Cerebral metabolic rate of oxygen (CMRO2) in pig brain determined by PET after resuscitation from cardiac arrest

Resuscitation 80 (2009) 701–706

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Experimental paper

Cerebral metabolic rate of oxygen (CMRO2 ) in pig brain determined by PET after resuscitation from cardiac arrest夽,夽夽 Erik Mörtberg a,∗ , Paul Cumming b , Lars Wiklund a , Sten Rubertsson a a b

Department of Surgical Sciences, Anaesthesiology and Intensive Care Medicine, Uppsala University Hospital, Uppsala, Sweden Department of Nuclear Medicine, Ludwig-Maximilians University, Munich, Germany

a r t i c l e

i n f o

Article history: Received 24 November 2008 Received in revised form 18 February 2009 Accepted 5 March 2009 Keywords: Cardiopulmonary resuscitation Cerebral blood flow Cerebral oxygen metabolism Positron emission tomography

a b s t r a c t Aim: To assess the regional vulnerability to ischemic damage and perfusion/metabolism mismatch of reperfused brain following restoration of spontaneous circulation (ROSC) after cardiac arrest. Method: We used positron emission tomography (PET) to map cerebral metabolic rate of oxygen (CMRO2 ), cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in brain of young pigs at intervals after resuscitation from cardiac arrest. After obtaining baseline PET recordings, ventricular fibrillation of 10 min duration was induced, followed by mechanical closed-chest cardiopulmonary resuscitation (CPR) in conjunction with i.v. administration of 0.4 U/kg of vasopressin. After CPR, external defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). CBF and CMRO2 were mapped and voxelwise maps of OEF were calculated at times of 60, 180, and 300 min after ROSC. Results: There was hypoperfusion throughout the telencephalon at 60 min, with a return towards baseline values at 300 min. In contrast, there was progressively increasing CBF in cerebellum throughout the observation period. The magnitude of CMRO2 decreased globally after ROSC, especially in cerebral cortex. The magnitude of OEF in cerebral cortex was 60% at baseline, tended to increase at 60 min after ROSC, and declined to 50% thereafter, thus suggesting transition to an ischemic state. Conclusion: The cortical regions tended most vulnerable to the ischemic insult with an oligaemic pattern and a low CMRO2 whereas the cerebellum instead showed a pattern of luxury perfusion. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The outcome for patients with resuscitation after cardiac arrest remains poor despite decades of intensive research and education in basic and advanced cardiac life support. In patients initially resuscitated, anoxic neurological injury is an important cause of morbidity and mortality.1 During the first 30 min after restoration of spontaneous circulation (ROSC), there is a transient cerebral hyperaemia which is followed by a protracted global and multifocal hypoperfusion in animal models of cardiac arrest and resuscitation.2–7 However, it is not known whether the alterations in cerebral blood flow (CBF) after successful ROSC are associated with concomitant changes in global and regional cerebral oxygen

夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2009.03.005. 夽夽 The authors are indebted to the Laerdal Foundation for Acute Medicine and the Swedish Heart Lung Foundation for financial support. ∗ Corresponding author at: Uppsala University Hospital, Thoracic Surgery and Anaesthesia, Akademiska sjukhuset, SE-751 85, Uppsala, Sweden. Tel.: +46 18 6119206; fax: +46 18 6113926. E-mail address: [email protected] (E. Mörtberg). 0300-9572/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2009.03.005

consumption, with consequent changes in the oxygen extraction fraction (OEF), in a manner predictive of the transition to ischemic injury. The magnitude of global cerebral metabolic rate of oxygen (gCMRO2 ) after resuscitation from cardiac arrest has been estimated from measuring the A–V difference in oxyhemoglobin concentration,8–10 and from focal measurements in experimental animals of cerebral tissue oxygen tension by near infrared spectroscopy (NIRS)11,12 or brain tissue PO2 (PbtO2 ).13 In these studies, only gCMRO2 or the regional CMRO2 in a particular brain region have been assessed, making it difficult to identify regions of particular vulnerability to ischemic damage. There are two published PET studies in which regional CBF, CMRO2 , and glucose consumption were measured in human brain after resuscitation from cardiac arrest.14,15 However, these studies do not describe the acute phase after ROSC, but instead were conducted at least 24 h after resuscitation. In a primate model of focal ischemia, regional CMRO2 in the initial hours after vessel occlusion has been shown to be a good predictor of irreversibility of brain damage, as documented by histologically verified infarction.16,17 In analogy to these studies, we chose to measure the global and regional CMRO2 during the first hours after ROSC in young pigs, so as to test the hypothesis that CMRO2 initially is heterogeneously reduced following successful

