Institute of Health Stroke Scale (NIH-SS) could as well be a useful clinical evaluation system. This scale grossly covers most vascular territories [5, 14]; it well correlates with infarct volumes at CT and MRI [14, 69, 88] and with other scales [69, 89], presenting a strong predictive value at 7 days and at 3 months for stroke patients [3, 69]. However, the NIHSS does not provide a detailed assessment of cranial nerves, nor does it confer enough weight to the brainstem or cerebellar ischemia [69]. Again, this scale is obviously impossible to use in intubated and/or sedated patients. Instrumental detection of cerebral vasospasm In order to attribute a clinical worsening to CV, an actual arterial narrowing has to be demonstrated. The golden standard for diagnosis of CV is cerebral catheter arteriography. However, recently, CT angiography (CTA) has been recognized as a valid, less invasive alternative [119]. A significant flow velocity increase at transcranial Doppler (TCD) allows an indirect detection of CV, given that the
velocity of blood flow in a vessel is inversely proportional to its diameter. Colour-coded duplex sonography may additionally permit assessment of the middle cerebral artery diameter [102]. Cerebral perfusion measurement SAH patients developing CV may present early alterations of cerebral perfusion [31, 59, 114]. There are several techniques available, including perfusion computed tomography (CTP), perfusion-weighted MRI (PWI), positron emission tomography (PET), Xenon computed tomography and single photon emission computed tomography (SPECT) [58]. These functional studies are aimed at differentiating ischemic tissues and penumbra, which represent a potentially salvageable tissue that should be targeted by proper therapies [56]. Thresholds for cerebral blood flow (CBF) are time dependent and vary with different specificity and sensitivity in terms of a probabilistic evolution following reperfusion, besides the fact that reported thresholds also vary between studies according to the imaging technique and the methods used for measurement: For an infarcted core, with a higher risk of necrosis, the upper threshold is about 12– 14 mL/100 g/min, and for ischemic penumbra CBF is comprised between 12–14 and 18–22 mL/100 g/min; hypoperfusion is defined for CBF above 22 mL/100 g/min and below 55 mL/100 g/min [56]. The latter is characterized by hypoperfusion without significant impairment of basal metabolism, membrane polarization and thus cellular integrity [8, 34, 60]. This condition entails several adaptive reactions as increased oxygen extraction [32] related to acidosis [13], anaerobic glucose metabolism, glutamate release, decreased neurotransmission [45] and protein synthesis inhibition. Arteriolar vasodilatation is one of the initial responses to hypoxia and hypoglycaemia [60]. In the presence of an intact autoregulation, vasodilatation increases cerebral blood volume (CBV) in relation to the degree of CV to maintain a normal CBF. Thus, cerebral autoregulation, when present, compensates the reduced perfusion pressure of a narrowed artery. Average CBV decreases with increasing degree of CV, while regional CBV increases in case of intact autoregulation and in the absence of exhausted hemodynamic reserve capacity. Angiographically visible arterial CV not always correlates with decreased CBF, as reduced CBF during CV exceeds the area of CV of the major proximal arteries. In contrast, a cerebral perfusion study is capable of evidencing microcirculatory CV as reduced CBF and CBV, even in the absence of angiographically visible narrowing, especially in territories not provided with collateral supplies as the basal ganglia [54] or watershed territories [137]. Mean transit time (MTT) is defined as the mean time required for blood to perfuse a region of tissue (MTT=CBV/ CBF; [125]) and is highly sensitive to hemodynamic
Neurosurg Rev
disturbance [59], providing the possibility to identify progressing CV (MTT greater than 20 % of the average) up to infarcted territories (MTT greater than 47 % of the average) [68]. Cerebral vascular reserve (CVR) can be assessed with a tolerance test with acetazolamide or CO2 [129, 148]. A decreased vascular response indicates a pre-existing parenchymal vasodilatation and loss of CVR [146].
1.3–2.4 % of patients, and in about 0.5 %, these deficits can be permanent [84, 140]. Due to its invasiveness and possible complications, it is important to limit angiography only to selected cases to confirm diagnosis and treat resistance to medical therapy (Tables 1, 2 and 3).
Transcranial Doppler Cerebral metabolism assessment Parenchymal pH, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), deoxyhaemoglobin and oxyhaemoglobin and other metabolites are markers of adequacy of cerebral perfusion. They can be measured with PET, SPECT, near-infrared spectroscopy (NIRS) and microdialysis. During early vasospasm, CBF decreases but CMRO2 is maintained by a compensatory increase of OEF [20]. As arterial constriction progresses, the extraction of oxygen decreases and CMRO2 is reduced as well [71, 118]. In severe CV, there is an uncoupling between flow and metabolism [134].
