Journal of Clinical Neuroscience xxx (2018) xxx–xxx
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Clinical study
Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage Cecilia Lindgren a,⇑, Lars-Owe Koskinen b, Rashida Ssozi a, Silvana Naredi c a
Dept of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Umeå University, Umeå, Sweden Department of Pharmacology and Clinical Neuroscience, Division of Neurosurgery, Umeå University, Sweden c Dept of Anaesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden b
a r t i c l e
i n f o
Article history: Received 8 May 2018 Accepted 5 October 2018 Available online xxxx Keywords: Cerebral aneurysms Cerebrovascular circulation Endovascular procedures Critical care outcomes Lactic acid Cerebrospinal fluid
a b s t r a c t Background: Increased lactate in cerebrospinal fluid (CSF) has been regarded as a marker for cerebral ischemia and damage in the central nervous system. The aim of this study was to evaluate if CSFlactate was associated with; impaired cerebral circulation, outcome, sex, age, clinical condition or treatment after subarachnoid haemorrhage (SAH). Methods: This study consists of 33 patients (22 females, 11 males) with aneurysmal SAH treated at Umeå university hospital 2008–2009. Samples were obtained from external ventricular catheters 0–240 h after SAH. Normal CFS-lactate was defined as 1.2–2–1 mmol/L. Hunt & Hess scale assessed clinical condition. Impaired cerebral circulation was evaluated by clinical examination, transcranial doppler, CT-scan, and cerebral angiography. Glasgow outcome scale (GOS) evaluated outcome. Results: Seventy-nine CSF-lactate samples were analysed. CSF-lactate >2.1 mmol/L was found in 25/33 (76%) patients and in 50/79 (63%) samples. No difference in CSF-lactate levels was found over time. No association was found between patients with CSF-lactate >2.1 mmol/L and; sex, severity of clinical condition, impaired cerebral circulation or outcome. CSF-lactate >2.1 mmol/L was more common in patients 61 years of age (p = 0.04) and in patients treated with endovascular coiling compared to surgical clipping (p = 0.0001). Conclusion: In patients with SAH, no association was found between increased CSF-lactate (>2.1 mmol/L) and severe clinical condition, impaired cerebral circulation or unfavourable outcome. Endovascular coiling and age 61 years was associated with CSF-lactate above >2.1 mmol/L. Ó 2018 Published by Elsevier Ltd.
1. Introduction Subarachnoid haemorrhage (SAH) is in the majority of all cases (80%), caused by the rupture of an intracranial arterial aneurysm that give rise to extravasation of blood into the subarachnoid space and a transitory rise of intracranial pressure (ICP) [1,2]. The breakdown of blood and the early brain injury caused by the sudden elevation of ICP starts a cascade of reactions that can contribute to disturbed cerebral circulation, cerebral ischemia, delayed ischemic deficit and unfavourable outcome [3–5]. Increased level of lactate in cerebrospinal fluid (CSF), as an end product of anaerobic glycolysis, has been reported to correlate with poor neurological outcome, vasospasm, and as a predictor for hydrocephalus after SAH [6–9].
⇑ Corresponding author at: Dept. of Surgical and Perioperative Sciences, Institution of Anaesthesiology and Intensive Care, Umeå University, 901 85 Umeå, Sweden. E-mail address:
[email protected] (C. Lindgren).
The primary aim of this study was to evaluate if increased CSFlactate in the acute phase after SAH was associated with signs of impaired cerebral circulation or outcome. A secondary aim was to investigate if CSF-lactate levels differed between sex, age, severity of the clinical condition, or treatment of the aneurysm.
