Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood Flow Following Surgery for Intracerebral Hemorrhage

Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood... Abstract BACKGROUND We hypothesized that reduced cerebral blood flow (CBF) and/or energy metabolic disturbances exist in the tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH). If present, such CBF and/or metabolic impairments may contribute to ongoing tissue injury and the modest clinical efficacy of ICH surgery. OBJECTIVE To conduct an observational study of CBF and the energy metabolic state in the perihemorrhagic zone (PHZ) tissue and in seemingly normal cortex (SNX) by microdialysis (MD) following surgical ICH evacuation. METHODS We evaluated 12 patients (median age 64; range 26-71 yr) for changes in CBF and energy metabolism following surgical ICH evacuation using Xenon-enhanced computed tomography (n = 10) or computed tomography perfusion (n = 2) for CBF and dual MD catheters, placed in the PHZ and the SNX at ICH surgery. RESULTS CBF was evaluated at a mean of 21 and 58 h postsurgery. In the hemisphere ipsilateral to the ICH, CBF improved between the investigations (36.6 ± 20 vs 40.6 ± 20 mL/100 g/min; P < .05). In total, 1026 MD samples were analyzed for energy metabolic alterations including glucose and the lactate/pyruvate ratio (LPR). The LPR was persistently elevated in the PHZ compared to the SNX region (P < .05). LPR elevations in the PHZ were predominately type II (pyruvate normal-high; indicating mitochondrial dysfunction) as opposed to type I (pyruvate low; indicating ischemia) at 4 to 48 h (70% vs 30%) and at 49 to 84 h (79% vs 21%; P < .05) postsurgery. CONCLUSION Despite normalization of CBF following ICH evacuation, an energy metabolic disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone. Cerebral blood flow, Energy metabolism, Intracerebral hemorrhage, Microdialysis, Xenon-enhanced computed tomography ABBREVIATIONS ABBREVIATIONS CBF cerebral blood flow CPP cerebral perfusion pressure CT computed tomography CTP computed tomography perfusion GCS-M motor component of Glasgow Coma Scale ICH intracerebral hemorrhage ICP intracranial pressure LPR lactate/pyruvate ratio MD microdialysis MML mixed models linear NCC neurocritical care PET positron emission tomography PHZ perihemorrhagic zone rCBF regional cerebral blood flow ROI regions of interest SD standard deviation SNX seemingly normal cortex Xe-CT Xenon-enhanced computed tomography Spontaneous, nonaneurysmal intracerebral hemorrhage (ICH) carries a 30-d mortality rate of 25% to 48%,1 and <40% of survivor reach functional independence.2 Despite refined stroke and neurocritical care (NCC) units, the case fatality rate has not markedly improved over the past decades.2 Surgical evacuation of an ICH is commonly life-saving, particularly for lobar ICHs, although it has not convincingly shown a distinct clinical benefit, compared to the best medical treatment, on clinical recovery in a larger selection of ICH patients.3,4 The causes of the modest clinical efficacy of surgery are unclear. There is an immediate mechanical disruption of glial cells, neurons, and axons at ICH onset,5 followed by a complex cascade of secondary injury factors, many of which remain unknown.6 Plausibly, these persisting secondary injury processes are insufficiently attenuated by surgical removal of the blood clot. In addition, a persistent energy metabolic crisis7 at time of regional hypoperfusion8 in the tissue surrounding the ICH, the perihemorrhagic zone (PHZ), may be crucial. Clinically, the energy metabolism may be assessed using cerebral microdialysis (MD) for the analysis of the lactate/pyruvate ratio (LPR), reflecting the cytoplasmatic redox state. Increased LPR may be caused by ischaemia, named type I LPR elevation, and mitochondrial dysfunction, named type II LPR elevation.9 The time course, type and extent of energy metabolic and blood flow disturbances in ICH remain to be established.8, 10 TABLE 1. Patient Characteristics Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  ICH, intracerebral hemorrhage; HT, hypertension, CVL, previous cerebrovascular lesion; AF, atrial fibrillation; VKA, vitamin-K antagonist (Warfarin) treatment; HepB, Hepatitis B; DM, diabetes mellitus; GCS-M, motor component of Glasgow Coma Scale score; NCC, neurocritical care; LOS, length of stay; mRS, modified Rankin Scale score assessed at 3 mo postsurgery; LTF, lost to follow-up. View Large TABLE 1. Patient Characteristics Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  ICH, intracerebral hemorrhage; HT, hypertension, CVL, previous cerebrovascular lesion; AF, atrial fibrillation; VKA, vitamin-K antagonist (Warfarin) treatment; HepB, Hepatitis B; DM, diabetes mellitus; GCS-M, motor component of Glasgow Coma Scale score; NCC, neurocritical care; LOS, length of stay; mRS, modified Rankin Scale score assessed at 3 mo postsurgery; LTF, lost to follow-up. View Large The aim of this study of surgically treated ICH patients was to investigate the energy metabolic situation in the PHZ compared to that in seemingly normal cortex (SNX) using dual MD catheters. In addition, cerebral blood flow (CBF) was evaluated at an early and late time point postoperatively. We hypothesized that surgical ICH removal is associated with an improved CBF and/or energy metabolism in the tissue surrounding the ICH. METHODS Study Design Prospectively recruited spontaneous ICH patients, surgically treated between November 2014 and November 2016, were included. The Regional Ethical Committee approved the study. A written informed consent was obtained from the patient's closest relative. Patient Characteristics and Management Patients >18 yr old requiring surgical evacuation of supratentorial ICH, receiving dual cerebral MD catheters and repeated evaluation of CBF during NCC were conveniently recruited. Surgical and clinical decisions were made by the consultant neurosurgeon on a case-by-case basis. Candidates for surgical evacuation and/or intracranial pressure (ICP) monitoring were ICH patients showing impaired or deteriorating level of consciousness and a surgically accessible ICH. Exclusion criteria were age <18 yr old, coagulopathy, and when a next of kin could not be located. Patients who did not receive dual MD catheters or 2 CBF investigations were also excluded. On admission, the clinical characteristics including the motor component of the Glasgow Coma Scale (GCS-M) score was noted (Table 1). For patients intubated at the referring hospital, the GCS-M preceding intubation was noted. Intubated patients were sedated using propofol (n = 12) and midazolam (n = 1) pre- and postoperatively. All patients were operated by routine craniotomy using a free bone flap, followed by microneurosurgical evacuation of the blood clot. ICP monitoring was performed in 10 patients (Figure 1). Postoperatively, the patients were managed in the NCC unit with a standardized treatment protocol including monitoring of secondary insults such as increased ICP and reduced cerebral perfusion pressure (CPP).11,12 ICP-monitoring was achieved using Neurovent-P parenchymal pressure monitoring device (Raumedic AG, Helmbrechts, Germany) or Bactiseal ventricular catheter (DePuy Synthes, Raynham, Massachusetts). Time to surgery was defined as time from known or presumed ictus to surgery. FIGURE 1. View largeDownload slide Native and Xenon-enhanced CT-scan; evaluation of CBF and placement of MD catheters. A, CT scan of a 67-yr-old man with a large left-sided ICH in the basal ganglia, emergently treated surgically by craniotomy and open evacuation of the clot. B, Postoperative CT scan shows the location of the 2 MD catheters, one (→) in the PHZ in the vicinity of the hemorrhage cavity (*), the other in SNX (⇒open arrow). C, First postoperative Xe-CT CBF evaluation showing the hand-drawn ROI surrounding the MD catheters. D, The second Xe-CT CBF evaluation at 66 h postoperatively shows the 20 standardized cortical ROIs used in the present study. FIGURE 1. View largeDownload slide Native and Xenon-enhanced CT-scan; evaluation of CBF and placement of MD catheters. A, CT scan of a 67-yr-old man with a large left-sided ICH in the basal ganglia, emergently treated surgically by craniotomy and open evacuation of the clot. B, Postoperative CT scan shows the location of the 2 MD catheters, one (→) in the PHZ in the vicinity of the hemorrhage cavity (*), the other in SNX (⇒open arrow). C, First postoperative Xe-CT CBF evaluation showing the hand-drawn ROI surrounding the MD catheters. D, The second Xe-CT CBF evaluation at 66 h postoperatively shows the 20 standardized cortical ROIs used in the present study. Three months postoperatively, the modified Rankin Scale13 was assessed using a questionnaire or a structured interview by telephone. Neuroradiology and Blood Flow Measurement The computed tomography (CT) scan preceding surgery was analyzed for midline shift (mm) and ICH volume, using the formula (a × b × c/2)14. All patients underwent a CT-angiography preoperatively. CBF was measured using Xenon-enhanced computed tomography (Xe-CT) according to locally adopted routines.15,16 Xenon is a metabolically inert and readily diffusible tracer, safely used for CBF evaluations in NCC.16,17 Patients underwent an early (day 0-2 postsurgery) and late (day 3-6 postsurgery) Xe-CT (CereTom 0-NL3000-001, Neurologica, Danvers, Massachusetts). A gas mixture of 28% Xenon was added during a 4.3 min long wash-in period to the ventilator air/O2-mixture. The computer software (Diversified Diagnostic Products Inc, Houston, Texas) enabled the timed Xenon delivery. A standard 4-level Xenon-CT CBF exam using 10 mm spacing between levels (using 8 scans per level, 2 baseline and 6 enhanced) was used and CBF (mL/100 g/min) calculated from the tissue enhancement by the Xenon.18,19 The CBF-values were visualized using a color-coded image (Figures 1C-1D). A modified Kety–Schmidt method was used,15,20 and mean cortical CBF for 20 evenly distributed regions of interest (ROI; Figure 1D) in each of the 4 levels were automatically calculated. The area of the MD catheters was identified on the structural CT and manually outlined (Figure 1C). This ROI was ≥200 mm2 for robust mathematical CBF calculations.19 At the time of Xe-CT CBF investigations, patients were sedated, ventilated, and physiologically monitored (Table 2). In 2 patients computed tomography perfusion (CTP) was used to estimate CBF, 1 due to obesity and 1 to early extubation. TABLE 2. MD and CBF Characteristics Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat, patient; h, hours; MD, microdialysis; PHZ, perihemorrhagic zone; ICH, intracerebral hemorrhage; CBF, cerebral blood flow Pre: CBF estimation evaluated prior to surgery. View Large TABLE 2. MD and CBF Characteristics Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat, patient; h, hours; MD, microdialysis; PHZ, perihemorrhagic zone; ICH, intracerebral hemorrhage; CBF, cerebral blood flow Pre: CBF estimation evaluated prior to surgery. View Large CTP images were obtained according to clinical routine using a 128-slice CT scanner.21,22 Iodinated contrast agent (45 ml; Joversol 350 mg/ml, Gothia Medical, Gothenburg, Sweden) was administered at a rate of 6 ml/s followed by a saline flush. Image acquisition was initiated 2 s after the start of the contrast injection. Quantitative perfusion data were obtained through repeated imaging of a 90 mm/84 mm slab of the brain during a 44/45 s time period, thus covering the first pass contrast inflow. Images were reconstructed into 10 mm thick slices and analyzed using a deconvolution-based algorithm. Perfusion data were presented as color-coded maps depicting CBF, cerebral blood volume, and mean transit time, with ROIs matching the Xe-CT investigations 21,22 and evaluated by a neuroradiologist blinded to the clinical data of each individual patient. CBF data were similar from Xenon-CT and CTP examinations and were pooled. Microdialysis At time of surgery, 1 MD catheter was placed adjacent (<1 cm) to the hematoma cavity (the PHZ). One control MD catheter was placed either via the craniotomy (n = 11) or a separate burr hole (n = 1) in the SNX of a noneloquent area. CMA 71 Brain MD Catheters, membrane length 10 mm and 100 kDa molecular weight cut-off (M Dialysis AB, Solna, Sweden) were used. The catheters are routinely, since 2013 in our department, perfused with a commercially available 5% human albumin solution to reduce fluid loss across the MD membrane23,24 (Albunorm, Octapharma, Stockholm, Sweden) at a rate of 0.3 μL/min. After MD catheter insertion, 2 h passed before sampling was initiated. MD is used for clinical monitoring and to reduce the samples analyzed, vials are routinely collected on a 2-h basis instead of each hour in our unit.23-25 Interstitial glucose, lactate, pyruvate, glycerol, and glutamate were analyzed bedside (ISCUSflex analyser; M-Dialysis AB). The LPR was calculated and urea monitored MD catheter performance.26 The following MD data