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resuscitation. Based on measurement of regional CBF in the same animals, we also calculated maps of OEF over time in order to identify regions of perfusion/metabolism mismatch, which are potentially vulnerable to ischemic damage and by identifying these regions also possibly prevent damage by means of increased cerebral perfusion pressure and other possible treatments. 2. Materials and methods The design of the present study, and the care and handling of the animals, were reviewed and approved by the Institutional Review Board for Animal Experimentation in Uppsala, Sweden. 2.1. Animal preparation Four young pigs of triple breed were included in the study. Animals were 10–12 weeks old, and had a mean weight of 25 ± 3 kg at the time of the PET study. All animals fasted, but had free access to water during the night before the experiment, and were delivered directly to the laboratory by the supplier on the morning of the experiment. Anaesthesia was induced with an intramuscular injection of tiletamine and zolazepam 6 mg/kg, xylazine 2 mg/kg, and atropine 0.04 mg/kg. A peripheral ear vein was cannulated for induction and maintenance of anaesthesia, and for fluid administration. Morphine 1 mg/kg and ketamine 100 mg were given i.v. as a single bolus injection. Anaesthesia was maintained by continuous intravenous infusion of 8 mg/(kg h) of pentobarbital, 0.25 mg/(kg h) of pancuronium bromide and 0.5 mg/(kg h) of morphine. Water loss was compensated with an i.v. infusion of 30 ml/kg of acetated Ringers solution during 1 h before the experiment, followed by a continuous i.v. infusion of 2.5% glucose at a rate of 10 ml/(kg h) during the whole experiment. The pigs were tracheostomised and mechanically ventilated (Servo Ventilator 900C, Siemens-Elema, Solna, Sweden) with a 70/30 mixture of N2 O/O2 during preparation. Volume-controlled ventilation was continuously adjusted to maintain the arterial PCO2 within the range of 5.0–5.5 kPa (38–41 mm Hg). A positive endexpiratory pressure (PEEP) of 5 cm H2 O was applied. Catheters (7 French) were inserted into the right atrium for drug administration and pressure monitoring and (18 Gauge) into the aortic arch via a branch of the right external carotid artery for pressure monitoring and blood sampling. Another catheter (7 French) was inserted into the right femoral vein for tracer injection. 2.2. Physiological measurements Standard lead II ECG, systemic arterial blood pressure and right atrial pressure were continuously monitored (Datex cardio cap II, Datex instrumentarium, Helsinki, Finland). Arterial blood gases (ABL 520, Radiometer, Copenhagen, Denmark) were measured at baseline, 5 min after ROSC, and thereafter approximately every 90 min throughout the experiment. 2.3. Experimental protocol Nitrous oxide administration was discontinued after completing the preparation described above, after which time the animals were ventilated with 30% O2 in air. After 45 min in this condition, a set of baseline PET recordings were obtained during an interval of 30–45 min. Ventricular fibrillation (VF) was then induced with a brief application of an alternating current shock of 40–60 V, administered by two subcutaneous needles placed on both sides of the thorax. Cardiac arrest was defined as VF on the ECG and the loss of arterial blood pressure. Ventilation was stopped at the onset of VF. After 10 min of untreated cardiac arrest, external mechanical chest compressions were initiated with the LUCASTM18