2. Patients and methods This investigation is part of a study designed for analysis of the degree of systemic inflammation in patients with SAH due to a ruptured cerebral aneurysm [10]. Included patients were admitted to the Neurosurgical department at Umeå University hospital Sweden, March 2008 until September 2009. Originally 56 patients were included and thus eligible for inclusion in this study, 39/56 (70%) patients obtained external ventricular drainage (EVD), and in 34/56 (61%) patients CSF lactate was analysed. One patient, with a positive bacterial culture in CSF was excluded. This study thus
https://doi.org/10.1016/j.jocn.2018.10.025 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Lindgren C et al. Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.025
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C. Lindgren et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
consists of 33 patients, 22 females and 11 males. Flow chart of the study population is given in Fig. 1. Inclusion criteria were; SAH due to a ruptured cerebral aneurysm, verified by digital subtraction angiography (DSA) or CT angiography (CTA), age 18 years, and arrival at the university hospital within 48 h (h) after the SAH. Exclusion criteria were; pregnant or lactating women and patients with medical history of previous SAH or recent intracranial surgery. Patients were treated according to a local protocol, in its main parts coherent with the Neurocritical Care Society’s Multidisciplinary Consensus Conference and American Heart Association (AHA) guidelines [11,12]. Normovolemia was maintained and cerebral perfusion pressure was kept 70 mmHg. Dobutamine was the first choice for cardiovascular support and vasoconstrictors (norepinephrine, phenylephrine) were mainly used during anaesthesia and postoperatively. Patients in need of mechanical ventilation were normoventilated (PaCO2 4.5–5.5 kPa), and PaO2 was kept >12 kPa. For prevention of delayed ischemic neurological deficit, nimodipine (NimotopÒ, Bayer) 0.2 mg/mL was administered intravenously. The cerebral aneurysms were usually secured within 24 h after admittance to the university hospital, by endovascular coiling or surgical clipping. If hydrocephalus was present, an EVD was inserted. The study protocol extended from the first symptoms of SAH that brought the patient to hospital (SAH0), to 240 h after SAH0. The severity of the neurological condition due to the SAH was scored according to the Hunt and Hess (H&H) scale, extending from 1 (asymptomatic/minimal headache, slight nuchal rigidity), to 5
(deep coma, moribund appearance) [13]. Severe clinical condition was defined as H&H 3–5 and a less severe condition as H&H 1–2. The amount of blood on the first CT scan was evaluated by the Fisher scale, extending from 1 (no haemorrhage evident), to 4 (SAH of any thickness with intraventricular or parenchymal haemorrhage) [14]. The Glasgow outcome scale (GOS) was used for evaluation of outcome approximately one year after the SAH [15]. GOS 4–5 was considered as favourable outcome and GOS 1–3 as unfavourable outcome. CSF samples were routinely obtained twice a week, and on suspicion of infection. Each CSF-lactate sample obtained was distributed into 24 h intervals after SAH0. CFS-lactate was measured using the Vitros 5.1 FS Bio-chemistry analyser by microslides and photometry (wavelength 540 nm) (Ortho Clinical Diagnostics, Rochester, NY, USA) [16]. The reference level of CSF-lactate, defined by our accredited University Hospital laboratory, was 1.2–2.1 mmol/L [17]. All Computer Tomography (CT), CTA, and DSA images were reevaluated by a consultant in neuroradiology, blinded for any laboratory values. Impaired cerebral circulation was defined as occurrence of any of the following: New focal neurological symptoms, worsening of existing neurological symptoms or a reduction of more than two points on the Glasgow coma scale (GCS), lasting for >1 h, without other obvious explanation [18] Transcranial doppler (TCD) detected mean flow velocity >120 cm/s in the middle cerebral artery [19] CT-verified suspected ischemic lesions after exclusion of procedure-related infarctions [18,20] Angiographic vasospasm detected with digital subtraction angiography (DSA) or CT angiography [20] 3. Ethics The Regional Ethical Review Board in Umeå, Sweden approved this study (07–186 M). Delayed informed consent was used for patients unable to approve inclusion in the study at admission. The protocol adheres to the principles of World Medical Association Declaration of Helsinki [21]. 4. Statistics The Kruskal-Wallis test was used to compare lactate values between groups. Fisher’s exact test was used for comparison of CSF-lactate and different clinical parameters. Two age groups were compared; the groups were defined according to under/over median age (61 years). A p < 0.05 was considered statistically significant. 5. Results
Fig. 1. Flow chart of the study population.
33 patients with a median age of 61 (26–77) years form the study population. Basic characteristic is given in Table 1. A total of 79 CSF-lactate samples were obtained and analysed. In three patients; four samples were obtained, in 13 patients; three samples, in 11 patients; two samples and in 6 patients; one sample. CSF-lactate above the upper reference limit of >2.1 mmol/L was found at any time during the study period in 26/33 (79%) patients and in 52/79 (66%) samples. Peak mean CSF-lactate (one value per patient) was 3.4 ± 1.4 mmol/L. There was no significant difference in CSF-lactate levels over time (Fig. 2).
Please cite this article in press as: Lindgren C et al. Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.025
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Fig. 2. Lactate levels in cerebrospinal fluid, 0–240 hours after subarachnoid haemorrhage.
Table 1 Basic characteristics of the study population.