were considered critical.27 MD-glucose: <0.2 mmol/L critical and <0.8 mmol/L considered a warning sign; LPR > 40 critical and LPR > 25 a warning sign. The incidence of LPR elevations type I, indicating ischemia (defined as LPR > 25 or > 40 and pyruvate < 70 μmol/L)28 was noted. The definition of type II LPR elevations, indicating mitochondrial disturbance, varies in the literature.27,28 For the 2 type II LPRs (>25 and >40), 2 values for pyruvate (>70 μmol/L or >120 μmol/L) were also used, as previously suggested.9,28,29 These calculations were performed on the first 4 to 84 h of MD sampling, and all analyses were performed by a researcher (L.T.) without the knowledge of the CBF data, and vice versa. The distance from the MD catheter tip to the ICH cavity was measured on postoperative CT scan. Statistical Methods The target sample size was based on the only previous clinical ICH study where 2 MD catheters were used.7 Due to the observed differences in the PHZ compared to putatively normal MD values observed in that study, and the complexity of the present study design, we aimed to include 18 patients expecting that some patients had to be excluded. SPSS Statistics 22 (IBM, Armonk, New York) was used. Paired t-test was used for normally distributed data and paired Wilcoxon rank test for nonnormally distributed data. Chi-square test was used for comparison of proportions. Correlation analysis was performed using Spearman's rank correlation of MD data to CBF. PHZ and SNX MD data were compared using a mixed models linear (MML) approach, with catheter location as fixed effect and patients as subject level and random effect.30 MML approach was also used for hemispheric CBF differences using hemisphere as fixed effect. A P-value < .05 was considered statistically significant. Normally distributed data are presented as means ± standard deviation (SD), nonnormally distributed data as median and range. For clarity, MD data are presented using mean ± SEM. RESULTS Eighteen surgically treated ICH patients >18 yr old were recruited. Six patients were then excluded; 4 since a MD catheter malfunctioned, and 2 since CBF measurements could not be performed according to protocol. Thus, 12 patients were included. Patient Characteristics and Radiology Median patient age was 64 yr (range 26-71 yr; Table 1). Median GCS-M score on arrival was 5 (range 3-6; Table 1). Ten patients had a central ICH and 2 a lobar ICH. Hemorrhages were evacuated at a mean of 14 h (range 3-37) after ICH onset. Ten patients received ICP monitoring. Postoperatively, no patients experienced ICP-elevations requiring ICP-lowering therapies such as decompressive craniectomy, hypertonic saline/mannitol, or barbiturates. The ICH and clinical characteristics are described in Table 1. CBF Measurements CBF measurements were performed 14.2 ± 24 h (Xe-CT 1) and 59.5 ± 19 h postsurgery (Xe-CT 2) in 10 patients. The 2 CT-perfusion studies were performed at 18 and 23 h (CTP 1) and 60 and 68 h postsurgery (CTP 2), respectively. ICP, CPP, MAP, pCO2, pO2, and the use of muscle relaxant, sedatives, and inotropic drugs remained stable during the CBF investigations and were similar between the first and second CBF study (Table 2). Global CBF was 37.5 ± 21 mL/100g/min at CBF1, which improved to 40.1 ± 19 mL/100g/min at CBF2 (P < .05; Figure 2A). Regional cerebral blood flow (rCBF) was lower in the hemisphere harbouring the ICH than contralaterally (36.6 ± 20 vs 38.3 ± 21 mL/100g/min, respectively, P < .05; Figure 2A) at CBF1. At CBF2, there were no differences between the hemispheres (40.6 ± 20 and 39.6 ± 19 mL/100g/min, respectively; Figure 2A). In the MD catheter ROIs, the CBF was significantly lower in ROIPHZ (25.7 ± 14 mL/100g/min) compared to in ROISNX (40.9 ± 20 mL/100g/min; P < .05; Figure 2B) at CBF1, but there was no statistically significant difference between these regions at CBF2 (36.5 ± 27 mL/100g/min in ROIPHZ and 42.7 ± 30 mL/100g/min in ROISNX; P = .426). FIGURE 2. View largeDownload slide CBF evaluated by Xenon-CT following surgical evacuation of ICH. A, Heat-map of 40 ROI in each hemisphere shows that CBF improved significantly (*) between the early (CBF1; 20.8 ± 10 h postsurgery) and late (CBF2; 57.7 ± 16 h postsurgery) globally. The CBF in the ipsilateral hemisphere was significantly lower (indicated by *) than in the contralateral hemisphere at the early (CBF1) postinjury time-point, but this difference was not present at CBF2. CBF improved significantly between CBF1 and CBF2 both in the ipsilateral hemisphere and contralateral hemisphere (P < .05 = *). B, CBF was lower in the local ROI centered on the MD catheter in the PHZ as compared to that of the SNX on the first CBF evaluation. At the second CBF evaluation, there was no difference in CBF between the ROIs in the SNX and PHZ. PHZ, perihemorrhagic zone; SNX, seemingly normal cortex; Ipsi, ipsilateral to the hemorrhage; Contra, contralateral to the hemorrhage; n.s., not significant. FIGURE 2. View largeDownload slide CBF evaluated by Xenon-CT following surgical evacuation of ICH. A, Heat-map of 40 ROI in each hemisphere shows that CBF improved significantly (*) between the early (CBF1; 20.8 ± 10 h postsurgery) and late (CBF2; 57.7 ± 16 h postsurgery) globally. The CBF in the ipsilateral hemisphere was significantly lower (indicated by *) than in the contralateral hemisphere at the early (CBF1) postinjury time-point, but this difference was not present at CBF2. CBF improved significantly between CBF1 and CBF2 both in the ipsilateral hemisphere and contralateral hemisphere (P < .05 = *). B, CBF was lower in the local ROI centered on the MD catheter in the PHZ as compared to that of the SNX on the first CBF evaluation. At the second CBF evaluation, there was no difference in CBF between the ROIs in the SNX and PHZ. PHZ, perihemorrhagic zone; SNX, seemingly normal cortex; Ipsi, ipsilateral to the hemorrhage; Contra, contralateral to the hemorrhage; n.s., not significant. MD Reveals a Persisting Energy Metabolic Disturbance in the PHZ Following ICH Surgery In total, 6598 analyses in 1026 MD samples were performed (glucose, lactate, pyruvate, glycerol, and glutamate). The mean duration from ICH onset to start of MD sampling was 20.6 ± 12 h (range 5-94 h), and the mean duration of sampling was 108 ± 41 h (range 56-184 h; Table 3). Five vials of the 1026 were excluded due to deviating urea values.26 The low-molecular weight analyses are shown in Figures 3A-3D. There was a significant difference between the PHZ and the SNX catheter for all metabolites except glycerol (P < .05; Figures 3A-3D). In the first 4 to 84 h, 48% of MD-Glucose levels in the PHZ were below <0.8 mmol/L and 9% < 0.2 mmol/L. In the SNX, 26% of MD-Glucose levels were <0.8 mmol/L although no sample was <0.2 mmol/L. FIGURE 3. View largeDownload slide Energy metabolic disturbance in the PHZ evaluated by MD following surgery for ICH. MD analyses for the first 4 to 84 h postsurgery of the MD samples obtained from the PHZ and SNX. A-D, Results for glucose, lactate, pyruvate, and the LPR are shown. The MD-glucose levels A were consistently lower while the MD-lactate levels B and MD-pyruvate levels C were consistently higher in the PHZ compared to the SNX (P < .05). D, The LPR in the PHZ was markedly elevated, the mean ratio being consistently higher when compared to the SNX (*P < .05). FIGURE 3. View largeDownload slide Energy metabolic disturbance in the PHZ evaluated by MD following surgery for ICH. MD analyses for the first 4 to 84 h postsurgery of the MD samples obtained from the PHZ and SNX. A-D, Results for glucose, lactate, pyruvate, and the LPR are shown. The MD-glucose levels A were consistently lower while the MD-lactate levels B and MD-pyruvate levels C were consistently higher in the PHZ compared to the SNX (P < .05). D, The LPR in the PHZ was markedly elevated, the mean ratio being consistently higher when compared to the SNX (*P < .05). TABLE 3. Clinical Parameters at the Time of CBF-Measurement Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  ICP, intracranial pressure; CPP, cerebral perfusion pressure; MAP, mean arterial blood pressure; NE, norepinephrine; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen All data presented as means ± SD. P-values from Student's t-test. View Large TABLE 3. Clinical Parameters at the Time of CBF-Measurement Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  ICP, intracranial pressure; CPP, cerebral perfusion pressure; MAP, mean arterial blood pressure; NE, norepinephrine; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen All data presented as means ± SD. P-values from Student's t-test. View Large The MD-lactate levels were consistently higher (P < .05; Figure 3B) in the PHZ compared to the SNX, as was MD-glutamate (P < .05; data not shown). The MD-pyruvate levels were also higher in the PHZ compared to the SNX (P < .05; Figure 3C). There was no significant difference in MD-glycerol between sampled regions (not shown). The lactate/pyruvate ratio was consistently elevated in the PHZ compared to the SNX (P < .05; Figure 3D). In the first 4 to 84 h, the LPR was >25 in 70% of all samples (298/424 samples) in the PHZ as compared to 23% (101/436 samples) in the SNX (P < .05). The LPR was >40 in 38% (163/424 samples) in the PHZ and 3% (14/472 samples) of all MD samples in the SNX (P < .05). The definition of type II LPR requires normal or elevated pyruvate levels >70 μmol/L. Of note, in previous definitions of type II LPR elevations pyruvate levels either >120 μmol/L or >70μmol/L were used.9,29,31,32 In our material, pyruvate levels >120 μmol/L were more common than 70 to 120 μmol/L in type II LPR elevations, presented in full detail in Figure 4A and 4B. In the following paragraph, all type II LPR elevations with pyruvate levels >70 μmol/L are reported. FIGURE 4. View largeDownload slide LPR elevations in the PHZ following surgical evacuation of ICH. Based on available literature and recommendations, a LPR elevation in MD samples may be defined as >25 A or >40 B. In addition, a type I LPR elevation (defined as an LPR elevation and pyruvate levels <70 μmol/L) indicates an ischemic situation, and a type II LPR elevation (defined as an LPR elevation and pyruvate level being either 70-120 or >120 mmol/L9,28,29,31,54,55) indicates mitochondrial dysfunction. A, When comparing the LPR elevations, here defined as an LPR > 25, obtained from MD catheters placed in the PHZ, the incidence of type I LPR and particularly type II LPR was higher than the values from MD catheters placed in SNX early (4-48 h) following ICH surgery. At the late postsurgery time-points (48-84 h) the energy metabolic disturbance persisted in the PHZ, although less pronounced than at the early time point. The majority of these LPR elevations were of type II, indicating persisting mitochondrial disturbance. B, Less MD samples met the criteria for type I and type II LPR elevations when an LPR > 40 was used as a cut-off. Still, both type I and type II LPR elevations were observed with similar relative frequencies observed when LPR > 25 was used as a cut-off. pyr, pyruvate; P < .05 between groups at both LPR > 25 and LPR > 40. FIGURE 4. View largeDownload slide LPR elevations in the PHZ following surgical evacuation of ICH. Based on available literature and recommendations, a LPR elevation in MD samples may be defined as >25 A or >40 B. In addition, a type I LPR elevation (defined as an LPR elevation and pyruvate levels <70 μmol/L) indicates an ischemic situation, and a type II LPR elevation (defined as an LPR elevation and pyruvate level being either 70-120 or >120 mmol/L9,28,29,31,54,55) indicates mitochondrial dysfunction. A, When comparing the LPR elevations, here defined as an LPR > 25, obtained from MD catheters placed in the PHZ, the incidence of type I LPR and particularly type II LPR was higher than the values from MD catheters placed in SNX early (4-48 h) following ICH surgery. At the late postsurgery time-points (48-84 h) the energy metabolic disturbance persisted in the PHZ, although less pronounced than at the early time point. The majority of these LPR elevations were of type II, indicating persisting mitochondrial disturbance. B, Less MD samples met the criteria for type I and type II LPR elevations when an LPR > 40 was used as a cut-off. Still, both type I and type II LPR elevations were observed with similar relative frequencies observed when LPR > 25 was used as a cut-off. pyr, pyruvate; P < .05 between groups at both LPR > 25 and LPR > 40. In the PHZ at 4 to 48 h, of all samples with LPR > 25 (n = 190/255 samples), 30% had type I and 70% type II LPR elevation. In the PHZ at 49 to 84 h, of all samples with LPR > 25 (n = 108/169 samples), 21% had a type I and 79% type II LPR elevation (P < .05; Figure 4A). In the SNX at 4 to 48 hours, of all samples with LPR > 25 (n = 72/257), 58% had a type I and 42% had type II LPR elevation. In the SNX at 49 to 84 h, of all samples with LPR > 25 (n = 29/179 samples), 62% had a type I and 