Alterations in cerebral oxygen metabolism after ... - SAGE Journals

Journal of Cerebral Blood Flow & Metabolism (2013) 33, 48–52 & 2013 ISCBFM All rights reserved 0271-678X/13 $32.00 www.jcbfm.com

ORIGINAL ARTICLE

Alterations in cerebral oxygen metabolism after traumatic brain injury in children Dustin K Ragan1, Robert McKinstry2, Tammie Benzinger2, Jeffrey R Leonard3 and Jose A Pineda1 Traumatic brain injury (TBI) is the most common cause of acquired disability in children. Metabolic defects, and in particular mitochondrial dysfunction, are important contributors to brain injury after TBI. Studies of metabolic dysfunction are limited, but magnetic resonance methods suitable for use in children are overcoming this limitation. We performed noninvasive measurements of cerebral blood flow and oxygen metabolic index (OMI) to assess metabolic dysfunction in children with severe TBI. Cerebral blood flow is variable after TBI but hypoperfusion and low OMI are predominant, supporting metabolic dysfunction. This finding is consistent with preclinical and adult clinical studies of brain metabolism and mitochondrial dysfunction after TBI. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 48–52; doi:10.1038/jcbfm.2012.130; published online 12 September 2012 Keywords: brain imaging; brain trauma; cerebral blood flow

INTRODUCTION Traumatic brain injury (TBI) is one of the most significant causes of death and disability in the pediatric population, affecting nearly 500,000 children each year.1 Effective development and implementation of therapies is hampered by limitations in our understanding of the pathology after TBI, which develops in an ongoing process after the immediate insult. Among the pathological processes that occur after TBI is the release of mitotoxic products.2 This has produced mitochondrial dysfunction in both animal models of TBI and ex vivo studies.3–5 In humans, mitochondrial function is studied noninvasively using physiologic markers that are affected by mitochondrial disturbance. Using advanced magnetic resonance imaging (MRI), it is possible to measure cerebral metabolism noninvasively without harmful irradiation.6 In children and adults, mitochondrial impairment decreases both aerobic metabolism and the oxygen extraction fraction (OEF).7,8 However, hypoextraction could also be caused by uncoupled (excessive) increase in cerebral blood flow (CBF), and a complete picture of oxygen consumption requires considering both delivery and extraction. Cerebral blood flow has been a frequent subject of investigations in TBI research for the past few decades. The overall significance of post-TBI CBF alterations is difficult to extract due to the complex, multiphasic response of the brain and the wide array of study designs that have been used. Ischemic hypoperfusion is widely considered to be a risk soon after TBI.9 Rodent and human studies have found that the CBF is decreased in the first 24 hours after TBI,10,11 followed by a period of increased CBF.12,13 The subacute phase is less studied, but CBF is reportedly decreased.14 Relatively few studies have been performed in children with TBI. Until recently, the techniques for measuring oxygen metabolism have been either invasive or involved ionizing radiation. More recently, MRI techniques have been developed for the measurement of CBF15 and OEF,6,16 allowing more comprehensive studies

of brain oxygen metabolism in children. Using these techniques we measured oxygen metabolism in children with TBI both during their early recovery (i.e., subacutely) and 3 months after injury.

MATERIALS AND METHODS All studies and procedures were approved by the institutional review board at Washington University. Informed consent was obtained in writing from the subject’s parents or guardian. Patients 0 to 17 years of age with severe TBI (postresuscitation Glasgow Coma Scale score 8 or lower) were approached for the study. Patients with neurologic or metabolic disease were excluded. Patients were imaged within the first 14 days after injury. One patient was not clinically able to be scanned within that window and received his initial scan 18 days after injury. Sedation was achieved using fentanyl or midazolam as necessary. Patients were mechanically ventilated during the MRI to maintain normal CO2, oxygen saturations, and blood pressure. Data were also obtained in 14 healthy control patients with no history of head injury. Studies were performed on a Siemens Trio 3.0 T MRI scanner (Siemens Medical Solutions, Malvern, PA, USA). In addition to the initial scan, imaging was repeated 3 months after injury. A highresolution T1-weighted anatomical image was acquired. A dualgradient echo sequence was used to obtain a 3D field map with acquisition parameters echo time (TE) ¼ 12.3/5.5 milliseconds, repetition time (TR) ¼ 25 milliseconds, nominal voxel size ¼ 2 2 1.5 mm3. Oxygen extraction fraction was determined by measuring the deoxyhemoglobin content of the superior sagittal sinus.6 Cerebral blood flow data were acquired using a pseudocontinous arterial spin labeling sequence17 with acquisition parameters: TE ¼ 29 milliseconds, TR ¼ 4,000 milliseconds, 22 slices, nominal resolution ¼ 2.3 2.3 mm2. The labeling plane was positioned 6 cm from the edge of the anatomical slices for children over 4 years old and at 4 cm for younger children. The nadir systolic