Table 2 Association between different parameters and cerebrospinal fluid lactate 2.1 mmol/ L or >2.1 mmol/L.
Sex Female/Male n (%)
22/11 (67/33)
Parameters
Age (years) median (range)
61 (26–77)
Clinical neurological assessment1 median (range) H&H2
3 (1–5)
CSF-Lactate 2.1 mmol/L
CSF-Lactate >2.1 mmol/L
Significance
Gender M/F (n)
2/6
9/16
ns
Age1 (years) <61/61
7/1
10/15
0.04
H&H2 1-2/3-5
3/7
5/18
ns
0/7
Assessment of SAH median (range) Fisher grade3
4 (4)
Medical history4 n (%) Smoker5 Hypertension6 Respiratory diseases7 Family history of SAH8 Ischemic stroke9 Hyperlipedemia6 Ischemic heart disease10 Diabetes mellitus Renal disease9
Intervention3 Coil/clip
20/4
0.0001
25/33(76) 11/33 (33) 6/33 (18) 5/33 (15) 2/33 (6) 2/33 (6) 1/33 (3) 0/33 (0) 0/33 (0)
Impaired cerebral circulation4 No/Yes 1/7
12/13
ns
GOS5 GOS 1-3/GOS 4-5
6/19
ns
Aneurysm location11 n (%) Anterior cerebral and communicating artery Middle cerebral artery Posterior communicating artery Basilar artery tip/trunk Internal carotid artery
14/33 (42) 8/33 (24) 5/33 (15) 3/33 (9) 3/33 (9)
Neurosurgical intervention n (%) Endovascular coiling Surgical clipping No intervention
20/33 (61) 11/33 (33) 2/33 (6)
n = number, SAH = subarachnoid haemorrhage. 1 All scoring was obtained from the first clinical examination performed by a physician, before eventual sedation and intubation. 2 Hunt & Hess: 1 asymptomatic/minimal headache, slight nuchal rigidity; 2 moderate/severe headache, nuchal rigidity, no neurological deficit other than cranial nerve palsy; 3 drowsiness, confusion or mild focal deficit; 4 stupor, moderate to severe hemiparesis; 5 deep coma, moribund appearance. 3 Grading scale for the appearance of subarachnoid haemorrhage (SAH) on the primary CT scan from 1 to 4; 1 = no haemorrhage evident, 2 = SAH < 1 mm thick, 3 = SAH > 1 mm thick, 4 = SAH of any thickness with intraventricular or parenchymal haemorrhage. 4 One patient can have more than one medical history. 5 Known current or previous smoker. 6 Pharmacologically treated. 7 Asthma and chronic obstructive lung disease, pharmacologically treated with inhalation drugs. 8 First-degree relative with SAH. 9 From medical record confirmed disease. 10 Previous acute myocardial infarction. 11 Lokalization of the probable source of bleeding.
3/5
1
Median age 60.5 years. H&H = Hunt &Hess; 1 asymptomatic/minimal headache, slight nuchal rigidity; 2 moderate/severe headache, nuchal rigidity, no neurological deficit other than cranial nerve palsy; 3 drowsiness, confusion or mild focal deficit; 4 stupor, moderate to severe hemiparesis; 5 deep coma, moribund appearance. 3 Neurosurgical Intervention: Coil = endovascular treatment with coil, Clip = Surgical treatment with clipping (two patients no intervention). 4 Impaired cerebral circulation: Clinical deterioration or a decrease of >2 points on the GCS lasting >1 h; not explained by other causes, Transcranial Doppler flow >120 cm/s in MCA, CT-verified suspected ischemia, Angiographic vasospasm detected with CT angiography or digital subtraction angiography. 5 GOS = Glasgow outcome scale: Favourable outcome 4–5, Unfavourable outcome 1–3. 2
There was no association between patients with CSF-lactate >2.1 mmol/L at any time during the study period and a more severe neurological condition (H&H 3–5), impaired cerebral circulation or unfavourable outcome (GOS 1–3) (Table 2). Patients 61 years old were significantly more likely to have a CSF-lactate >2.1 mmol/L (p < 0.04) compared to patients <61 years (Table 2). The difference in age remained when the samples were divided according to early samples (0–120 h) after SAH0, p = 0.03 and late samples (121– 240 h) after SAH0, p = 0.03. All 20 patients treated with endovascular coiling had a CSFlactate >2.1 mmol/L at any time, 0–240 h after SAH, compared to patients treated with surgical clipping where 6/11 (55%), had a CSF-lactate >2.1 mmol/L at any time, 0–240 h after SAH (p < 0.0001). The difference between patients treated with endovascular coiling or surgical clipping did not remain when
Please cite this article in press as: Lindgren C et al. Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.025
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C. Lindgren et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