38% had a type II LPR elevation (P < .05; Figure 4A). In the PHZ at 4 to 48 h, of all samples with LPR elevations >40 (n = 103/255), 41% had type I and 59% a type II LPR elevation. In the PHZ at 49 to 84 h, of all samples with LPR > 40 (n = 60/169 samples), 32% had a type I and 68% a type II LPR elevation. In the SNX at 4 to 48 h, LPR was >40 in only 5 of 257 samples, of these 60% had a type I and 40% had a type II LPR elevation. At 49 to 84 h in the SNX, 9 of 179 samples had an LPR > 40 and of these, 89% had a type I and 11% had a type II LPR elevation (P < .05; Figure 4B). There was no correlation between CBF and LPR analyzed in time periods of 2, 4, 6, or 10 h prior to CBF investigation (data not shown). DISCUSSION The present study, the first to use dual MD catheters combined with repeated evaluations of CBF, shows a persisting energy metabolic disturbance in the brain tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH) despite a normalization of CBF. Moreover, the pattern of LPR elevations indicates a persistent mitochondrial disturbance. CBF Changes Following ICH Surgery Most rCBF levels were higher than those typically associated with ischemia, both in the ipsilateral hemisphere and in the PHZ. Furthermore, an improved CBF ipsilateral to the evacuated hematoma was observed between the 2 CBF studies, conducted at 21 and 58 h postsurgery. We cannot exclude that time to ICH removal, which varied among the patients, influenced the CBF values. In nonevacuated ICH, a hypoperfusion zone surrounding the hemorrhage was observed in both the experimental33-36 and clinical setting.37-39 Using positron emission tomography (PET), the PHZ displayed a reduced CBF up to 43 h postictus,40 although not reaching ischemic levels.38,40,41 Additionally, no evidence of PHZ ischemia was observed in conservatively treated ICH patients using magnetic resonance spectroscopy.37 Although no CBF studies comparing surgically and conservatively treated ICH patients over time are available, previous experimental and clinical studies report an improved CBF following ICH removal, 35,42-44 implying that surgical blood clot removal aids in restoring CBF. In conservatively treated ICH patients, a varying pattern of initial hypoperfusion was coupled to hypometabolism in the PHZ.37,38,44-48 Although some reports show a gradual normalization of CBF over time,8 others show a variable decrease.40,44,45,47,48 For clinical reasons, we used 2 techniques for investigating CBF, Xe-CT in 10 and CTP in 2 patients, with good correlation between these methods.49,50 Since CTP determines only relative, not absolute CBF, it was used here only when Xe-CT could not be performed. Energy Metabolic Disturbances in Brain Tissue Following ICH Surgery An ICH may be surrounded by a potentially salvageable PHZ different from the penumbra of ischemic stroke, in which the supply of oxygen and substrate is sufficient for cell survival although insufficient for normal neuronal activity.51 Although there was gradual improvement of MD glucose, lactate, and the LPR, normalization did not occur suggesting a pattern of persistent metabolic impairment in the PHZ, evident by an elevated LPR. In a previous study, 1 to 3 PHZ MD catheters were used and the immediate LPR increase following ICH surgery gradually normalized, similarly to our results. Glucose levels were normal, whereas pyruvate levels were not presented.7 In addition, CBF was not evaluated and no distinction between type I and II LPR elevations was made.7 Similar to traumatic brain injury,9,52 subarachnoid hemorrhage28 and bacterial meningitis patients,32 the LPR elevations observed in the present study suggest a mitochondrial dysfunction, which could contribute to the rather modest motor improvement observed postsurgery in our cohort. There are no established criteria for type I or type II LPR elevations. Based on available literature, we used 2 different LPRs as well as pyruvate levels, based on the suggested reference pyruvate values (166 ± 47 μmol/L).9,28,29,31,32,53-55 Regardless of the definition, the PHZ displayed higher LPRs, mainly type II, than the SNX. In contrast, glucose levels were above critical thresholds indicating sufficient substrate delivery. We cannot exclude that the surgical approach contributed to the suggested mitochondrial dysfunction since no nonsurgical control group was available. However, our data support previous work using PET-studies obtained 5 to 22 h after ICH onset, and work using a single perioperative biopsy, obtained at 6 to 72 h in 6 patients, showing reduced oxygen extraction fraction, hypometabolism, and mitochondrial dysfunction in the PHZ.38,45,56 Persisting mitochondrial dysfunction with a reduced capacity for ATP generation may cause ongoing exacerbation of the ICH-induced tissue injury in the PHZ, as suggested by studies in traumatic brain injury,57 and be an important secondary injury factor leading to delayed neuronal necrosis and/or apoptosis. Presumably, many factors contribute to mitochondrial dysfunction although complex metabolomics alterations could not be assessed using the present methodology. A few studies have evaluated possible treatment options for mitochondrial dysfunction in acute brain injury, including administrating succinate to the damaged tissue58 or treating patients with suggested mitochondrial dysfunction with cyclosporine A,59 hyperbaric oxygen,60 or lactate, 61 interesting also for future ICH studies. Study Limitations The present data are based on a relatively small number of patients, included at a variable time point after ICH onset, and with a variable ICH location and volume. Since MD cannot be used in conservatively treated patients, we compared the energy metabolic situation in the PHZ with that in normal cortex. Although the control MD catheter was aimed at an area distant from the PHZ, preoperative pressure caused by ICH may have influenced the MD values of the SNX. Most devices for ICP monitoring were inserted ipsilaterally, and a separate burr hole solely for MD insertion could not be justified. No preoperative CBF measurements could be obtained and both the ICH itself and the surgery may have contributed to our results. Also, the small sample size did not allow us to evaluate any potential differences in CBF and metabolic disturbances across age groups or between patients with deep vs lobar hemorrhages. MD monitors a ∼2 cm3 brain region,62 and the MD catheters were placed at a predefined location. Since all PHZ MD catheters were within 10 mm of the ICH, the influence of variations in MD catheter positioning on our results was presumably minor. Since the tissue injury imposed by the surgical approach may influence CBF and/or MD values, we cannot establish whether the observed CBF changes was caused by the surgical manipulation needed for ICH removal per se or merely reflected its natural course. Although no patient suffered from increased ICP postoperatively, we cannot exclude that preoperative ICP elevations resulted in persisting changes in CBF and/or MD results. Finally, the MD results could have been influenced by the variable time from ICH onset to initiation of sampling. CONCLUSION Our data show that global and hemispheric CBF was gradually normalized following surgical evacuation of ICH. However, despite improved CBF a pattern of energy metabolic disturbance suggestive of mitochondrial dysfunction persisted in the PHZ. This may indicate that secondary pathological cascades triggered by the blood and/or the surgical trauma result in an ongoing energy metabolic crisis. Future studies are needed to determine if an earlier ICH evacuation could help restore the energy metabolic situation. Since it is plausible that surgical ICH removal contributes to improved CBF, future therapies may aim to target the mitochondrial dysfunction persisting in surgically treated ICHs. Disclosures This study was supported by STROKE-Riksförbundet (Skärholmen, Sweden), and the Anaesthesia, Operations and Specialty Surgery Centre, and local hospital ALF-funds (Region Östergötland, Linköping, Sweden). None of the financing agencies had any influence on the design or implementation of the study, the analysis and interpretation of results, or the writing of the manuscript. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes The preliminary results of this study were presented as a poster at the European Stroke Organisation Conference in Prague, Czech Republic on 16th May 2017, and the meeting abstract was published in European Stroke Journal 2017, vol. 2, 1_suppl: pp. 496-562. REFERENCES 1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol . 2009; 8( 4): 355- 369. Google Scholar CrossRef Search ADS PubMed  2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol . 2010; 9( 2): 167- 176. Google Scholar CrossRef Search ADS PubMed  3. Mendelow AD, Gregson BA, Fernandes HM et al.  . Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet . 2005; 365( 9457): 387- 397. Google Scholar CrossRef Search ADS PubMed  4. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet . 2013; 382( 9890): 397- 408. Google Scholar CrossRef Search ADS PubMed  5. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med . 2001; 344( 19): 1450- 1460. Google Scholar CrossRef Search ADS PubMed  6. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet . 2009; 373( 9675): 1632- 1644. Google Scholar CrossRef Search ADS PubMed  7. Nilsson OG, Polito A, Saveland H, Ungerstedt U, Nordstrom CH. Are primary supratentorial intracerebral hemorrhages surrounded by a biochemical penumbra? A microdialysis study. Neurosurgery . 2006; 59( 3): 521- 528; discussion 521-528. Google Scholar CrossRef Search ADS PubMed  8. Qureshi AI, Hanel RA, Kirmani JF, Yahia AM, Hopkins LN. Cerebral blood flow changes associated with intracerebral hemorrhage. Neurosurg Clin N Am . 2002; 13( 3): 355- 370. Google Scholar CrossRef Search ADS PubMed  9. Nordstrom CH, Nielsen TH, Schalen W, Reinstrup P, Ungerstedt U. Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion. Acta Neurochir . 2016; 158( 7): 1231- 1240. Google Scholar CrossRef Search ADS PubMed  10. Siddique MS, Fernandes HM, Wooldridge TD, Fenwick JD, Slomka P, Mendelow AD. Reversible ischemia around intracerebral hemorrhage: a single-photon emission computerized tomography study. J Neurosurg . 2002; 96( 4): 736- 741. Google Scholar CrossRef Search ADS PubMed  11. Elf K, Nilsson P, Enblad P. Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care*. Crit Care Med . 2002; 30( 9): 2129- 2134. Google Scholar CrossRef Search ADS PubMed  12. Grande PO, Asgeirsson B, Nordstrom CH. Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments. Acta Anaesthesiol Scand . 2002; 46( 8): 929- 941. Google Scholar CrossRef Search ADS PubMed  13. Bruno A, Shah N, Lin C et al.  . Improving modified Rankin Scale assessment with a simplified questionnaire. Stroke . 2010; 41( 5): 1048- 1050. Google Scholar CrossRef Search ADS PubMed  14. Webb AJ, Ullman NL, Morgan TC et al.  . Accuracy of the ABC/2 Score for Intracerebral Hemorrhage. Stroke . 2015; 46( 9): 2470- 2476. Google Scholar CrossRef Search ADS PubMed  15. Hillman J, Sturnegk P, Yonas H et al.  . Bedside monitoring of CBF with xenon-CT and a mobile scanner: a novel method in neurointensive care. Brit J Neurosurg . 2005; 19( 5): 395- 401. Google Scholar CrossRef Search ADS   16. Sturnegk P, Mellergard P, Yonas H, Theodorsson A, Hillman J. Potential use of quantitative bedside CBF monitoring (Xe-CT) for decision making in neurosurgical intensive care. Brit J Neurosurg . 2007; 21( 4): 332- 339. Google Scholar CrossRef Search ADS   17. Carlson AP, Brown AM, Zager E et al.  . Xenon-enhanced cerebral blood flow at 28% xenon provides uniquely safe access to quantitative, clinically useful cerebral blood flow information: a multicenter study. Am J Neuroradiol.  2011; 32( 7): 1315- 1320. Google Scholar CrossRef Search ADS   18. Good WF, Gur D, Herron JM, Kennedy WH. The development of a xenon/computed tomography cerebral blood flow quality assurance phantom. Med Phys . 1987; 14( 5): 867- 869. Google Scholar CrossRef Search ADS PubMed  19. Fatouros PP, Wist AO, Kishore PR et al.  . Xenon/computed tomography cerebral blood flow measurements methods and accuracy. Invest Radiol . 1987; 22( 9): 705- 712. Google Scholar CrossRef Search ADS PubMed  20. Rostami E, Engquist H, Johnson U et al.  . Monitoring of cerebral blood flow and metabolism bedside in patients with subarachnoid hemorrhage-a Xenon-CT and microdialysis study. Front Neurol . 2014; 5: 89. Google Scholar PubMed  21. Hoeffner EG, Case I, Jain R et al.  . Cerebral perfusion CT: technique and clinical applications. Radiology . 2004; 231( 3): 632- 644. Google Scholar CrossRef Search ADS PubMed  22. Konstas AA, Goldmakher GV, Lee TY, Lev MH. Theoretic basis and technical implementations of CT perfusion in acute ischemic stroke, part 1: Theoretic basis. Am J Neuroradiol.  