1 Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA; 2Department of Radiology, Washington University School of Medicine, St Louis, Missouri, USA and 3Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri, USA. Correspondence: Dr JA Pineda, Department of Pediatrics and Neurology, Division of Critical Care Medicine, Washington University School of Medicine, Campus Box 8116, One Children’s Place, NWT-10, St Louis, MO 63110, USA. E-mail: [email protected] Financial support was received from the Robert Wood Johnson Foundation, the American Heart Association and from the Washington University Institute of Clinical and Translational Sciences (KL2 RRO24994, 12POST8860002, and UL1 RR024992). Received 9 March 2012; revised 2 July 2012; accepted 31 July 2012; published online 12 September 2012

Oxygen metabolism in pediatric TBI DK Ragan et al

49 and diastolic arterial blood pressures during the scan were determined from the patient’s medical record during the scan. Blood hemoglobin measurements were obtained from the medical record for the TBI population and were available for 14 subjects. The correlation between CBF and hemoglobin was determined because anemia has been associated with elevated CBF.18,19 Normal hemoglobin values were assumed for the calculation of OEF because it was not available in the control patients. Image processing was performed using the FSL toolbox (FMRIB, Oxford, UK). Individual images were coregistered with MCFLIRT (FMRIB).20 Dewarping was performed using FUGUE (FMRIB).21 Removal of cerebrospinal fluid was achieved through segmentation of the high-resolution T1-weighted image.22 Whole-brain CBF was determined from the resulting images.23 Data analysis was performed using unpaired t-tests to compare the whole-brain CBF between patients at each time point and between TBI patients and age-matched controls. Bonferroni correction for multiple comparisons was used. The relationship between CBF and outcome was assessed using Spearman’s correlation coefficient. The oxygen metabolic index (OMI) was calculated as the product of CBF and OEF;24 this quantity differs from CMRO2 (cerebral metabolic rate of oxygen consumption) in that it does not account for variations in the oxygen content of blood. Oxygen metabolic index was also compared at both time point using unpaired t-tests. Because of reported excessive perfusion 2 to 4 days after injury,25 analysis was repeated after subdividing the severe TBI population into those imaged on the first 5 days after injury and Z6 days after injury. The relationship between CBF and OEF was explored to determine if supranormal perfusion is a potential explanation for low OEF by using correlation analysis. Bias-corrected accelerated bootstrap analysis was used to determine 95% confidence intervals for Spearman’s correlation coefficient. Spearman’s coefficient was used because of potential contamination in the initial time point data from patients scanned on days 2 to 4, where high CBF has been reported.25

with 40 mL per minute per 100 g; P ¼ 0.01). The difference in initial CBF between early and late scans was not significant (P ¼ 0.08). The difference is clearer at the 3-month time point, where the CBF values in TBI patients are consistently depressed compared with control subjects (Po0.0001; Figure 2). All study patients were normotensive during the study. This was also the case for CBF and hemoglobin (r2 ¼ 0.004). Oxygen extraction fraction was also decreased at both time points, consistent with our previous results (P ¼ 0.0001).26 Oxygen metabolic index was significantly decreased in TBI patients at both the initial and the 3-month scan (Figure 2; Po0.0001 for both). The CBF of the control patients demonstrated a dependence upon age. The infants had relatively low CBF, while CBF declined with age in the older children and adolescents (Figure 3A). Excluding infants, in whom a lower CBF is expected, age and CBF are significantly correlated (r ¼ 0.71, Po0.01). This pattern is not significant in the TBI patients (r ¼ 0.37, P ¼ 0.2) (Figure 3B). At both time points, OEF and CBF had a weak, negative correlation (Figure 4). The 95% confidence intervals for both coefficients at both time points excluded 1. For the initial scan, the Spearman coefficient was 0.15 with a 95% interval of ( 0.80, 0.62). At 3 months, the Spearman coefficient was 0.02 ( 0.67, 0.75). A scatter plot of OMI and TBI was constructed to display the relationship between oxygen consumption and CBF (Figure 5). Traumatic brain injury and control subjects were clearly separated by OMI, even though perfusion values overlapped. Even patients with CBF in the upper end of the normal rage demonstrated low cerebral metabolism.