device applied with a frequency of 100/min, and ventilation was resumed with 100% O2 . The pigs received one bolus dose of arginine–vasopressin (Sigma–Aldrich Corp. Saint Louis, MO, USA) 0.4 U/kg i.v. 2 min after the start of CPR. External defibrillatory shocks of 200 J were administered after 8 min of CPR. In cases when two unsuccessful defibrillatory attempts were made, the energy for defibrillatory shocks was raised to 360 J. ROSC was defined as a pulsatile rhythm with a systolic aortic blood pressure greater than 60 mm Hg maintained for at least 10 min. The inspired fraction of oxygen (Fi O2 ) was reset to 0.3 at 5 min after ROSC. The ventilation rate was increased, aiming at an arterial PCO2 of 5.0–5.5 kPa (38–41 mm Hg). If the mean arterial pressure (MAP) dropped below 40 mm Hg, an infusion of adrenaline (epinephrine) in a low (80–160 ng/(kg min)) dose was started to maintain the MAP above 40 mm Hg. There were no other interventions during the observation period. 2.4. PET methods Sets of three PET recordings were acquired in each pig at baseline and at 60, 180 and 300 min after ROSC. The PET recordings were obtained with a Siemens ECAT EXACT HR+ (Siemens/CTI, Knoxville, TN), that produced 63 slices with 2.46 mm slice spacing, and had axial and transaxial resolution of 5 mm full width at half maximum (FWHM). All emission recordings were corrected for photon attenuation using a transmission scan, and were reconstructed with a 5 mm (ECAT) Hanning filter. The PET data were corrected for scattered radiation and random coincidences. For measuring CBF, a water bolus autoradiographic method was used. A bolus of [15 O]-H2 O (800 MBq) was injected into the femoral vein. A series of blood samples for measurement of radioactivity were drawn through the arterial line for measurement of radioactivity using a well-counter cross-calibrated to the tomograph. Voxelwise maps of CBF were calculated according to the method described by Herscovitch et al.19 and Raichle et al.20 For calculation of CMRO2 and subsequently OEF, a modification of the steady-state continuous 15 O-oxygen inhalation technique21 was used. Correction for intravascular oxygen was performed as previously described,22,23 based on the rCBV map calculated from a single-breath C15 O.24 Labelled gases were administered through the inspiratory limb from the ventilator. Each set of three PET recordings thus resulted in measurements of CBF, cerebral blood volume (CBV), CMRO2 , and (by calculation) OEF. All frames were reconstructed for verification of steady-state, summed and converted to voxelwise parametric maps of CBF, CMRO2 , OEF and CBV according to standard procedures. 2.5. PET data analysis All individual CBF maps were manually co-registered to the pig magnetic resonance imaging (MRI) atlas in the common stereotaxic space25 using the REGISTER program26 and nine degrees of freedom. For the registration, midline tag points were placed at the frontal and occipital poles, the extreme dorsal extension of the cerebral cortex, the most dorsal part of cerebellum and the medulla oblongata. Other tag points were placed bilaterally in the frontal lobes, in the lateral cerebellar hemispheres and in the temporal cortex. After spatial normalization of the parametric maps, mean magnitudes of CBF, CMRO2 and OEF were calculated in the statistically defined anatomical volume of interest (VOI) templates25 for the cerebellum, thalamus, striatum, frontal cortex, occipital cortex, temporal cortex, diencephalon and mesencephalon. The weighted averages of physiological parameters were then calculated for each VOI in order to estimate the global CBF, CMRO2 and OEF. We also defined three regions: the cerebellum, subcortical regions (the weighted mean of thalamus, striatum, diencephalon and

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mesencephalon) and cortical regions (weighted mean of frontal, occipital and temporal cortex). 2.6. Statistical analysis All data are expressed as mean ± standard deviation. The differences for each region between the values after ROSC and baseline were compared with the t-test for dependent samples. p-Values <0.05 were considered significant. The statistical analyses were calculated using the program STATISTICA (Statsoft Scandinavia, Uppsala, Sweden). 3. Results ROSC was established in all four pigs. The MAP showed an initial peak, followed by a decrease at approximately 30 min after ROSC, with a slow recovery after 60 min towards baseline values (Fig. 1). All four animals needed an adrenaline infusion to maintain MAP above 40 mm Hg. 3.1. rCBF The mean global CBF (gCBF) at baseline was 27 ± 5 ml Hg−1 min−1 . The gCBF decreased compared to baseline at 60 min (p < 0.05) and returned to baseline levels at 180 and 300 min. There was no difference between the three regions in regional CBF (rCBF) at baseline with the paired t-test. At 60, 180 and 300 min after ROSC, the rCBF differed between the three regions with the highest rCBF in the cerebellum and the lowest rCBF in the cortex (p < 0.05). Although the watershed regions were not specifically defined as a VOI template, visual inspection of the parametric maps did not indicate the presence of discernible watershed hypoperfusion after ROSC. The regional CBF (rCBF) for the different brain regions as a function of time after ROSC is presented in Table 1. The corresponding mean parametric maps (in the horizontal and sagittal planes) of CBF are illustrated in Fig. 2. The rCBF for the three weighted regions are displayed in Fig. 3A. 3.2. rCMRO2 The mean global CMRO2 (gCMRO2 ) at baseline was 83 ± 1 ␮mol Hg−1 min−1 . The gCMRO2 decreased compared to baseline at 60 min (p < 0.05) and remained decreased compared