2009; 30( 4): 662- 668. Google Scholar CrossRef Search ADS   23. Hillman J, Aneman O, Anderson C, Sjogren F, Saberg C, Mellergard P. A microdialysis technique for routine measurement of macromolecules in the injured human brain. Neurosurgery . 2005; 56( 6): 1264- 1270; discussion 1268-1270. Google Scholar CrossRef Search ADS PubMed  24. Hillered L, Dahlin AP, Clausen F et al.  . Cerebral microdialysis for protein biomarker monitoring in the neurointensive care setting-a technical approach. Front Neurol . 2014; 5: 245. Google Scholar CrossRef Search ADS PubMed  25. Hillman J, Milos P, Yu ZQ, Sjogren F, Anderson C, Mellergard P. Intracerebral microdialysis in neurosurgical intensive care patients utilising catheters with different molecular cut-off (20 and 100?kD). Acta Neurochir (Wien) . 2006; 148( 3): 319- 324; discussion 324. Google Scholar CrossRef Search ADS PubMed  26. Ronne-Engstrom E, Cesarini KG, Enblad P et al.  . Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound. J Neurosurg . 2001; 94( 3): 397- 402. Google Scholar CrossRef Search ADS PubMed  27. Hutchinson PJ, Jalloh I, Helmy A et al.  . Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med . 2015; 41( 9): 1517- 1528. Google Scholar CrossRef Search ADS PubMed  28. Jacobsen A, Nielsen TH, Nilsson O, Schalen W, Nordstrom CH. Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand . 2014; 130( 3): 156- 163. Google Scholar CrossRef Search ADS PubMed  29. Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordstrom CH. Cerebral energy metabolism during induced mitochondrial dysfunction. Acta Anaesthesiol Scand . 2013; 57( 2): 229- 235. Google Scholar CrossRef Search ADS PubMed  30. Field A. Discovering Statistics Using IBM SPSS Statistics: And Sex And Drugs And Rock ‘N’ Roll.  4th ed. United Kingdom, Europe: Sage; 2013. 31. Nielsen TH, Olsen NV, Toft P, Nordstrom CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand . 2013; 57( 6): 793- 801. Google Scholar CrossRef Search ADS PubMed  32. Poulsen FR, Schulz M, Jacobsen A et al.  . Bedside evaluation of cerebral energy metabolism in severe community-acquired bacterial meningitis. Neurocrit Care . 2015; 22( 2): 221- 228. Google Scholar CrossRef Search ADS PubMed  33. Bullock R, Brock-Utne J, van Dellen J, Blake G. Intracerebral hemorrhage in a primate model: effect on regional cerebral blood flow. Surg Neurol . 1988; 29( 2): 101- 107. Google Scholar CrossRef Search ADS PubMed  34. Nehls DG, Mendelow AD, Graham DI, Sinar EJ, Teasdale GM. Experimental intracerebral hemorrhage: progression of hemodynamic changes after production of a spontaneous mass lesion. Neurosurgery . 1988; 23( 4): 439- 444. Google Scholar CrossRef Search ADS PubMed  35. Nehls DG, Mendelow DA, Graham DI, Teasdale GM. Experimental intracerebral hemorrhage: early removal of a spontaneous mass lesion improves late outcome. Neurosurgery . 1990; 27( 5): 674- 682; discussion 682. Google Scholar CrossRef Search ADS PubMed  36. Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg . 1994; 81( 1): 93- 102. Google Scholar CrossRef Search ADS PubMed  37. Carhuapoma JR, Wang PY, Beauchamp NJ, Keyl PM, Hanley DF, Barker PB. Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage. Stroke . 2000; 31( 3): 726- 732. Google Scholar CrossRef Search ADS PubMed  38. Zazulia AR, Diringer MN, Videen TO et al.  . Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab.  2001; 21( 7): 804- 810. Google Scholar CrossRef Search ADS PubMed  39. Schellinger PD, Fiebach JB, Hoffmann K et al.  . Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra? Stroke . 2003; 34( 7): 1674- 1679. Google Scholar CrossRef Search ADS PubMed  40. Hirano T, Read SJ, Abbott DF et al.  . No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage. Neurology . 1999; 53( 9): 2179- 2179. Google Scholar CrossRef Search ADS PubMed  41. Powers WJ, Zazulia AR, Videen TO et al.  . Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology . 2001; 57( 1): 18- 24. Google Scholar CrossRef Search ADS PubMed  42. Etminan N, Beseoglu K, Turowski B, Steiger HJ, Hanggi D. Perfusion CT in patients with spontaneous lobar intracerebral hemorrhage: effect of surgery on perihemorrhagic perfusion. Stroke . 2012; 43( 3): 759- 763. Google Scholar CrossRef Search ADS PubMed  43. Tanizaki Y. Improvement of cerebral blood flow following stereotactic surgery in patients with putaminal haemorrhage. Acta Neurochir . 1988; 90( 3-4): 103- 110. Google Scholar CrossRef Search ADS PubMed  44. Siddique MS, Fernandes HM, Arene NU, Wooldridge TD, Fenwick JD, Mendelow AD. Changes in cerebral blood flow as measured by HMPAO SPECT in patients following spontaneous intracerebral haemorrhage. Acta Neurochir Suppl.  2000; 76: 517- 520. Google Scholar PubMed  45. Kawakami H, Kutsuzawa T, Uemura K, Sakurai Y, Nakamura T. Regional cerebral blood flow in patients with hypertensive intracerebral hemorrhage. Stroke . 1974; 5( 2): 207- 212. Google Scholar CrossRef Search ADS PubMed  46. Miyazawa N, Mitsuka S, Asahara T et al.  . Clinical features of relative focal hyperfusion in patients with intracerebral hemorrhage detected by contrast-enhanced xenon CT. AJNR Am J Neuroradiol.  1998; 19( 9): 1741- 1746. Google Scholar PubMed  47. Mayer SA, Lignelli A, Fink ME et al.  . Perilesional blood flow and edema formation in acute intracerebral hemorrhage : a SPECT study. Stroke . 1998; 29( 9): 1791- 1798. Google Scholar CrossRef Search ADS PubMed  48. Tayal AH, Gupta R, Yonas H et al.  . Quantitative perihematomal blood flow in spontaneous intracerebral hemorrhage predicts in-hospital functional outcome. Stroke . 2007; 38( 2): 319- 324. Google Scholar CrossRef Search ADS PubMed  49. Wintermark M, Thiran JP, Maeder P, Schnyder P, Meuli R. Simultaneous measurement of regional cerebral blood flow by perfusion CT and stable xenon CT: a validation study. AJNR Am J Neuroradiol.  2001; 22( 5): 905- 914. Google Scholar PubMed  50. Honda M, Sase S, Yokota K et al.  . Early cerebral circulation disturbance in patients suffering from different types of severe traumatic brain injury: a xenon CT and perfusion CT study. Acta Neurochir Suppl.  2013; 118: 259- 263. Google Scholar PubMed  51. Cipolla MJ. The Cerebral Circulation . San Rafael (CA): Morgan & Claypool Life Sciences; 2009. 52. Vespa P, Bergsneider M, Hattori N et al.  . Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab . 2005; 25( 6): 763- 774. Google Scholar CrossRef Search ADS PubMed  53. Hutchinson P, O’Phelan K. International multidisciplinary consensus conference on multimodality monitoring: cerebral metabolism. Neurocrit Care . 2014; 21( S2): 148- 158. Google Scholar CrossRef Search ADS   54. Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, Nordstrom CH. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery . 2000; 47( 3): 701- 709; discussion 709-710. Google Scholar PubMed  55. Nielsen TH, Schalen W, Stahl N, Toft P, Reinstrup P, Nordstrom CH. Bedside diagnosis of mitochondrial dysfunction after malignant middle cerebral artery infarction. Neurocrit Care . 2014; 21( 1): 35- 42. Google Scholar CrossRef Search ADS PubMed  56. Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke . 2006; 37( 10): 2457- 2462. Google Scholar CrossRef Search ADS PubMed  57. Xu Y, McArthur DL, Alger JR et al.  . Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury. J Cereb Blood Flow Metab . 2010; 30( 4): 883- 894. Google Scholar CrossRef Search ADS PubMed  58. Jalloh I, Helmy A, Howe DJ et al.  . Focally perfused succinate potentiates brain metabolism in head injury patients. J Cereb Blood Flow Metab . 2016; 37( 7): 2626- 2638. Google Scholar CrossRef Search ADS PubMed  59. Cour M, Abrial M, Jahandiez V et al.  . Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure. J Appl Physiol . 2014; 117( 8): 930- 936. Google Scholar CrossRef Search ADS PubMed  60. Hiebert JB, Shen Q, Thimmesch AR, Pierce JD. Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci . 2015; 350( 2): 132- 138. Google Scholar CrossRef Search ADS PubMed  61. Dienel GA. Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations. J Cereb Blood Flow Metab . 2014; 34( 11): 1736- 1748. Google Scholar CrossRef Search ADS PubMed  62. Maurer MH, Haux D, Unterberg AW, Sakowitz OW. Proteomics of human cerebral microdialysate: from detection of biomarkers to clinical application. Prot Clin Appl.  2008; 2( 3): 437- 443. Google Scholar CrossRef Search ADS   Acknowledgements The authors thank neuroradiologists Inger Eveman and Jakob de Geer for valuable methodological insights and assistance. COMMENTS The clinical benefit of evacuation of ICH has been difficult to show. The authors have investigated whether reduced CBF and/or metabolic energy disturbances exist in the tissue surrounding a surgically evacuated ICH. CBF was measured using xenon-enhanced CT or CT perfusion, and metabolic state was measured using dual microdialysis probes, 1 in the perihemorrhagic zone and 1 in presumed normal tissue. The authors conclude that CBF is normalized following ICH evacuation, whereas a metabolic energy disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone. Although the series is relatively small and heterogeneous, the data set add some information on the pathophysiological mechanisms of brain damage after spontaneous ICH. Since there is no control group, for good reasons, the effect of surgery on the observed changes is, however, still uncertain. One of the main reasons to evacuate an ICH is to prevent secondary injury in the penumbral area around the hematoma. Since CBF was normalized whereas a metabolic energy disturbance persisted after evacuation, future studies should aim at investigating whether there is a time window for evacuation that will increase the probability of restoring the metabolic state. The slight improvement in both glucose, lactate, and LPR in the perihemorrhagic zone over time although normalization was not reached, may indicate that earlier surgical intervention can improve the metabolic state in the perihemorrhagic zone. Jon Berg-Johnsen Oslo, Norway The authors offer a manuscript describing the results of a prospective study of cerebral blood flow measurements via Xenon CT and cellular energy metabolism via microdialysis (MD) in patients undergoing open surgical evacuation of ICH. While this study is small, it is well designed and provides valuable prospective paired data on the state of brain CBF and metabolism in the initial postoperative period as well as in a delayed fashion after surgery. The study is enhanced by having MD data from both the perihemorrhagic zone as well as from seemingly normal brain cortex. The authors conclude that while surgery seemingly restores CBF, metabolic derangement in the tissue persist for at least a few days postoperatively. I think this study is particularly timely with recent trends in minimally invasive ICH evacuation, and while it involves maximally invasive craniotomies, I think the data can be applied to more recent surgical trends. This study will lay the groundwork for future studies of CBF and metabolism in surgically vs conservatively managed ICH patients. Joshua Osbun St. Louis, Missouri The authors should be congratulated, for this elegant microdialysis study, which makes 2 novel contributions… First, It offers new insight into the reasons why patients do not seem to robustly improve after removal of intracerebral hemorrhage, and second it shows the potential of intracerebral microdialysis to uniquely provide hard neurochemical evidence of metabolic changes in the living human brain. Several authors have documented CBF reduction in the perihemorrhagic zone around an intracerebral hematoma, to accord with neuropathological studies showing a zone of ischemic neuronal death, and damage, up to 1–2 cm around the clot. 1,2 This study however, suggests a larger zone of perihemorrhagic mitochondrial functional impairment, involving fairly large areas of the ipsilateral cortex, which persists several days after clot removal, and which offers a reason for the ongoing edema, (therefore mostly cytotoxic) and persisting neurological impairment usually seen in these patients postoperatively. Most importantly, however this study raises the possibility of treatments aimed at optimizing mitochondrial function, such as delivering more oxygen, or fuels such as lactate, succinate, or oxaloacetate, combined with clot removal surgery. Ross Bullock Miami, Florida 1. Tanizaki Y. Improvement of cerebral blood flow following stereotactic surgery in patients 430 with putaminal haemorrhage. Acta neurochirurgica . 1988; 90( 3–4): 103- 110. Google Scholar CrossRef Search ADS PubMed  2. Kawakami H Kutsuzawa T Uemura K Sakurai Y Nakamura T. Regional cerebral blood flow in 435 patients with hypertensive intracerebral hemorrhage. Stroke . 1974; 5( 2): 207- 212 Google Scholar CrossRef Search ADS PubMed  © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood Flow Following Surgery for Intracerebral Hemorrhage

Loading next page...
 
/lp/ou_press/persistent-metabolic-disturbance-in-the-perihemorrhagic-zone-despite-a-M0xYQX2NT9
Publisher
Congress of Neurological Surgeons
Copyright
© Congress of Neurological Surgeons 2018.
