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Repeated magnetic resonance imaging and cerebral performance after cardiac arrest—A pilot study
Resuscitation 82 (2011) 549–555
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Clinical paper
Repeated magnetic resonance imaging and cerebral performance after cardiac arrest—A pilot study Bård E. Heradstveit a,∗ , Elna-Marie Larsson b , Håvard Skeidsvoll c , Stig-Morten Hammersborg a,d , Tore Wentzel-Larsen e , Anne Berit Guttormsen a,d , Jon-Kenneth Heltne a,d a
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway Department of Radiology, Uppsala University Hospital, Uppsala, Sweden Department of Neurology, Section of Neurophysiology, Haukeland University Hospital, Bergen, Norway d Section for Anaesthesiology and Intensive Care, Dept of Surgical Sciences, University of Bergen, Bergen, Norway e Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway b c
a r t i c l e
i n f o
Article history: Received 21 October 2010 Received in revised form 22 December 2010 Accepted 17 January 2011
Keywords: Cardiac arrest Magnetic resonance imaging Cerebral performance Prognosis Therapeutic hypothermia Outcome
a b s t r a c t Aim of the study: Prognostication may be difficult in comatose cardiac arrest survivors. Magnetic resonance imaging (MRI) is potentially useful in the prediction of neurological outcome, and it may detect acute ischemia at an early stage. In a pilot setting we determined the prevalence and development of cerebral ischemia using serial MRI examinations and neurological assessment. Methods: Ten witnessed out-of-hospital cardiac arrest patients were included. MRI was carried out approximately 2 h after admission to the hospital, repeated after 24 h of therapeutic hypothermia and 96 h after the arrest. The images were assessed for development of acute ischemic lesions. Neurophysiological and cognitive tests as well as a self-reported quality-of-life questionnaire, Short Form-36 (SF-36), were administered minimum 12 months after discharge. Results: None of the patients had acute cerebral ischemia on MRI at admission. Three patients developed ischemic lesions after therapeutic hypothermia. There was a change in the apparent diffusion coefficient, which significantly correlated with the temperature (p < 0.001). The neurophysiological tests appeared normal. The patients scored significantly better on SF 36 than the controls as regards both bodily pain (p = 0.023) and mental health (p = 0.016). Conclusions: MRI performed in an early phase after cardiac arrest has limitations, as MRI performed after 24 and 96 h revealed ischemic lesions not detectable on admission. ADC was related to the core temperature, and not to the volume distributed intravenously. Follow-up neurophysiologic tests and self-reported quality of life were good. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among resuscitated CA patients treated in an intensive care unit (ICU), approximately 50% regain consciousness, while the remaining 50% remain comatose until they die.1 The results of computed tomography (CT) performed early after cardiac arrest are most often normal, and thus of limited value.2 Magnetic resonance imaging (MRI) using diffusion-weighted imaging (DWI) may detect acute brain ischemia at an early stage.3,4 However, only a few DWI studies have been published of cardiac arrest patients treated with hypothermia, and they usually include only
A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.01.018. ∗ Corresponding author. Tel.: +47 55976850. E-mail address: [email protected] (B.E. Heradstveit). 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2011.01.018
a single MRI examination several days after the insult.5–8 They found that an increased number of lesions, especially in the parietal lobe and deep grey nuclei, were associated with worse outcome. Reports are lacking on MRI of the brain on admission to hospital, and on the influence of pre-hospital cardiac life support. A favourable outcome for the patient may not be revealed until therapeutic hypothermia and sedation have been terminated. The cell-protecting mechanisms during therapeutic hypothermia9 indicate a potential influence on ischemic changes in the brain tissue after the cardiac arrest. This has not previously been evaluated by repeated MRI examinations with DWI in the same patients. We have prospectively studied serial MRI examinations of the brain during the first 96 h after the return of spontaneous circulation (ROSC) and assessed the neurological outcome after discharge.
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2. Materials and methods
hyperintensity (DWMH) was graded as absent (0), punctuate foci (1), confluence of foci (2) and large confluent areas (3).