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Table 1 The mean magnitudes of rCBF, rCMRO2 and rOEF for the different regions as a function of time after ROSC. Each figure represents the mean of the four pigs. All data are displayed as mean ± standard deviation. Mean CBF (ml Hg−1 min−1 )

Base

60 min

180 min

300 min

27 ± 6 27 ± 5 28 ± 4

29 ± 7 17 ± 2* 22 ± 4*

36 ± 5* 22 ± 2 29 ± 5

39 ± 10* 24 ± 4 31 ± 7

Mean CMRO2 (␮M Hg−1 min−1 ) Cerebellum 77 ± 7 Cortex 83 ± 2 Subcortex 86 ± 3

68 ± 20 64 ± 14 75 ± 16

63 ± 5* 57 ± 5* 68 ± 5*

63 ± 9 59 ± 1* 68 ± 3*

Mean OEF (%) Cerebellum Cortex Subcortex

46 ± 22 71 ± 22 65 ± 23

33 ± 2* 48 ± 6 44 ± 6

32 ± 8* 48 ± 7 43 ± 7*

Cerebellum Cortex Subcortex

*

55 ± 6 59 ± 9 60 ± 9

p < 0.05 compared to baseline values.

to baseline throughout the experiment (p < 0.05). There was no difference between the three regions in regional CMRO2 (rCMRO2 ) at baseline with the paired t-test. At 60, 180 and 300 min after ROSC, the rCMRO2 in the cortex was lower than in the subcortex (p < 0.05). The mean magnitudes of rCMRO2 for the different regions as a function of time after ROSC are presented in Table 1. The corresponding mean parametric maps (in the horizontal and sagittal planes) of CMRO2 are illustrated in Fig. 2. The rCMRO2 for the three weighted regions are displayed in Fig. 3B. 3.3. rOEF The mean global OEF (gOEF) at baseline was 59 ± 9%. The gOEF decreased compared to baseline at 180 and 300 min (p < 0.05). There was no difference between the three regions in regional OEF (rOEF) at baseline with the paired t-test. At 60 min after ROSC, the cerebellum had a lower regional OEF (rOEF) than the cortex and the subcortex (p < 0.05). At 180 min after ROSC there was a tendency towards a low rOEF for the cerebellum compared to the subcortex (p = 0.06). At 300 min after ROSC the cortex had a higher rOEF than the subcortex (p < 0.05). The mean estimates of rOEF for the different regions as a function of time after ROSC are presented in Table 1. The corresponding mean parametric maps (in the horizontal and sagittal planes) of OEF are illustrated in Fig. 2. The rOEF for the three weighted regions are displayed in Fig. 3C. 4. Discussion

Fig. 1. Mean arterial pressure of the four pigs as mean ± standard deviation. Time 0 = ROSC.