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyy179
Publisher site
See Article on Publisher Site

Abstract

Abstract BACKGROUND We hypothesized that reduced cerebral blood flow (CBF) and/or energy metabolic disturbances exist in the tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH). If present, such CBF and/or metabolic impairments may contribute to ongoing tissue injury and the modest clinical efficacy of ICH surgery. OBJECTIVE To conduct an observational study of CBF and the energy metabolic state in the perihemorrhagic zone (PHZ) tissue and in seemingly normal cortex (SNX) by microdialysis (MD) following surgical ICH evacuation. METHODS We evaluated 12 patients (median age 64; range 26-71 yr) for changes in CBF and energy metabolism following surgical ICH evacuation using Xenon-enhanced computed tomography (n = 10) or computed tomography perfusion (n = 2) for CBF and dual MD catheters, placed in the PHZ and the SNX at ICH surgery. RESULTS CBF was evaluated at a mean of 21 and 58 h postsurgery. In the hemisphere ipsilateral to the ICH, CBF improved between the investigations (36.6 ± 20 vs 40.6 ± 20 mL/100 g/min; P < .05). In total, 1026 MD samples were analyzed for energy metabolic alterations including glucose and the lactate/pyruvate ratio (LPR). The LPR was persistently elevated in the PHZ compared to the SNX region (P < .05). LPR elevations in the PHZ were predominately type II (pyruvate normal-high; indicating mitochondrial dysfunction) as opposed to type I (pyruvate low; indicating ischemia) at 4 to 48 h (70% vs 30%) and at 49 to 84 h (79% vs 21%; P < .05) postsurgery. CONCLUSION Despite normalization of CBF following ICH evacuation, an energy metabolic disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone. Cerebral blood flow, Energy metabolism, Intracerebral hemorrhage, Microdialysis, Xenon-enhanced computed tomography ABBREVIATIONS ABBREVIATIONS CBF cerebral blood flow CPP cerebral perfusion pressure CT computed tomography CTP computed tomography perfusion GCS-M motor component of Glasgow Coma Scale ICH intracerebral hemorrhage ICP intracranial pressure LPR lactate/pyruvate ratio MD microdialysis MML mixed models linear NCC neurocritical care PET positron emission tomography PHZ perihemorrhagic zone rCBF regional cerebral blood flow ROI regions of interest SD standard deviation SNX seemingly normal cortex Xe-CT Xenon-enhanced computed tomography Spontaneous, nonaneurysmal intracerebral hemorrhage (ICH) carries a 30-d mortality rate of 25% to 48%,1 and <40% of survivor reach functional independence.2 Despite refined stroke and neurocritical care (NCC) units, the case fatality rate has not markedly improved over the past decades.2 Surgical evacuation of an ICH is commonly life-saving, particularly for lobar ICHs, although it has not convincingly shown a distinct clinical benefit, compared to the best medical treatment, on clinical recovery in a larger selection of ICH patients.3,4 The causes of the modest clinical efficacy of surgery are unclear. There is an immediate mechanical disruption of glial cells, neurons, and axons at ICH onset,5 followed by a complex cascade of secondary injury factors, many of which remain unknown.6 Plausibly, these persisting secondary injury processes are insufficiently attenuated by surgical removal of the blood clot. In addition, a persistent energy metabolic crisis7 at time of regional hypoperfusion8 in the tissue surrounding the ICH, the perihemorrhagic zone (PHZ), may be crucial. Clinically, the energy metabolism may be assessed using cerebral microdialysis (MD) for the analysis of the lactate/pyruvate ratio (LPR), reflecting the cytoplasmatic redox state. Increased LPR may be caused by ischaemia, named type I LPR elevation, and mitochondrial dysfunction, named type II LPR elevation.9 The time course, type and extent of energy metabolic and blood flow disturbances in ICH remain to be established.8, 10 TABLE 1. Patient Characteristics Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  ICH, intracerebral hemorrhage; HT, hypertension, CVL, previous cerebrovascular lesion; AF, atrial fibrillation; VKA, vitamin-K antagonist (Warfarin) treatment; HepB, Hepatitis B; DM, diabetes mellitus; GCS-M, motor component of Glasgow Coma Scale score; NCC, neurocritical care; LOS, length of stay; mRS, modified Rankin Scale score assessed at 3 mo postsurgery; LTF, lost to follow-up. View Large TABLE 1. Patient Characteristics Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  Patient no.  Age (yr)  Co-morbidities  ICH size (mL)  Midline shift (mm)  GCS-M on arrival  NCC LOS (d)  GCS-M on departure  Outcome (mRS)  1  48  HT, CVL  57.4  11  5  7  5  4  2  55  HT  86.6  10  5  5  4  6  3  26  HT  64.2  9  5  9  6  3  4  62  0  24.7  3  5  6  4  4  5  68  HT, AF, VKA  89.5  9  5  5  3  4  6  51  HepB  81.4  5  5  5  5  LTF  7  67  HT, DM  44.1  9  5  7  5  LTF  8  52  HT  35.5  4  6  4  6  2  9  71  0  75.0  5  5  3  6  2  10  66  0  90.5  14  3  5  4  6  11  68  0  41.2  13  5  9  6  4  12  65  0  42.4  5  5  9  6  3  ICH, intracerebral hemorrhage; HT, hypertension, CVL, previous cerebrovascular lesion; AF, atrial fibrillation; VKA, vitamin-K antagonist (Warfarin) treatment; HepB, Hepatitis B; DM, diabetes mellitus; GCS-M, motor component of Glasgow Coma Scale score; NCC, neurocritical care; LOS, length of stay; mRS, modified Rankin Scale score assessed at 3 mo postsurgery; LTF, lost to follow-up. View Large The aim of this study of surgically treated ICH patients was to investigate the energy metabolic situation in the PHZ compared to that in seemingly normal cortex (SNX) using dual MD catheters. In addition, cerebral blood flow (CBF) was evaluated at an early and late time point postoperatively. We hypothesized that surgical ICH removal is associated with an improved CBF and/or energy metabolism in the tissue surrounding the ICH. METHODS Study Design Prospectively recruited spontaneous ICH patients, surgically treated between November 2014 and November 2016, were included. The Regional Ethical Committee approved the study. A written informed consent was obtained from the patient's closest relative. Patient Characteristics and Management Patients >18 yr old requiring surgical evacuation of supratentorial ICH, receiving dual cerebral MD catheters and repeated evaluation of CBF during NCC were conveniently recruited. Surgical and clinical decisions were made by the consultant neurosurgeon on a case-by-case basis. Candidates for surgical evacuation and/or intracranial pressure (ICP) monitoring were ICH patients showing impaired or deteriorating level of consciousness and a surgically accessible ICH. Exclusion criteria were age <18 yr old, coagulopathy, and when a next of kin could not be located. Patients who did not receive dual MD catheters or 2 CBF investigations were also excluded. On admission, the clinical characteristics including the motor component of the Glasgow Coma Scale (GCS-M) score was noted (Table 1). For patients intubated at the referring hospital, the GCS-M preceding intubation was noted. Intubated patients were sedated using propofol (n = 12) and midazolam (n = 1) pre- and postoperatively. All patients were operated by routine craniotomy using a free bone flap, followed by microneurosurgical evacuation of the blood clot. ICP monitoring was performed in 10 patients (Figure 1). Postoperatively, the patients were managed in the NCC unit with a standardized treatment protocol including monitoring of secondary insults such as increased ICP and reduced cerebral perfusion pressure (CPP).11,12 ICP-monitoring was achieved using Neurovent-P parenchymal pressure monitoring device (Raumedic AG, Helmbrechts, Germany) or Bactiseal ventricular catheter (DePuy Synthes, Raynham, Massachusetts). Time to surgery was defined as time from known or presumed ictus to surgery. FIGURE 1. View largeDownload slide Native and Xenon-enhanced CT-scan; evaluation of CBF and placement of MD catheters. A, CT scan of a 67-yr-old man with a large left-sided ICH in the basal ganglia, emergently treated surgically by craniotomy and open evacuation of the clot. B, Postoperative CT scan shows the location of the 2 MD catheters, one (→) in the PHZ in the vicinity of the hemorrhage cavity (*), the other in SNX (⇒open arrow). C, First postoperative Xe-CT CBF evaluation showing the hand-drawn ROI surrounding the MD catheters. D, The second Xe-CT CBF evaluation at 66 h postoperatively shows the 20 standardized cortical ROIs used in the present study. FIGURE 1. View largeDownload slide Native and Xenon-enhanced CT-scan; evaluation of CBF and placement of MD catheters. A, CT scan of a 67-yr-old man with a large left-sided ICH in the basal ganglia, emergently treated surgically by craniotomy and open evacuation of the clot. B, Postoperative CT scan shows the location of the 2 MD catheters, one (→) in the PHZ in the vicinity of the hemorrhage cavity (*), the other in SNX (⇒open arrow). C, First postoperative Xe-CT CBF evaluation showing the hand-drawn ROI surrounding the MD catheters. D, The second Xe-CT CBF evaluation at 66 h postoperatively shows the 20 standardized cortical ROIs used in the present study. Three months postoperatively, the modified Rankin Scale13 was assessed using a questionnaire or a structured interview by telephone. Neuroradiology and Blood Flow Measurement The computed tomography (CT) scan preceding surgery was analyzed for midline shift (mm) and ICH volume, using the formula (a × b × c/2)14. All patients underwent a CT-angiography preoperatively. CBF was measured using Xenon-enhanced computed tomography (Xe-CT) according to locally adopted routines.15,16 Xenon is a metabolically inert and readily diffusible tracer, safely used for CBF evaluations in NCC.16,17 Patients underwent an early (day 0-2 postsurgery) and late (day 3-6 postsurgery) Xe-CT (CereTom 0-NL3000-001, Neurologica, Danvers, Massachusetts). A gas mixture of 28% Xenon was added during a 4.3 min long wash-in period to the ventilator air/O2-mixture. The computer software (Diversified Diagnostic Products Inc, Houston, Texas) enabled the timed Xenon delivery. A standard 4-level Xenon-CT CBF exam using 10 mm spacing between levels (using 8 scans per level, 2 baseline and 6 enhanced) was used and CBF (mL/100 g/min) calculated from the tissue enhancement by the Xenon.18,19 The CBF-values were visualized using a color-coded image (Figures 1C-1D). A modified Kety–Schmidt method was used,15,20 and mean cortical CBF for 20 evenly distributed regions of interest (ROI; Figure 1D) in each of the 4 levels were automatically calculated. The area of the MD catheters was identified on the structural CT and manually outlined (Figure 1C). This ROI was ≥200 mm2 for robust mathematical CBF calculations.19 At the time of Xe-CT CBF investigations, patients were sedated, ventilated, and physiologically monitored (Table 2). In 2 patients computed tomography perfusion (CTP) was used to estimate CBF, 1 due to obesity and 1 to early extubation. TABLE 2. MD and CBF Characteristics Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat, patient; h, hours; MD, microdialysis; PHZ, perihemorrhagic zone; ICH, intracerebral hemorrhage; CBF, cerebral blood flow Pre: CBF estimation evaluated prior to surgery. View Large TABLE 2. MD and CBF Characteristics Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat. no.  