the samples were divided according to early samples (0–120 h) after SAH0, and late samples after SAH0, p = 0.5. No significant difference in age was found between patients treated with endovascular coiling (median 61.5 (35–77) years, compared to patients treated with surgical clipping median 53.5 (26–68) years. 6. Discussion In contrast to other published studies no associations between CSF-lactate and impaired cerebral circulation or outcome was found [7,8]. Only higher age and treatment with endovascular coiling was significantly associated with a CSF-lactate above the reference value of 2.1 mmol/L. Increased CSF-lactate has been reported as a marker of poor neurological outcome and a predictor for delayed cerebral ischemia and shunt dependent hydrocephalus in patients with SAH [6–9]. The initial SAH may cause a high intracranial pressure, ceased cerebral circulation, reduced oxygen delivery, global ischemia, anaerobic metabolism and increased CSF-lactate [22,23]. Degradation of red blood cells may also contribute to CSF-lactate accumulation [22]. Increased interstitial levels of CSF-lactate and pyruvate were found in SAH patients with global cerebral oedema in a microdialysis study [23]. Recent studies have indicated that elevated CSF-lactate could have positive effects in the injured brain, where lactate might constitute a major aerobic substrate for neurons [24–28]. However, this is under debate [29]. A study in TBI-patients found that a CSF-lactate increase was mainly found in non-ischemic patients [27]. These results may correspond to the findings in this study where no correlation between CSF-lactate and signs of impaired cerebral circulation or unfavourable outcome was detected. In the present study a statistically significant associations of CSF-lactate above the reference level was observed in patients older than the median age of 61 years and in patients treated with endovascular coiling as compared to patients treated with surgical clipping. That higher age can be associated with increased CSF-lactate has been previously reported, but even so, age is normally not considered in studies reporting CSF-lactate [30]. We have not, up to this date, found any published studies comparing CSF-lactate between different treatment modalities in SAH patients. The clinical importance of this finding needs further investigation. Conclusion: In SAH patients, no associations was found between CSF-lactate levels and impaired cerebral circulation or unfavourable outcome. Age 61 years of age and treatment with endovascular coiling was associated with a CSF-lactate above a reference level of >2.1 mmol/L in the acute phase after SAH. Competing interests The authors declare that they have no competing inter interests. Acknowledgements The study was supported by a grant from The Swedish Society of Medicine, The Faculty of Medicine at Umeå University, Kempe Foundation and The Stroke Foundation of Northern Sweden. References [1] Suarez JI. Diagnosis and management of subarachnoid hemorrhage. Continuum (Minneap Minn) 2015;21:1263–87. https://doi.org/10.12/ CON.0000000000000217.
[2] Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet 2017;389:655–66. https://doi.org/10.1016/S0140-6736(16)30668-7. Epub 2016 Sep 13. [3] Carr KR, Zuckerman SL, Mocco J. Inflammation, cerebral vasospasm, and evolving theories of delayed cerebral ischemia. Neurol Res Int 2013;2013:506584. [4] Naredi S, Lambert G, Friberg P, et al. Sympathetic activation and inflammatory response in patients with subarachnoid haemorrhage. Intensive Care Med 2006;32:1955–61. [5] Penn DL, Witte SR, Komotar RJ, Sander Connolly Jr E. Pathological mechanisms underlying aneurysmal subarachnoid haemorrhage and vasospasm. J Clin Neurosci 2015;22:1–5. https://doi.org/10.1016/j.jocn.2014.05.025. Epub Aug 10. [6] Cengiz SL, Ak A, Ustun ME, Karakose S. Lactate contents from cerebrospinal fluid in experimental subarachnoid hemorrhage, well correlate with vasospasm: ongoing and neurologic status. J Neurosurg Anesthesiol 2007;19:166–70. [7] Shimoda M, Yamada S, Yamamoto I, Tsugane R, Sato O. Time course of CSF lactate level in subarachnoid haemorrhage. Correlation with clinical grading and prognosis. Acta Neurochir (Wien) 1989;99:127–34. [8] Stein M, Schomacher J, Scharbrodt W, Preuss M, Oertel MF. Cerebrospinal fluid lactate concentration