DISCUSSION Cerebral blood flow is dynamic after TBI, with both hyperperfusion and depressed CBF being reported in children, and this

RESULTS Patient demographic data are presented in Table 1. A total of 17 TBI patients were enrolled. Of these, 16 patients had data at the initial time point and 7 at the 3-month time point. The number of subjects at the 3-month time point is lower because seven patients did not return for follow-up (seven patients) or OEF data were not successfully obtained during the initial scan due to the presence of blood products near the superior sagittal sinus (two patients). No patients were scanned within 24 hours of injury, but two were scanned within 48 hours. Eight of the patients were scanned in the first week after injury. Data were obtained in 10 control subjects. Example images are shown in Figure 1. The mean CBF was not significantly decreased in TBI patients during the initial scan (Figure 2). These values were widely distributed and CBF values obtained on days 2 to 4 after injury appeared to be higher. In patients scanned over 1 week from injury (days 7 to 18), CBF was significantly decreased compared with controls (29 compared Table 1.

Demographic information on patients with traumatic brain

injury Age (years) Admission GCS Postresuscitation GCS Days in PICU Days in hospital

8.1±6.0 (0.1–17.2) 4.4±2.4 4.8±2.4 14.8±9.9 (3–31) 43.1±34.3 (5–116)

GCS, Glasgow Coma scale; PICU, pediatric intensive care unit. Data are expressed as mean±s.d. (range).

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Figure 1. Anatomical images and cerebral blood flow (CBF) maps from a healthy 15-year-old female (mean CBF ¼ 33 mL per minute per 100 g) and a 17-year-old female (mean CBF ¼ 22 mL per minute per 100 g). Global perfusion is depressed in the traumatic brain injury (TBI) patient. A hemorrhagic contusion is visible in the anatomical images; this region is not included in the mean CBF because the anatomical segmentation correctly excludes both hemorrhagic contusions and cerebrospinal fluid (CSF). Journal of Cerebral Blood Flow & Metabolism (2013), 48 – 52


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Figure 2. Mean cerebrospinal fluid (CBF) and oxygen metabolic index (OMI) values categorized by group and time point. CBF decreases within the first two weeks after traumatic brain injury (TBI) (P ¼ 0.01) and remains depressed at 3 months after injury (Po0.001). In the first week after injury (early) CBF, was no different from control, but it became significantly different from control values when measured in the second week after injury. Overall oxygen metabolism is consistently depressed at both time points (Po0.0001 for both).

Figure 3. Cerebral blood flow (CBF) as a function of age. (A) CBF in healthy children is lower in infants, increases in childhood, and decreases throughout late childhood and adolescence, consistent with previous reports in the literature. (B) The relationship between CBF and age is disrupted in traumatic brain injury (TBI) patients.

phenomena appears to be time dependent.13 Such dynamic behavior makes studies of CBF in children with severe TBI challenging given the ability to conduct imaging studies is contingent on clinical stability. The heterogeneity of CBF is noted in Figure 3B. Despite this limitation, our results are consistent with and expand upon previously published data. Multiple investigators9,13,27 have found depressed CBF in the early hours after TBI, with increased perfusion later.13,25 The subacute phase (3 months Journal of Cerebral Blood Flow & Metabolism (2013), 48 – 52

Figure 4. Cerebrospinal fluid (CBF) and oxygen extraction fraction (OEF) are unrelated in traumatic brain injury (TBI) patients. Under normal circumstances, changes in CBF will be accounted for by a balanced change in OEF, producing a negative correlation. In the subacute phase (A), there is no overall correlation between the two. However, there is one point with very low CBF that has elevated extraction relative to the other TBI patients, and one point with very high CBF that has unusually low extraction. At 3 months (B), there is also no significant correlation between the two, reflecting persistent metabolic abnormalities after TBI.

Figure 5. Graph comparing cerebrospinal fluid (CBF) and oxygen metabolic index (OMI) in traumatic brain injury (TBI) patients and control subjects. Calculation of OMI reveals low oxygen metabolism in severe TBI patients, regardless of CBF.

after injury) is less well studied, but low CBF has been reported.7,28 This time course is remarkably consistent with the crosssectional view provided by our data. In our cohort, CBF was measured using arterial spin labeling. This technique, in use now for several years,29 has more recently been shown to provide consistent measurements of CBF in children,30 and compares favorably with gold-standard techniques such as PET (positron emission tomography) and microsphere & 2013 ISCBFM