Time from ictus to surgery (h)  Time from ictus to onset of MD sampling (h)  Duration of MD sampling (h)  Distance of PHZ-catheter to ICH (mm)  Time from surgery to CBF1 (h)  Time from surgery to CBF2 (h)  1  6  10  172  5  23  89  2  4  16  86  2  18  68  3  22  30  184  10  27  58  4  22  30  70  5  22  45  5  8  14  108  3  45  67  6  5  16  112  3  10  70  7  17  16  140  8  21  66  8  3  12  84  2  23  60  9  10  18  74  10  22  53  10  37  42  56  2  11  36  11  3  5  130  2  19  46  12  36  38  82  8  9  34  Pat, patient; h, hours; MD, microdialysis; PHZ, perihemorrhagic zone; ICH, intracerebral hemorrhage; CBF, cerebral blood flow Pre: CBF estimation evaluated prior to surgery. View Large CTP images were obtained according to clinical routine using a 128-slice CT scanner.21,22 Iodinated contrast agent (45 ml; Joversol 350 mg/ml, Gothia Medical, Gothenburg, Sweden) was administered at a rate of 6 ml/s followed by a saline flush. Image acquisition was initiated 2 s after the start of the contrast injection. Quantitative perfusion data were obtained through repeated imaging of a 90 mm/84 mm slab of the brain during a 44/45 s time period, thus covering the first pass contrast inflow. Images were reconstructed into 10 mm thick slices and analyzed using a deconvolution-based algorithm. Perfusion data were presented as color-coded maps depicting CBF, cerebral blood volume, and mean transit time, with ROIs matching the Xe-CT investigations 21,22 and evaluated by a neuroradiologist blinded to the clinical data of each individual patient. CBF data were similar from Xenon-CT and CTP examinations and were pooled. Microdialysis At time of surgery, 1 MD catheter was placed adjacent (<1 cm) to the hematoma cavity (the PHZ). One control MD catheter was placed either via the craniotomy (n = 11) or a separate burr hole (n = 1) in the SNX of a noneloquent area. CMA 71 Brain MD Catheters, membrane length 10 mm and 100 kDa molecular weight cut-off (M Dialysis AB, Solna, Sweden) were used. The catheters are routinely, since 2013 in our department, perfused with a commercially available 5% human albumin solution to reduce fluid loss across the MD membrane23,24 (Albunorm, Octapharma, Stockholm, Sweden) at a rate of 0.3 μL/min. After MD catheter insertion, 2 h passed before sampling was initiated. MD is used for clinical monitoring and to reduce the samples analyzed, vials are routinely collected on a 2-h basis instead of each hour in our unit.23-25 Interstitial glucose, lactate, pyruvate, glycerol, and glutamate were analyzed bedside (ISCUSflex analyser; M-Dialysis AB). The LPR was calculated and urea monitored MD catheter performance.26 The following MD data were considered critical.27 MD-glucose: <0.2 mmol/L critical and <0.8 mmol/L considered a warning sign; LPR > 40 critical and LPR > 25 a warning sign. The incidence of LPR elevations type I, indicating ischemia (defined as LPR > 25 or > 40 and pyruvate < 70 μmol/L)28 was noted. The definition of type II LPR elevations, indicating mitochondrial disturbance, varies in the literature.27,28 For the 2 type II LPRs (>25 and >40), 2 values for pyruvate (>70 μmol/L or >120 μmol/L) were also used, as previously suggested.9,28,29 These calculations were performed on the first 4 to 84 h of MD sampling, and all analyses were performed by a researcher (L.T.) without the knowledge of the CBF data, and vice versa. The distance from the MD catheter tip to the ICH cavity was measured on postoperative CT scan. Statistical Methods The target sample size was based on the only previous clinical ICH study where 2 MD catheters were used.7 Due to the observed differences in the PHZ compared to putatively normal MD values observed in that study, and the complexity of the present study design, we aimed to include 18 patients expecting that some patients had to be excluded. SPSS Statistics 22 (IBM, Armonk, New York) was used. Paired t-test was used for normally distributed data and paired Wilcoxon rank test for nonnormally distributed data. Chi-square test was used for comparison of proportions. Correlation analysis was performed using Spearman's rank correlation of MD data to CBF. PHZ and SNX MD data were compared using a mixed models linear (MML) approach, with catheter location as fixed effect and patients as subject level and random effect.30 MML approach was also used for hemispheric CBF differences using hemisphere as fixed effect. A P-value < .05 was considered statistically significant. Normally distributed data are presented as means ± standard deviation (SD), nonnormally distributed data as median and range. For clarity, MD data are presented using mean ± SEM. RESULTS Eighteen surgically treated ICH patients >18 yr old were recruited. Six patients were then excluded; 4 since a MD catheter malfunctioned, and 2 since CBF measurements could not be performed according to protocol. Thus, 12 patients were included. Patient Characteristics and Radiology Median patient age was 64 yr (range 26-71 yr; Table 1). Median GCS-M score on arrival was 5 (range 3-6; Table 1). Ten patients had a central ICH and 2 a lobar ICH. Hemorrhages were evacuated at a mean of 14 h (range 3-37) after ICH onset. Ten patients received ICP monitoring. Postoperatively, no patients experienced ICP-elevations requiring ICP-lowering therapies such as decompressive craniectomy, hypertonic saline/mannitol, or barbiturates. The ICH and clinical characteristics are described in Table 1. CBF Measurements CBF measurements were performed 14.2 ± 24 h (Xe-CT 1) and 59.5 ± 19 h postsurgery (Xe-CT 2) in 10 patients. The 2 CT-perfusion studies were performed at 18 and 23 h (CTP 1) and 60 and 68 h postsurgery (CTP 2), respectively. ICP, CPP, MAP, pCO2, pO2, and the use of muscle relaxant, sedatives, and inotropic drugs remained stable during the CBF investigations and were similar between the first and second CBF study (Table 2). Global CBF was 37.5 ± 21 mL/100g/min at CBF1, which improved to 40.1 ± 19 mL/100g/min at CBF2 (P < .05; Figure 2A). Regional cerebral blood flow (rCBF) was lower in the hemisphere harbouring the ICH than contralaterally (36.6 ± 20 vs 38.3 ± 21 mL/100g/min, respectively, P < .05; Figure 2A) at CBF1. At CBF2, there were no differences between the hemispheres (40.6 ± 20 and 39.6 ± 19 mL/100g/min, respectively; Figure 2A). In the MD catheter ROIs, the CBF was significantly lower in ROIPHZ (25.7 ± 14 mL/100g/min) compared to in ROISNX (40.9 ± 20 mL/100g/min; P < .05; Figure 2B) at CBF1, but there was no statistically significant difference between these regions at CBF2 (36.5 ± 27 mL/100g/min in ROIPHZ and 42.7 ± 30 mL/100g/min in ROISNX; P = .426). FIGURE 2. View largeDownload slide CBF evaluated by Xenon-CT following surgical evacuation of ICH. A, Heat-map of 40 ROI in each hemisphere shows that CBF improved significantly (*) between the early (CBF1; 20.8 ± 10 h postsurgery) and late (CBF2; 57.7 ± 16 h postsurgery) globally. The CBF in the ipsilateral hemisphere was significantly lower (indicated by *) than in the contralateral hemisphere at the early (CBF1) postinjury time-point, but this difference was not present at CBF2. CBF improved significantly between CBF1 and CBF2 both in the ipsilateral hemisphere and contralateral hemisphere (P < .05 = *). B, CBF was lower in the local ROI centered on the MD catheter in the PHZ as compared to that of the SNX on the first CBF evaluation. At the second CBF evaluation, there was no difference in CBF between the ROIs in the SNX and PHZ. PHZ, perihemorrhagic zone; SNX, seemingly normal cortex; Ipsi, ipsilateral to the hemorrhage; Contra, contralateral to the hemorrhage; n.s., not significant. FIGURE 2. View largeDownload slide CBF evaluated by Xenon-CT following surgical evacuation of ICH. A, Heat-map of 40 ROI in each hemisphere shows that CBF improved significantly (*) between the early (CBF1; 20.8 ± 10 h postsurgery) and late (CBF2; 57.7 ± 16 h postsurgery) globally. The CBF in the ipsilateral hemisphere was significantly lower (indicated by *) than in the contralateral hemisphere at the early (CBF1) postinjury time-point, but this difference was not present at CBF2. CBF improved significantly between CBF1 and CBF2 both in the ipsilateral hemisphere and contralateral hemisphere (P < .05 = *). B, CBF was lower in the local ROI centered on the MD catheter in the PHZ as compared to that of the SNX on the first CBF evaluation. At the second CBF evaluation, there was no difference in CBF between the ROIs in the SNX and PHZ. PHZ, perihemorrhagic zone; SNX, seemingly normal cortex; Ipsi, ipsilateral to the hemorrhage; Contra, contralateral to the hemorrhage; n.s., not significant. MD Reveals a Persisting Energy Metabolic Disturbance in the PHZ Following ICH Surgery In total, 6598 analyses in 1026 MD samples were performed (glucose, lactate, pyruvate, glycerol, and glutamate). The mean duration from ICH onset to start of MD sampling was 20.6 ± 12 h (range 5-94 h), and the mean duration of sampling was 108 ± 41 h (range 56-184 h; Table 3). Five vials of the 1026 were excluded due to deviating urea values.26 The low-molecular weight analyses are shown in Figures 3A-3D. There was a significant difference between the PHZ and the SNX catheter for all metabolites except glycerol (P < .05; Figures 3A-3D). In the first 4 to 84 h, 48% of MD-Glucose levels in the PHZ were below <0.8 mmol/L and 9% < 0.2 mmol/L. In the SNX, 26% of MD-Glucose levels were <0.8 mmol/L although no sample was <0.2 mmol/L. FIGURE 3. View largeDownload slide Energy metabolic disturbance in the PHZ evaluated by MD following surgery for ICH. MD analyses for the first 4 to 84 h postsurgery of the MD samples obtained from the PHZ and SNX. A-D, Results for glucose, lactate, pyruvate, and the LPR are shown. The MD-glucose levels A were consistently lower while the MD-lactate levels B and MD-pyruvate levels C were consistently higher in the PHZ compared to the SNX (P < .05). D, The LPR in the PHZ was markedly elevated, the mean ratio being consistently higher when compared to the SNX (*P < .05). FIGURE 3. View largeDownload slide Energy metabolic disturbance in the PHZ evaluated by MD following surgery for ICH. MD analyses for the first 4 to 84 h postsurgery of the MD samples obtained from the PHZ and SNX. A-D, Results for glucose, lactate, pyruvate, and the LPR are shown. The MD-glucose levels A were consistently lower while the MD-lactate levels B and MD-pyruvate levels C were consistently higher in the PHZ compared to the SNX (P < .05). D, The LPR in the PHZ was markedly elevated, the mean ratio being consistently higher when compared to the SNX (*P < .05). TABLE 3. Clinical Parameters at the Time of CBF-Measurement Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  ICP, intracranial pressure; CPP, cerebral perfusion pressure; MAP, mean arterial blood pressure; NE, norepinephrine; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen All data presented as means ± SD. P-values from Student's t-test. View Large TABLE 3. Clinical Parameters at the Time of CBF-Measurement Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  Parameter  CBF1 (n = 12)  CBF2 (n = 12)  P-value  ICP (cmH20; n = 10)  12.7 ± 6  13.7 ± 3  .96  CPP (mmHg; n = 10)  67.3 ± 10  73.4 ± 11  .33  MAP (mmHg)  86.6 ± 10  92.8 ± 12  .25  Propofol 20 mg/mL (mL/h)  15.3 ± 7  15.2 ± 8  .95  Remifentanil 100 μg/mL (mL/h)  5.0 ± 4  5.5 ± 4  .22  NE 40 μg/mL (mL/h)  7.2 ± 6  5.8 ± 4  .34  pCO2 (kPa)  5.4 ± 0.3  5.3 ± 0.5  .13  pO2 (kPa)  13.0 ± 2  14.2 ± 2  .39  ICP, intracranial pressure; CPP, cerebral perfusion pressure; MAP, mean arterial blood pressure; NE, norepinephrine; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen All data presented as means ± SD. P-values from Student's t-test. View Large The MD-lactate levels were consistently higher (P < .05; Figure 3B) in the PHZ compared to the SNX, as was MD-glutamate (P < .05; data not shown). The MD-pyruvate levels were also higher in the PHZ compared to the SNX (P < .05; Figure 3C). There was no significant difference in MD-glycerol between sampled regions (not shown). The lactate/pyruvate ratio was consistently elevated in the PHZ compared to the SNX (P < .05; Figure 3D). In the first 4 to 84 h, the LPR was >25 in 70% of all samples (298/424 samples) in the PHZ as compared to 23% (101/436 samples) in the SNX (P < .05). The LPR was >40 in 38% (163/424 samples) in the PHZ and 3% (14/472 samples) of all MD samples in the SNX (P < .05). The definition of type II LPR requires normal or elevated pyruvate levels >70 μmol/L. Of note, in previous definitions of type II LPR elevations pyruvate levels either >120 μmol/L or >70μmol/L were used.9,29,31,32 In our material, pyruvate levels >120 μmol/L were more common than 70 to 120 μmol/L in type II LPR elevations, presented in full detail in Figure 4A and 4B. In the following paragraph, all type II LPR elevations with pyruvate levels >70 μmol/L are reported. FIGURE 4. View largeDownload slide LPR elevations in the PHZ following surgical evacuation of ICH. Based on available literature and recommendations, a LPR elevation in MD samples may be defined as >25 A or >40 B. In addition, a type I LPR elevation (defined as an LPR elevation and pyruvate levels <70 μmol/L) indicates an ischemic situation, and a type II LPR elevation (defined as an LPR elevation and pyruvate level being either 70-120 or >120 mmol/L9,28,29,31,54,55) indicates mitochondrial dysfunction. A, When comparing the LPR elevations, here defined as an LPR > 25, obtained from MD catheters placed in the PHZ, the incidence of type I LPR and particularly type II LPR was higher than the values from MD catheters placed in SNX early (4-48 h) following ICH surgery. At the late postsurgery time-points (48-84 h) the energy metabolic disturbance persisted in the PHZ, although less pronounced than at the early time point. The majority of these LPR elevations were of type II, indicating persisting mitochondrial disturbance. B, Less MD samples met the criteria for type I and type II LPR elevations when an LPR > 40 was used as a cut-off. Still, both type I and type II LPR elevations were observed with similar relative frequencies observed when LPR > 25 was used as a cut-off. pyr, pyruvate; P < .05 between groups at both LPR > 25 and LPR > 40. FIGURE 4. View largeDownload slide LPR elevations in the PHZ following surgical evacuation of ICH. Based on available literature and recommendations, a LPR elevation in MD samples may be defined as >25 A or >40 B. In addition, a type I LPR elevation (defined as an LPR elevation and pyruvate levels <70 μmol/L) indicates an ischemic situation, and a type II LPR elevation (defined as an LPR elevation and pyruvate level being either 70-120 or >120 mmol/L9,28,29,31,54,55) indicates mitochondrial dysfunction. A, When comparing the LPR elevations, here defined as an LPR > 25, obtained from MD catheters placed in the PHZ, the incidence of type I LPR and particularly type II LPR was higher than the values from MD catheters placed in SNX early (4-48 h) following ICH surgery. At the late postsurgery time-points (48-84 h) the energy metabolic disturbance persisted in the PHZ, although less pronounced than at the early time point. The majority of these LPR elevations were of type II, indicating persisting mitochondrial disturbance. B, Less MD samples met the