Our findings, although obtained in a small number of animals, extend and support previous work in experimental animals showing the occurrence of acute cortical hypoperfusion followed by slow recovery in the first few hours after resuscitation from cardiac arrest.27,28 The present finding of a slow and progressive decrease in gCMRO2 following ROSC is also similar to results from other studies in dog,8,10 in man29 and in pig9 models. The cardiac arrest of 10 min duration would not likely have produced a homogenous and global cerebral infarction in the resuscitated pigs, since the gCMRO2 remained at approximately 70% of baseline values for the 5 h after resuscitation; the maintenance of oxygen metabolism after ROSC was apparently sustained by increased OEF. However, at 60 min after resuscitation, we found in some brain regions low CBF and particularly high OEF, a circumstance indeed indicative of ischemia, or at least suggesting the occurrence of decreased hemodynamic reserve, as has been reported clinically in comatose survivors with resuscitation after cardiac arrest.15 When comparing the sequence of changing CBF, CMRO2 , and OEF in the cerebellum, and in the pooled subcortical regions and cortical regions, several distinct patterns appear (Fig. 3A–C). In cerebellum,

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Fig. 2. Mean parametric maps of CBF, CMRO2 and OEF at baseline and at intervals following resuscitation. Each image is the mean of four separate PET scans, presented in sagittal and horizontal planes and projected upon the MR in common stereotaxic coordinates.

hyperperfusion is already evident in the CBF maps at 60 min after ROSC, although there was no significant difference in the VOI analysis (Table 1); close examination of the CBF maps suggest that the increase was in the central part of the cerebellum but not in the superficial part. Nonetheless, increased CBF within the entire cerebellum came to predominate at three and 5 h after reperfusion. In the presence of increasing CBF, there was a non-significant decline in rCMRO2 , such that the OEF had declined to only 32% in cerebellum at 5 h after reperfusion, i.e. a circumstance of luxury perfusion in cerebellum.

In all cortical regions, there was distinct hypoperfusion compared to lesser declines in subcortical CBF during the 5 h after ROSC. In addition, the rCMRO2 declined post ROSC in the pooled cortical regions by a mean of 27%, versus a 19% reduction the subcortical structures; given the transient decline in cortical and subcortical CBF, the magnitude of rOEF in cortex initially increased to 70% at 60 min after ROSC, and then declined to 48% at 5 h after ROSC. Although these cortical OEF changes were not significant relative to baseline, the data and Fig. 2 suggest a transient oligaemia experienced especially by the frontal and temporal cortex but also by the

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Fig. 3. (A–C) Mean ± standard deviation for cerebellum, cortical regions and subcortical regions. Each point is the mean of the four pigs. The CBF, CMRO2 and OEF are displayed in A–C, respectively. * denotes p < 0.05.

subcortical regions. It might be speculated that the ongoing infusion of pentobarbital could have contributed to decreased CMRO2 seen in this study. However, such an effect should have affected all cerebral regions in the same manner. Indeed, results of previous studies showed the cerebral cortex to be especially vulnerable to global ischemia.30,31 Thus, we speculate that the declining CMRO2 reflects the onset of secondary brain damage in the hours after ROSC.32 Long-term follow-up of neurological function in conjunction with histology would have been required to verify the occurrence of ischemic brain damage in these animals. Although there was not a VOI template defined for the hippocampus, visual inspection of the parametric maps suggests that there was an increasing hyperperfusion in the vicinity of the hippocampus during the hours after ROSC. Indeed, hippocampus is known to be the brain region most vulnerable to ischemia,33 suggesting that hyperperfusion could thus be a sign of the onset of neuronal damage. The infusion of adrenaline should not have affected cerebral circulation more than the effect of an increased MAP. A previous study has not detected any additional effects of adrenaline on CBF compared to other means of increasing MAP.8 The present observation of clear hyperperfusion in cerebellum after resuscitation was unexpected, and has not been described

before. Other studies of rCBF after resuscitation from cardiac arrest have not shown cerebellar hyperperfusion simultaneously with a cortical hypoperfusion.34–36 In focal supratentorial ischemia in humans, the crossed cerebellar diaschisis phenomenon has been described.37 The cause for the decreased CBF in the cerebellum contralateral to the lesion is a decrease of the excitatory inputs from the cerebral cortex to the cerebellar cortex.38 In our study, the cortical ischemia was bilateral, and there was a bilateral increase in cerebellar CBF. The relatively high CBF seen in the posterior cerebral circulation could be attributed to the effect of gravity during prolonged anaesthesia in a supine position. However, such an effect should also have been evident in our earlier CBF study in a similar pig ROSC model, in which resuscitation was obtained at 5 min of cardiac arrest.3 However, cerebellar hyperperfusion was notably absent in that earlier study. This difference suggests the presence of a time threshold for untreated cardiac arrest prior to successful ROSC in the anaesthetized pig, with the development of cerebellar hyperperfusion, occurring only as a consequence of the more severe conditions of the present study, with ROSC after 10 min of cardiac arrest. However, this observation must be qualified with the caveat that the two groups also differed with respect to the use in the present study of mechanical resuscitation and arginine–vasopressin instead of adrenaline, although both