Diagnostic techniques for the study of cerebral blood flow alterations The following sections recall the basic principles of several diagnostic tools that have been used on a routine basis as well as for research purposes. Three tables complete the overview for the techniques we consider more suitable in clinical practice to detect and monitor vascular impairment in SAH patients. The first table analyses the capability of detecting flow and metabolic alterations of each selected technique and its timely application. The second table displays diagnostic criteria, sensitivity and specificity. Finally, the third table aims at summarizing their advantages, complications, limits and possible radiation dose. Cerebral digital subtraction angiography Two-dimensional digital subtraction angiography (2D-DSA) is the gold standard for diagnosing CV [28, 87]. It provides a dynamic idea of circulation time and allows the study of all vascular compartments (arterial, arteriolar, capillary, venular and venous). After selective catheterization of the vertebral and carotid arteries, different bidimensional projections of the contrast-enhanced vessel tree are obtained. Rotational angiography (RA) and three-dimensional DSA (3D-DSA) are not generally used for this purpose. Clinical complications of DSA are not much described in the medical literature, though awareness of their existence is widely shared. Neurological complications related to angiography occur in about
Transcranial Doppler utilizes low-frequency pulsed insonation (2 MHz) to measure blood flow velocity within proximal cerebral arteries, obtaining systolic and diastolic peaks and mean flow velocities (MFV). The latter is defined as (systolic+diastolic)/3+diastolic velocities. Further, TCD data to be considered include the pulsatility index ((systolic−diastolic)/mean flow velocity) [9] and the resistance index ((systolic−diastolic)/systolic flow velocity) [106], which correlate well with intracranial pressure and cerebral perfusion [29]. A pulsatility index or a resistance index higher than 0.8 and 0.57, respectively, seems to correlate with poorer outcomes [122, 126]. Acoustic cranial bone windows are defined as sites where the cranial bone is particularly thin as the temporal window or even absent, such as the orbital window. They are essential to perform TCD. The temporal window allows the study of the major supratentorial vessels. Middle and anterior cerebral arteries can be both examined in their more proximal and distal tracts at 36–60 and 60–70 mm depth, respectively [12], while the internal carotid artery siphon and the posterior cerebral artery at a depth of 58–65 and 55–75 mm, respectively [4]. The vertebral arteries and the basilar artery can be monitored as well through the occipital foramen posteriorly at a depth range of approximately 40–75 and 80–105 mm [4], but it is generally more difficult. The middle cerebral artery (MCA) is certainly the easiest artery to monitor with TCD and the most described. CV is diagnosed when the mean flow velocity is above normal thresholds (see Table 2). Ultrasonography alterations occur even 60 h before the onset of symptoms in nearly 70 % of patients [52, 98, 124, 135]. If mean flow velocity is increased, the Lindegaard Index (LI) improves the specificity of TCD for CV [105]. This index can be calculated dividing the highest MFV in a given intracranial vessel by the highest MFV in the ipsilateral extracranial carotid artery [86]. It helps discriminating between velocity increase related to increased blood flow (as in increased systolic pressure or in decreased distal resistances for lost CVR) and increased velocity related to arterial narrowing. In a study plotting cerebral blood flow velocities with arterial blood pressure in different timeframes after SAH, loss of CVR could be followed: CVR impairment may precede CV and CV can in turn also worsen CVR [78].
Neurosurg Rev Table 1
Selected diagnostic techniques for detection of flow and metabolic alterations: chronological characteristics and suggested timing Vasospasm
Parenchymal alterations
Continuous
Timing
Until day 14 (facultative) Baseline exam within 72 h after SAH Repeat daily up to day 14 [103, 136] (or until discharge) Clinical suspicion and/or positive TCD, or suspected false negative TCD
Proximal
Distal
Blood flow
Metabolic
NIRS TCD
No Yes
No No
No No
Yes No
Yes Possible
CTA CTP DSA
Yes No Yes
No No Yes
No Yes Yes
No No No
No No No
PWI
No
No
Yes
No
No
CVR can also be measured as flow changes detected under careful and brief CO2 modulation based on the fact that the effect
Table 2
NIRS Cortical oxygen saturation reduction TCD MCA
ACA PCA
CTP
ICA VA BA Arterial diameter VS of proximal segments VS of the distal segments (A2, A3 of ACA, M2, M3 of MCA, P2, P3 of PCA) CBF MTT
DSA
PWI
a
of moderate blood-gas alterations (hypercapnia and hypoxia) can be detected as flow velocity alterations on cerebral vessels [139].
Selected diagnostic techniques for detection of flow and metabolic alterations: diagnostic criteria, sensitivity and specificity Diagnostic criteria
CTA
Clinical suspicion and/or other positive tests for CV and insufficient response to medical treatment (see flow chart) If iodinated contrast medium counterindicated For DCI quantification
Overall Arterial diameter Parenchymal blush Flow dynamics a TTP DWI 50 %
Angiographic vasospasm
b
Clinical vasospasm
c
Unspecified vasospasm
Sensitivity
Specificity
Ref.
100 %a (very small sample size) 38–100 %a, 69 %b [43] 77 %b, 78a [43]
85.7 %a
[147]
70–100 %a, 84 %b [43] 87 %b, 85a [43]
13–35 %a 48–75 %a
65–68a 69–70 %a
[1, 16, 72, 79, 85, 90, 122] [1, 105], [2, 72], [39, 50] [90, 144] [90, 144]
MFV >130 cm/s MFV >80 cm/s MFV >95 cm/s Arterial diameter decrease
100 %c 27–43 %a 39–76.9 %a 80 %a 90–91 %a 82–90 %a
100 %c 88–100 %a 79–100 %a 73–93 %a 73–93 %a 50–92 %a
[16] [90, 123] [90, 123] [49] [49, 119] [49, 119]
Decreased, but no standards [49], e.g. 6.4 s [141]
83 %a
95 %a
[141]
92 %a
81 %a
[141]
3.9–6.4 % MFV >120 cm/s LI >3 MFV increase 25–35 cm/s/day MFV increase 50 cm/s/day MFV >130 cm/s MFV >110 cm/s
Slow and poor flow might indicate also brain edemaa
93 %a [49] 74 %a 100 % 84 % (3D volume [74] (3D volume rendering DSA) rendering DSA)
endovascular treatment of VS if at N.A. MR: TTP delay >2 s and DWI decrease