criteria for type I and type II LPR elevations when an LPR > 40 was used as a cut-off. Still, both type I and type II LPR elevations were observed with similar relative frequencies observed when LPR > 25 was used as a cut-off. pyr, pyruvate; P < .05 between groups at both LPR > 25 and LPR > 40. In the PHZ at 4 to 48 h, of all samples with LPR > 25 (n = 190/255 samples), 30% had type I and 70% type II LPR elevation. In the PHZ at 49 to 84 h, of all samples with LPR > 25 (n = 108/169 samples), 21% had a type I and 79% type II LPR elevation (P < .05; Figure 4A). In the SNX at 4 to 48 hours, of all samples with LPR > 25 (n = 72/257), 58% had a type I and 42% had type II LPR elevation. In the SNX at 49 to 84 h, of all samples with LPR > 25 (n = 29/179 samples), 62% had a type I and 38% had a type II LPR elevation (P < .05; Figure 4A). In the PHZ at 4 to 48 h, of all samples with LPR elevations >40 (n = 103/255), 41% had type I and 59% a type II LPR elevation. In the PHZ at 49 to 84 h, of all samples with LPR > 40 (n = 60/169 samples), 32% had a type I and 68% a type II LPR elevation. In the SNX at 4 to 48 h, LPR was >40 in only 5 of 257 samples, of these 60% had a type I and 40% had a type II LPR elevation. At 49 to 84 h in the SNX, 9 of 179 samples had an LPR > 40 and of these, 89% had a type I and 11% had a type II LPR elevation (P < .05; Figure 4B). There was no correlation between CBF and LPR analyzed in time periods of 2, 4, 6, or 10 h prior to CBF investigation (data not shown). DISCUSSION The present study, the first to use dual MD catheters combined with repeated evaluations of CBF, shows a persisting energy metabolic disturbance in the brain tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH) despite a normalization of CBF. Moreover, the pattern of LPR elevations indicates a persistent mitochondrial disturbance. CBF Changes Following ICH Surgery Most rCBF levels were higher than those typically associated with ischemia, both in the ipsilateral hemisphere and in the PHZ. Furthermore, an improved CBF ipsilateral to the evacuated hematoma was observed between the 2 CBF studies, conducted at 21 and 58 h postsurgery. We cannot exclude that time to ICH removal, which varied among the patients, influenced the CBF values. In nonevacuated ICH, a hypoperfusion zone surrounding the hemorrhage was observed in both the experimental33-36 and clinical setting.37-39 Using positron emission tomography (PET), the PHZ displayed a reduced CBF up to 43 h postictus,40 although not reaching ischemic levels.38,40,41 Additionally, no evidence of PHZ ischemia was observed in conservatively treated ICH patients using magnetic resonance spectroscopy.37 Although no CBF studies comparing surgically and conservatively treated ICH patients over time are available, previous experimental and clinical studies report an improved CBF following ICH removal, 35,42-44 implying that surgical blood clot removal aids in restoring CBF. In conservatively treated ICH patients, a varying pattern of initial hypoperfusion was coupled to hypometabolism in the PHZ.37,38,44-48 Although some reports show a gradual normalization of CBF over time,8 others show a variable decrease.40,44,45,47,48 For clinical reasons, we used 2 techniques for investigating CBF, Xe-CT in 10 and CTP in 2 patients, with good correlation between these methods.49,50 Since CTP determines only relative, not absolute CBF, it was used here only when Xe-CT could not be performed. Energy Metabolic Disturbances in Brain Tissue Following ICH Surgery An ICH may be surrounded by a potentially salvageable PHZ different from the penumbra of ischemic stroke, in which the supply of oxygen and substrate is sufficient for cell survival although insufficient for normal neuronal activity.51 Although there was gradual improvement of MD glucose, lactate, and the LPR, normalization did not occur suggesting a pattern of persistent metabolic impairment in the PHZ, evident by an elevated LPR. In a previous study, 1 to 3 PHZ MD catheters were used and the immediate LPR increase following ICH surgery gradually normalized, similarly to our results. Glucose levels were normal, whereas pyruvate levels were not presented.7 In addition, CBF was not evaluated and no distinction between type I and II LPR elevations was made.7 Similar to traumatic brain injury,9,52 subarachnoid hemorrhage28 and bacterial meningitis patients,32 the LPR elevations observed in the present study suggest a mitochondrial dysfunction, which could contribute to the rather modest motor improvement observed postsurgery in our cohort. There are no established criteria for type I or type II LPR elevations. Based on available literature, we used 2 different LPRs as well as pyruvate levels, based on the suggested reference pyruvate values (166 ± 47 μmol/L).9,28,29,31,32,53-55 Regardless of the definition, the PHZ displayed higher LPRs, mainly type II, than the SNX. In contrast, glucose levels were above critical thresholds indicating sufficient substrate delivery. We cannot exclude that the surgical approach contributed to the suggested mitochondrial dysfunction since no nonsurgical control group was available. However, our data support previous work using PET-studies obtained 5 to 22 h after ICH onset, and work using a single perioperative biopsy, obtained at 6 to 72 h in 6 patients, showing reduced oxygen extraction fraction, hypometabolism, and mitochondrial dysfunction in the PHZ.38,45,56 Persisting mitochondrial dysfunction with a reduced capacity for ATP generation may cause ongoing exacerbation of the ICH-induced tissue injury in the PHZ, as suggested by studies in traumatic brain injury,57 and be an important secondary injury factor leading to delayed neuronal necrosis and/or apoptosis. Presumably, many factors contribute to mitochondrial dysfunction although complex metabolomics alterations could not be assessed using the present methodology. A few studies have evaluated possible treatment options for mitochondrial dysfunction in acute brain injury, including administrating succinate to the damaged tissue58 or treating patients with suggested mitochondrial dysfunction with cyclosporine A,59 hyperbaric oxygen,60 or lactate, 61 interesting also for future ICH studies. Study Limitations The present data are based on a relatively small number of patients, included at a variable time point after ICH onset, and with a variable ICH location and volume. Since MD cannot be used in conservatively treated patients, we compared the energy metabolic situation in the PHZ with that in normal cortex. Although the control MD catheter was aimed at an area distant from the PHZ, preoperative pressure caused by ICH may have influenced the MD values of the SNX. Most devices for ICP monitoring were inserted ipsilaterally, and a separate burr hole solely for MD insertion could not be justified. No preoperative CBF measurements could be obtained and both the ICH itself and the surgery may have contributed to our results. Also, the small sample size did not allow us to evaluate any potential differences in CBF and metabolic disturbances across age groups or between patients with deep vs lobar hemorrhages. MD monitors a ∼2 cm3 brain region,62 and the MD catheters were placed at a predefined location. Since all PHZ MD catheters were within 10 mm of the ICH, the influence of variations in MD catheter positioning on our results was presumably minor. Since the tissue injury imposed by the surgical approach may influence CBF and/or MD values, we cannot establish whether the observed CBF changes was caused by the surgical manipulation needed for ICH removal per se or merely reflected its natural course. Although no patient suffered from increased ICP postoperatively, we cannot exclude that preoperative ICP elevations resulted in persisting changes in CBF and/or MD results. Finally, the MD results could have been influenced by the variable time from ICH onset to initiation of sampling. CONCLUSION Our data show that global and hemispheric CBF was gradually normalized following surgical evacuation of ICH. However, despite improved CBF a pattern of energy metabolic disturbance suggestive of mitochondrial dysfunction persisted in the PHZ. This may indicate that secondary pathological cascades triggered by the blood and/or the surgical trauma result in an ongoing energy metabolic crisis. Future studies are needed to determine if an earlier ICH evacuation could help restore the energy metabolic situation. Since it is plausible that surgical ICH removal contributes to improved CBF, future therapies may aim to target the mitochondrial dysfunction persisting in surgically treated ICHs. Disclosures This study was supported by STROKE-Riksförbundet (Skärholmen, Sweden), and the Anaesthesia, Operations and Specialty Surgery Centre, and local hospital ALF-funds (Region Östergötland, Linköping, Sweden). None of the financing agencies had any influence on the design or implementation of the study, the analysis and interpretation of results, or the writing of the manuscript. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes The preliminary results of this study were presented as a poster at the European Stroke Organisation Conference in Prague, Czech Republic on 16th May 2017, and the meeting abstract was published in European Stroke Journal 2017, vol. 2, 1_suppl: pp. 496-562. REFERENCES 1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol . 2009; 8( 4): 355- 369. Google Scholar CrossRef Search ADS PubMed  2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol . 2010; 9( 2): 167- 176. Google Scholar CrossRef Search ADS PubMed  3. Mendelow AD, Gregson BA, Fernandes HM et al.  . Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet . 2005; 365( 9457): 387- 397. Google Scholar CrossRef Search ADS PubMed  4. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet . 2013; 382( 9890): 397- 408. Google Scholar CrossRef Search ADS PubMed  5. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med . 2001; 344( 19): 1450- 1460. Google Scholar CrossRef Search ADS PubMed  6. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet . 2009; 373( 9675): 1632- 1644. Google Scholar CrossRef Search ADS PubMed  7. Nilsson OG, Polito A, Saveland H, Ungerstedt U, Nordstrom CH. Are primary supratentorial intracerebral hemorrhages surrounded by a biochemical penumbra? A microdialysis study. Neurosurgery . 2006; 59( 3): 521- 528; discussion 521-528. Google Scholar CrossRef Search ADS PubMed  8. Qureshi AI, Hanel RA, Kirmani JF, Yahia AM, Hopkins LN. Cerebral blood flow changes associated with intracerebral hemorrhage. Neurosurg Clin N Am . 2002; 13( 3): 355- 370. Google Scholar CrossRef Search ADS PubMed  9. Nordstrom CH, Nielsen TH, Schalen W, Reinstrup P, Ungerstedt U. Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion. Acta Neurochir . 2016; 158( 7): 1231- 1240. Google Scholar CrossRef Search ADS PubMed  10. Siddique MS, Fernandes HM, Wooldridge TD, Fenwick JD, Slomka P, Mendelow AD. Reversible ischemia around intracerebral hemorrhage: a single-photon emission computerized tomography study. J Neurosurg . 2002; 96( 4): 736- 741. Google Scholar CrossRef Search ADS PubMed  11. Elf K, Nilsson P, Enblad P. Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care*. Crit Care Med . 2002; 30( 9): 2129- 2134. Google Scholar CrossRef Search ADS PubMed  12. Grande PO, Asgeirsson B, Nordstrom CH. Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments. Acta Anaesthesiol Scand . 2002; 46( 8): 929- 941. Google Scholar CrossRef Search ADS PubMed  13. Bruno A, Shah N, Lin C et al.  . Improving modified Rankin Scale assessment with a simplified questionnaire. Stroke . 2010; 41( 5): 1048- 1050. Google Scholar CrossRef Search ADS PubMed  14. Webb AJ, Ullman NL, Morgan TC et al.  . Accuracy of the ABC/2 Score for Intracerebral Hemorrhage. Stroke . 2015; 46( 9): 2470- 2476. Google Scholar CrossRef Search ADS PubMed  15. Hillman J, Sturnegk P, Yonas H et al.  . Bedside monitoring of CBF with xenon-CT and a mobile scanner: a novel method in neurointensive care. Brit J Neurosurg . 2005; 19( 5): 395- 401. Google Scholar CrossRef Search ADS   16. Sturnegk P, Mellergard P, Yonas H, Theodorsson A, Hillman J. Potential use of quantitative bedside CBF monitoring (Xe-CT) for decision making in neurosurgical intensive care. Brit J Neurosurg . 2007; 21( 4): 332- 339. Google Scholar CrossRef Search ADS   17. Carlson AP, Brown AM, Zager E et al.  . Xenon-enhanced cerebral blood flow at 28% xenon provides uniquely safe access to quantitative, clinically useful cerebral blood flow information: a multicenter study. Am J Neuroradiol.  2011; 32( 7): 1315- 1320. Google Scholar CrossRef Search ADS   18. Good WF, Gur D, Herron JM, Kennedy WH. The development of a xenon/computed tomography cerebral blood flow quality assurance phantom. Med Phys . 1987; 14( 5): 867- 869. Google Scholar CrossRef Search ADS PubMed  19. Fatouros PP, Wist AO, Kishore PR et al.  . Xenon/computed tomography cerebral blood flow measurements methods and accuracy. Invest Radiol . 1987; 22( 9): 705- 712. Google Scholar CrossRef Search ADS PubMed  20. Rostami E, Engquist H, Johnson U et al.  . Monitoring of cerebral blood flow and metabolism bedside in patients with subarachnoid hemorrhage-a Xenon-CT and microdialysis study. Front Neurol . 2014; 5: 89. Google Scholar PubMed  21. Hoeffner EG, Case I, Jain R et al.  . Cerebral perfusion CT: technique and clinical applications. Radiology . 2004; 231( 3): 632- 644. Google Scholar CrossRef Search ADS PubMed  22. Konstas AA, Goldmakher GV, Lee TY, Lev MH. Theoretic basis and technical implementations of CT perfusion in acute ischemic stroke, part 1: Theoretic basis. Am J Neuroradiol.  2009; 30( 4): 662- 668. Google Scholar CrossRef Search ADS   23. Hillman J, Aneman O, Anderson C, Sjogren F, Saberg C, Mellergard P. A microdialysis technique for routine measurement of macromolecules in the injured human brain. Neurosurgery . 2005; 56( 6): 1264- 1270; discussion 1268-1270. Google Scholar CrossRef Search ADS PubMed  24. Hillered L, Dahlin AP, Clausen F et al.  . Cerebral microdialysis for protein biomarker monitoring in the neurointensive care setting-a technical approach. Front Neurol . 2014; 5: 245. Google Scholar CrossRef Search ADS PubMed  25. Hillman J, Milos P, Yu ZQ, Sjogren F, Anderson C, Mellergard P. Intracerebral microdialysis in neurosurgical intensive care patients utilising catheters with different molecular cut-off (20 and 100?kD). Acta Neurochir (Wien) . 2006; 148( 3): 319- 324; discussion 324. Google Scholar CrossRef Search ADS PubMed  26. Ronne-Engstrom E, Cesarini KG, Enblad P et al.  . Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound. J Neurosurg . 2001; 94( 3): 397- 402. Google Scholar CrossRef Search ADS PubMed  27. Hutchinson PJ, Jalloh I, Helmy A et al.  . Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med . 2015; 41( 9): 1517- 1528. Google Scholar CrossRef Search ADS PubMed  28. Jacobsen A, Nielsen TH, Nilsson O, Schalen W, Nordstrom CH. Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand . 2014; 130( 3): 156- 163. Google Scholar CrossRef Search ADS PubMed  29. Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordstrom CH. Cerebral energy metabolism during induced mitochondrial dysfunction. Acta Anaesthesiol Scand . 2013; 57( 2): 229- 235. Google Scholar CrossRef Search ADS PubMed  30. Field A. Discovering Statistics Using IBM SPSS Statistics: And Sex And Drugs And Rock ‘N’ Roll.  4th ed. United Kingdom, Europe: Sage; 2013. 31. Nielsen TH, Olsen NV, Toft P, Nordstrom CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand . 2013; 57( 6): 793- 801. Google Scholar CrossRef Search ADS PubMed  32. Poulsen FR, Schulz M, Jacobsen A et al.  . Bedside evaluation of cerebral energy metabolism in severe community-acquired bacterial meningitis. Neurocrit Care . 2015; 22( 2): 221- 228. Google Scholar CrossRef Search ADS PubMed  33. Bullock R, Brock-Utne J, van Dellen J, Blake G. Intracerebral hemorrhage in a primate model: effect on regional cerebral blood flow. Surg Neurol . 1988; 29( 2): 101- 107. Google Scholar CrossRef Search ADS PubMed  34. Nehls DG, Mendelow AD, Graham DI, Sinar EJ, Teasdale GM. Experimental intracerebral hemorrhage: progression of hemodynamic changes after production of a spontaneous mass lesion. Neurosurgery . 1988; 23( 4): 439- 444. Google Scholar CrossRef Search ADS PubMed  35. Nehls DG, Mendelow DA, Graham DI, Teasdale GM. Experimental intracerebral hemorrhage: early removal of a spontaneous mass lesion improves late outcome. Neurosurgery . 1990; 27( 5): 674- 682; discussion 682. Google Scholar CrossRef Search ADS PubMed  36. Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg . 1994; 81( 1): 93- 102. Google Scholar CrossRef Search ADS PubMed  37. Carhuapoma JR, Wang PY, Beauchamp NJ, Keyl PM, Hanley DF, Barker PB. Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage. Stroke . 2000; 31( 3): 726- 732. Google Scholar CrossRef Search ADS PubMed  38. Zazulia AR, Diringer MN, Videen TO et al.  . Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab.  2001; 21( 7): 804- 810. Google Scholar CrossRef Search ADS PubMed  39. Schellinger PD, Fiebach JB, Hoffmann K et al.  . Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra? Stroke . 2003; 34( 7): 1674- 1679. Google Scholar CrossRef Search ADS PubMed  40. Hirano T, Read SJ, Abbott DF et al.  . No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage. Neurology . 1999; 53( 9): 2179- 2179. Google Scholar CrossRef Search ADS PubMed  41. Powers WJ, Zazulia AR, Videen TO et al.  . Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology . 2001; 57( 1): 18- 24. Google Scholar CrossRef Search ADS PubMed  42. Etminan N, Beseoglu K, Turowski B, Steiger HJ, Hanggi D. Perfusion CT in patients with spontaneous lobar intracerebral hemorrhage: effect of surgery on perihemorrhagic perfusion. Stroke . 2012; 43( 3): 759- 763. Google Scholar CrossRef Search ADS PubMed  43. Tanizaki Y. Improvement of cerebral blood flow following stereotactic surgery in patients with putaminal haemorrhage. Acta Neurochir . 1988; 90( 3-4): 103- 110. Google Scholar CrossRef Search ADS PubMed  44. Siddique MS, Fernandes HM, Arene NU, Wooldridge TD, Fenwick JD, Mendelow AD. Changes in cerebral blood flow as measured by HMPAO SPECT in patients following spontaneous intracerebral haemorrhage. Acta Neurochir Suppl.  2000; 76: 517- 520. Google Scholar PubMed  45. Kawakami H, Kutsuzawa T, Uemura K, Sakurai Y, Nakamura T. Regional cerebral blood flow in patients with hypertensive intracerebral hemorrhage. Stroke . 1974; 5( 2): 207- 212. Google Scholar CrossRef Search ADS PubMed  46. Miyazawa N, Mitsuka S, Asahara T et al.  . Clinical features of relative focal hyperfusion in patients with intracerebral hemorrhage detected by contrast-enhanced xenon CT. AJNR Am J Neuroradiol.  1998; 19( 9): 1741- 1746. Google Scholar PubMed  47. Mayer SA, Lignelli A, Fink ME et al.  . Perilesional blood flow and edema formation in acute intracerebral hemorrhage : a SPECT study. Stroke . 1998; 29( 9): 1791- 1798. Google Scholar CrossRef Search ADS PubMed  48. Tayal AH, Gupta R, Yonas H et al.  . Quantitative perihematomal blood flow in spontaneous intracerebral hemorrhage predicts in-hospital functional outcome. Stroke . 2007; 38( 2): 319- 324. Google Scholar CrossRef Search ADS PubMed  49. Wintermark M, Thiran JP, Maeder P, Schnyder P, Meuli R. Simultaneous measurement of regional cerebral blood flow by perfusion CT and stable xenon CT: a validation study. AJNR Am J Neuroradiol.  2001; 22( 5): 905- 914. Google Scholar PubMed  50. Honda M, Sase S, Yokota K et al.  . Early cerebral circulation disturbance in patients suffering from different types of severe traumatic brain injury: a xenon CT and perfusion CT study. Acta Neurochir Suppl.  2013; 118: 259- 263. Google Scholar PubMed  51. Cipolla MJ. The Cerebral Circulation . San Rafael (CA): Morgan & Claypool Life Sciences; 2009. 52. Vespa P, Bergsneider M, Hattori N et al.  . Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab . 2005; 25( 6): 763- 774. Google Scholar CrossRef Search ADS PubMed  53. Hutchinson P, O’Phelan K. International multidisciplinary consensus conference on multimodality monitoring: cerebral metabolism. Neurocrit Care . 2014; 21( S2): 148- 158. Google Scholar CrossRef Search ADS   54. Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, Nordstrom CH. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery . 2000; 47( 3): 701- 709; discussion 709-710. Google Scholar PubMed  55. Nielsen TH, Schalen W, Stahl N, Toft P, Reinstrup P, Nordstrom CH. Bedside diagnosis of mitochondrial dysfunction after malignant middle cerebral artery infarction. Neurocrit Care . 2014; 21( 1): 35- 42. Google Scholar CrossRef Search ADS PubMed  56. Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke . 2006; 37( 10): 2457- 2462. Google Scholar CrossRef Search ADS PubMed  57. Xu Y, McArthur DL, Alger JR et al.  . Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury. J Cereb Blood Flow Metab . 2010; 30( 4): 883- 894. Google Scholar CrossRef Search ADS PubMed  58. Jalloh I, Helmy A, Howe DJ et al.  . Focally perfused succinate potentiates brain metabolism in head injury patients. J Cereb Blood Flow Metab . 2016; 37( 7): 2626- 2638. Google Scholar CrossRef Search ADS PubMed  59. Cour M, Abrial M, Jahandiez V et al.  . Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure. J Appl Physiol . 2014; 117( 8): 930- 936. Google Scholar CrossRef Search ADS PubMed  60. Hiebert JB, Shen Q, Thimmesch AR, Pierce JD. Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci . 2015; 350( 2): 132- 138. Google Scholar CrossRef Search ADS PubMed  61. Dienel GA. Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations. J Cereb Blood Flow Metab . 2014; 34( 11): 1736- 1748. Google Scholar CrossRef Search ADS PubMed  62. Maurer MH, Haux D, Unterberg AW, Sakowitz OW. Proteomics of human cerebral microdialysate: from detection of biomarkers to clinical application. Prot Clin Appl.  2008; 2( 3): 437- 443. Google Scholar CrossRef Search ADS   Acknowledgements The authors thank neuroradiologists Inger Eveman and Jakob de Geer for valuable methodological insights and assistance. COMMENTS The clinical benefit of evacuation of ICH has been difficult to show. The authors have investigated whether reduced CBF and/or metabolic energy disturbances exist in the tissue surrounding a surgically evacuated ICH. CBF was measured using xenon-enhanced CT or CT perfusion, and metabolic state was measured using dual microdialysis probes, 1 in the perihemorrhagic zone and 1 in presumed normal tissue. The authors conclude that CBF is normalized following ICH evacuation, whereas a metabolic energy disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone. Although the series is relatively small and heterogeneous, the data set add some information on the pathophysiological mechanisms of brain damage after spontaneous ICH. Since there is no control group, for good reasons, the effect of surgery on the observed changes is, however, still uncertain. One of the main reasons to evacuate an ICH is to prevent secondary injury in the penumbral area around the hematoma. Since CBF was normalized whereas a metabolic energy disturbance persisted after evacuation, future studies should aim at investigating whether there is a time window for evacuation that will increase the probability of restoring the metabolic state. The slight improvement in both glucose, lactate, and LPR in the perihemorrhagic zone over time although normalization was not reached, may indicate that earlier surgical intervention can improve the metabolic state in the perihemorrhagic zone. Jon Berg-Johnsen Oslo, Norway The authors offer a manuscript describing the results of a prospective study of cerebral blood flow measurements via Xenon CT and cellular energy metabolism via microdialysis (MD) in patients undergoing open surgical evacuation of ICH. While this study is small, it is well designed and provides valuable prospective paired data on the state of brain CBF and metabolism in the initial postoperative period as well as in a delayed fashion after surgery. The study is enhanced by having MD data from both the perihemorrhagic zone as well as from seemingly normal brain cortex. The authors conclude that while surgery seemingly restores CBF, metabolic derangement in the tissue persist for at least a few days postoperatively. I think this study is particularly timely with recent trends in minimally invasive ICH evacuation, and while it involves maximally invasive craniotomies, I think the data can be applied to more recent surgical trends. This study will lay the groundwork for future studies of CBF and metabolism in surgically vs conservatively managed ICH patients. Joshua Osbun St. Louis, Missouri The authors should be congratulated, for this elegant microdialysis study, which makes 2 novel contributions… First, It offers new insight into the reasons why patients do not seem to robustly improve after removal of intracerebral hemorrhage, and second it shows the potential of intracerebral microdialysis to uniquely provide hard neurochemical evidence of metabolic changes in the living human brain. Several authors have documented CBF reduction in the perihemorrhagic zone around an intracerebral hematoma, to accord with neuropathological studies showing a zone of ischemic neuronal death, and damage, up to 1–2 cm around the clot. 1,2 This study however, suggests a larger zone of perihemorrhagic mitochondrial functional impairment, involving fairly large areas of the ipsilateral cortex, which persists several days after clot removal, and which offers a reason for the ongoing edema, (therefore mostly cytotoxic) and persisting neurological impairment usually seen in these patients postoperatively. Most importantly, however this study raises the possibility of treatments aimed at optimizing mitochondrial function, such as delivering more oxygen, or fuels such as lactate, succinate, or oxaloacetate, combined with clot removal surgery. Ross Bullock Miami, Florida 1. Tanizaki Y. Improvement of cerebral blood flow following stereotactic surgery in patients 430 with putaminal haemorrhage. Acta neurochirurgica . 1988; 90( 3–4): 103- 110. Google Scholar CrossRef Search ADS PubMed  2. Kawakami H Kutsuzawa T Uemura K Sakurai Y Nakamura T. Regional cerebral blood flow in 435 patients with hypertensive intracerebral hemorrhage. Stroke . 1974; 5( 2): 207- 212 Google Scholar CrossRef Search ADS PubMed  © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Journal

NeurosurgeryOxford University Press

Published: May 21, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off