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groups of pigs were otherwise treated identically with respect to blood gases, blood pressure and anaesthesia. Although vasopressin improves microcirculatory flow compared to adrenalin39 this difference tends to last less than 15 min, and our first PET scan was performed after 60 min. Nevertheless, our new findings seem in agreement with the clinical experience that the extent of neurological damage is related to the duration of untreated ventricular fibrillation and CPR preceding the successful restoration of spontaneous circulation.40,41 Our findings and further study of the injuries in the brain after cardiac arrest with the following ischemia reperfusion injury might help in understanding the need for further treatment and rehabilitation of the surviving patients. Conflict of interest statement None of the authors have any conflict of interest regarding this manuscript. Acknowledgements The authors are indebted to the Laerdal Foundation for Acute Medicine and the Swedish Heart Lung Foundation for financial support. The authors also wish to thank Elisabeth Pettersson and Anders Nordgren, research assistants, and the staff at Uppsala Imanet for excellent technical help, and thank Dr. Anders Rodell of the Aarhus University PET Centre for assistance in producing the parametric maps. References 1. Westal RE, Reissman S, Doering G. Out-of-hospital cardiac arrests: an 8-year New York City experience. Am J Emerg Med 1996;14:364–8. 2. Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 2008;79:350–79. 3. Mortberg E, Cumming P, Wiklund L, Wall A, Rubertsson S. A PET study of regional cerebral blood flow after experimental cardiopulmonary resuscitation. Resuscitation 2007;75:98–104. 4. Fischer M, Hossmann KA. No-reflow after cardiac arrest. Intens Care Med 1995; 21:132–41. 5. Hossmann KA, Fischer M, Bockhorst K, Hoehn-Berlage M. NMR imaging of the apparent diffusion coefficient (ADC) for the evaluation of metabolic suppression and recovery after prolonged cerebral ischemia. J Cereb Blood Flow Metab 1994;14:723–31. 6. Nozari A, Rubertsson S, Gedeborg R, Nordgren A, Wiklund L. Maximisation of cerebral blood flow during experimental cardiopulmonary resuscitation does not ameliorate post-resuscitation hypoperfusion. Resuscitation 1999;40:27–35. 7. Gedeborg R, Silander HC, Rubertsson S, Wiklund L. Cerebral ischaemia in experimental cardiopulmonary resuscitation—comparison of epinephrine and aortic occlusion. Resuscitation 2001;50:319–29. 8. Gervais HW, Schleien CL, Koehler RC, Berkowitz ID, Shaffner DH, Traystman RJ. Effect of adrenergic drugs on cerebral blood flow, metabolism, and evoked potentials after delayed cardiopulmonary resuscitation in dogs. Stroke 1991;22:1554–61. 9. Kirsch JR, Helfaer MA, Blizzard K, Toung TJ, Traystman RJ. Age-related cerebrovascular response to global ischemia in pigs. Am J Physiol 1990;259:H1551–8. 10. Sterz F, Leonov Y, Safar P, et al. Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 1992;24:27–47. 11. Chien JC, Jeng MJ, Chang HL, et al. Cerebral oxygenation during hypoxia and resuscitation by using near-infrared spectroscopy in newborn piglets. J Chin Med Assoc 2007;70:47–55. 12. Bein B, Cavus E, Stadlbauer KH, et al. Monitoring of cerebral oxygenation with near infrared spectroscopy and tissue oxygen partial pressure during cardiopulmonary resuscitation in pigs. Eur J Anaesthesiol 2006;23:501–9. 13. Gopinath SP, Valadka AB, Uzura M, Robertson CS. Comparison of jugular venous oxygen saturation and brain tissue Po2 as monitors of cerebral ischemia after head injury. Crit Care Med 1999;27:2337–45.

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