51 techniques.31–35 The technique for measuring OEF is less well established. However, it is sensitive to physiological changes due to hypercapnia36 and caffeine37 and has been used by multiple groups to produce results consistent with normative physiological data.6,38 It does have the limitation of only providing a single value of OEF for the whole brain. Although TBI often produces focal lesions, it includes a substantial diffuse injury component,39–41 which can be reasonably described with whole-brain data.42,43 The OEF measurement technique is relatively new and has not been compared with any gold-standard measurements. However, it is sensitive to physiological changes induced by hypercapnia and breath holding.36,44 In addition, it is related to injury severity and outcome in patients with TBI.26 One important limitation however is that heterogeneous distribution of metabolic abnormalities including areas of ischemic penumbra cannot be detected. The use of PET could overcome this limitation but PET is not currently feasible in children due to significant radiation exposure risk. In the context of these methodological limitations, it is important to note that in our patients overall oxygen consumption (OMI) was consistently and significantly depressed in the TBI patients. Oxygen metabolic index was used to quantify metabolism because it can be calculated purely from MR-based measures without requiring invasive measurement of the arterial oxygen content of blood.24 Oxygen metabolic index allowed us to determine the relative overall contributions of low extraction and high perfusion. When both CBF and OEF are decreased, a defect in oxygen utilization is clearly present. When CBF is normal or high, as was the case in one-third of our subjects, consideration of the overall metabolic level is required. We found that when CBF elevations were present, they were insufficient to produce normal cerebral metabolism, except in one case. This implies that there may be an overall challenge to oxygen utilization in the brain after severe TBI, even at 3 months after injury. Cerebral blood flow and OEF relate to each other weakly in TBI patients. Normally if cerebral metabolism is stable and CBF is altered, then OEF will change in the opposite direction to compensate (such as in OEF elevations during ischemia). In healthy brain tissue, perfusion defects can be balanced by increased extraction, producing a substantial negative correlation between the two parameters.45 This underscores the metabolic derangement that occurs in the aftermath of TBI. Our study has several limitations. First, we focused on TBI patients who are clinically stable, after ICP (intracranial pressure) and CPP (cerebral perfusion pressure) monitoring and treatment were discontinued. This is in contrast to the report by Nortje et al,46 in which patients were studied at a median 2 days after injury while still receiving ICP- and CPP-directed therapies. The likelihood of metabolic failure due to ischemia (as opposed to adequate supply coupled to abnormal oxygen utilization) is higher under such physiological circumstances. In fact, some patients in the Nortje study had elevated ICP and/or low CPP at the time of their PET study. Furthermore, metabolic measurements at this time are more likely to find signs of ischemia due to impaired brain oxygen diffusion. Similar findings were reported by Tisdall et al47 in patients who were studied in the first 48 hours after injury. These studies are consistent with previous reports, suggesting that ischemia is important early after TBI.48 While our data does not disprove that ischemia is a component of metabolic abnormalities observed after TBI, ischemia is less likely in the subacute phase, particularly at 3-month after injury time point. Our data support that complex metabolic abnormalities are present in children with TBI even after the acute phase after injury, and emphasize the need for future studies to define the nature of such abnormalities. It is important to note that our data only represent one point in time, unlike metabolic studies in the acute phase of TBI where invasive multimodality continuous monitoring is possible. & 2013 ISCBFM

Second, our data are potentially confounded by the use of sedatives during the early scans for the severe TBI patients since sedatives may lead to decreases in CBF and OMI.49,50 This is not sufficient to explain the entire observed effect, particularly since our 3-month data were obtained in the absence of sedatives. In addition, sedation does not account for the observed differences in CBF between patients imaged before and after 1 week after injury, all of whom were sedated. We do not believe that sedation was a large factor in our measurements. Low doses of sedation are associated with relatively small changes in oxygen metabolism in CMRO2,49,50 which are insufficient to explain drop of nearly 70% in OMI that we observed. It is important to note that CBF in the control subjects decreased from age 8 through adolescence. Infants also displayed low perfusion. This is consistent with results from a large crosssectional study of Japanese children.51 The average CBF in the control cohort is somewhat higher than the CBF values reported in young adults using arterial spin labeling.52 Cerebral blood flow displayed significant intersubject variability, with even the healthy controls spanning a range of almost 30 to 60 mL per minute per 100 g. Since the outcome of interest is the difference between the two patient samples (TBI and control subjects), we did not conduct paired analysis. Future studies will address this limitation to study individual patient changes in metabolism over time after TBI. A limitation of our study is the relatively low follow-up at the second time point. This reduces our ability to compare the change in CBF in the TBI patients from the initial time point to the 3-month time point. However, even with the reduced power available, we are still able to identify reduced CBF at the later time point. Our findings are consistent with preclinical and clinical studies, supporting that TBI induces a persistent metabolic crisis.3,7 Although they are present, changes in perfusion are insufficient to fully explain all of the metabolic changes that occur. It appears that the brain is unable to effectively use oxygen after severe TBI, a phenomenon consistent with the hypothesis of mitochondrial failure after TBI.53 Alternatively, abnormal oxygen extraction could be the result of tissue loss, which is known to occur in TBI patients.54 Futures studies using MRI techniques that allow regional OEF measurements and colocalization with anatomical indicators of ischemic tissue damage will permit more refined testing of this hypothesis. DISCLOSURE/CONFLICT OF INTEREST The authors declare no conflict of interest.

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