after withdrawal of metabolic suppressive therapy in subarachnoid hemorrhage. Acta Neurochir Suppl 2012;114(333–337). https:// doi.org/10.1007/978-3-7091-0956-4_64. [9] Wang KC, Tang SC, Lee JE, et al. Intrathecal lactate predicting hydrocephalus after aneurysmal subarachnoid hemorrhage. J Surg Res 2015;199:523–8. https://doi.org/10.1016/j.jss.2014.09.022. Epub Sep 28. [10] Lindgren C, Hultin M, Koskinen LO, Lindvall P, Borota L, Naredi S. ADMA levels and arginine/ADMA ratios reflect severity of disease and extent of inflammation after subarachnoid hemorrhage. Neurocrit Care 2014;21:91–101. https://doi.org/10.1007/s12028-013-9945-8. [11] Bederson JB, Connolly Jr ES, Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009;40:994–1025. https://doi.org/10.161/ STROKEAHA.108.191395. Epub 2009 Jan 22. [12] Diringer MN, Bleck TP, Claude Hemphill 3rd J, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care 2011;15:211–40. https://doi.org/ 10.1007/s12028-011-9605-9. [13] Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14–20. [14] Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6:1–9. [15] Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;1:480–4. [16] Johannes Aufenanger OS. Evaluation of the VITROS 5,1 FS analyzer in a large clinical laboratory: comparison of methods using different specimens and chemistry systems. J Lab Med 2009;33:22–32. [17] Zhang WM, Natowicz MR. Cerebrospinal fluid lactate and pyruvate concentrations and their ratio. Clin Biochem 2013;46:694–7. https://doi.org/ 10.1016/j.clinbiochem.2012.11.008. Epub Nov 27. [18] Vergouwen MD, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010;41:2391–5. https://doi.org/10.1161/ STROKEAHA.110.589275. Epub 2010 Aug 26. [19] Carrera E, Schmidt JM, Oddo M, et al. Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Neurosurgery 2009;65:316–23. https://doi.org/10.1227/01.NEU.0000349209.69973.88. discussion 23-4. [20] Wagner M, Steinbeis P, Guresir E, et al. Beyond delayed cerebral vasospasm: infarct patterns in patients with subarachnoid hemorrhage. Clin Neuroradiol 2013;23:87–95. https://doi.org/10.1007/s00062-012-0166-x. Epub 2012 Aug 23. [21] World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA 2013;310:2191–4. https:// doi.org/10.1001/jama.2013.281053. [22] Mori K, Nakajima K, Maeda M. Long-term monitoring of CSF lactate levels and lactate/pyruvate ratios following subarachnoid haemorrhage. Acta Neurochir (Wien) 1993;125:20–6. [23] Zetterling M, Hallberg L, Hillered L, Karlsson T, Enblad P, Ronne Engstrom E. Brain energy metabolism in patients with spontaneous subarachnoid hemorrhage and global cerebral edema. Neurosurgery 2010;66:1102–10. https://doi.org/10.227/01.NEU.0000370893.04586.73. [24] Gallagher CN, Carpenter KL, Grice P, et al. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain 2009;132:2839–49. https://doi.org/ 10.1093/brain/awp202. Epub 2009 Aug 20. [25] Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 2004;558:5–30. Epub 2004 May 6. [26] Oddo M, Levine JM, Frangos S, et al. Brain lactate metabolism in humans with subarachnoid hemorrhage. Stroke 2012;43:1418–21. https://doi.org/10.161/ STROKEAHA.111.648568. Epub 2012 Feb 16.
Please cite this article in press as: Lindgren C et al. Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.025
C. Lindgren et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx [27] Sala N, Suys T, Zerlauth JB, et al. Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury. J Cereb Blood Flow Metab 2013;33:1815–22. https://doi.org/10.038/ jcbfm.2013.142. Epub Aug 21. [28] Dienel GA. Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations. J Cereb Blood Flow Metab 2014;34:1736–48. https://doi.org/10.038/jcbfm.2014.153. Epub Sep 10.
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[29] Tang BL. Brain activity-induced neuronal glucose uptake/glycolysis: Is the lactate shuttle not required? Brain Res Bull 2018;2018(137):225–8. [30] Leen WG, Willemsen MA, Wevers RA, Verbeek MM. Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. PLoS One 2012;7:. https://doi.org/10.1371/journal.pone.0042745. Epub 2012 Aug 6e42745.
Please cite this article in press as: Lindgren C et al. Cerebrospinal fluid lactate and neurological outcome after subarachnoid haemorrhage. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.025