2.1. Ethics 2.6. Neurophysiological tests and cognitive performance The study was approved by the Regional Committees for Medical Research Ethics, the Data Inspectorate, the Directorate for Health and Social Affairs and the Norwegian Medicines Agency. Deferred consent was used, and patients’ families had an opportunity to withdraw patients from the study at any time. All patients included were informed about the study when they were able to receive the information, and they signed a written informed consent form. 2.2. Study population and environment The study was carried out on 10 patients with witnessed outof-hospital cardiac arrest of cardiac aetiology (using the Utstein style definition10 ) between September 2005 and March 2007 at Haukeland University Hospital (Bergen, Norway). The patients were cooled and included in a fluid study, described elsewhere.11 All patients had to be provided with advanced medical life support within 15 min, gained return of spontaneous circulation within 60 min and still be comatose upon arrival at the hospital. Patients strongly in need of nursing before the arrest, suffering a primary coagulopathy or given >2000 ml of fluid upon admittance were excluded. 2.3. MRI MRI was performed after cardiac intervention and if the patient did not have an intra-aortic-balloon pump (IABP). Repeated MRI was scheduled after 24 and 96 h. The MRI examinations were performed at 1.5 T with morphological sequences including T2weighted fluid attenuated inversion recovery images (FLAIR). Diffusion-weighted imaging (DWI) was added to the protocol and performed using single-shot spin-echo echo planar imaging (SE EPI) with diffusion gradients in three directions, b-values 0 and 1000 mm2 /s, repetition time (TR) 3200 ms, echo time (TE) 94 ms, slice thickness 5 mm, matrix 128 × 128, three averages. Twenty to 23 slices were obtained to cover the brain, and the scan time was approximately 1 min.
At least 12 months after the cardiac arrest, the fully conscious patients were invited to a follow-up test consisting of auditory evoked potential (P300), Mini Mental Status Examination (MMSE), Short Form-36 (SF-36) and CPC (Cognitive Performance Category). 2.7. Electroencephalogram (EEG) The EEG was recorded using a 21-channel digital recorder in a standardised manner according to the International 10-20 System (Nervus Taugagreining, Iceland), evaluated by experienced neurophysiologists and categorised into normal (1), abnormal (2) and slightly pathological (3). The EEG was recorded in a quiet room for 20 min, during which the patients, on request, performed opening/closing of the eyes, hyperventilation, flash light stimulation, testing number memory, and, finally, there was also a quiet period during which the patient was left alone. Reactivity of the EEG was assessed as a change in background and the dominant ␣-activity following stimulation. 2.8. Event-related cognitive cortical evoked response (P300) In a silent room, the patients, lying comfortably on a couch with their eyes closed, were presented with two different tones through earphones, the same sound on each side. The tones had different pitches (1000 Hz or 2000 Hz), appeared at random intervals of 1–3 s and lasted for an equal length of time, but the tone with the highest pitch was only heard 20% of the time. The patient was instructed to ignore the frequently presented tone, but when the infrequent tone appeared he was to press a button with the dominant hand. This marked the patient’s motor reaction time, and also gave information about correct or wrong response. The cerebral cortical responses were recorded from three positions along the midline (Fz, Cz and Pz according to the International 10-20 System). Eye artefact was controlled for and the analysis time was 1 s. Amplitude and latency of the cortical response were measured together with the motor reaction time (Keypoint, Dantec, Denmark).
2.4. DWI analysis Apparent diffusion coefficient (ADC) maps were calculated using the scanner software. ADC was measured in six reproducible regions of interest (ROI) (three in each hemisphere) in all MRI examinations using a picture archiving and communications system (PACS) workstation. The ROIs were manually positioned by an experienced neuroradiologist in the centrum semiovale (a circular ROI area measuring approximately 100 mm2 ), lentiform nucleus (a triangular freehand ROI area measuring 220–240 mm2 ) and mid-cerebellar hemisphere (a circular ROI area measuring 250–270 mm2 ). In addition, qualitative evaluation of the cortex, the subcortical grey matter and the white matter was performed by visual inspection of DWI and ADC maps and the total number of acute ischemic lesions was noted. ADC was measured in these lesions, and only lesions containing regions with ADC values below 0.6 × 10 −3 mm2 were classified as acute ischemia.12
2.9. Quality of life, Mini Mental Status Examination and cognitive performance The patients were presented with the SF-36 (standard version 1.0) one week before the tests. The SF-36 was chosen due to high sensitivity in cardiac patients.14 The SF-36 was evaluated by a physician, before a Mini Mental Status Examination (MMSE) was performed. The SF-36 scores were compared with expected scores, based on a historic control of a normal population.15 A Cognitive Performance Category (CPC) was assigned by the physician at the end of the consultation.16 The CPC score is a five-category scale: 1 = conscious and alert with normal cerebral function; 2 = conscious and alert with moderate cerebral function; 3 = conscious with severe cerebral disability; 4 = comatose or in persistent vegetative state; 5 = dead. 2.10. Statistics
2.5. FLAIR images and analyses of white matter Chronic ischemic/degenerative white matter lesions were evaluated with regard to number and appearance according to Fazekas’s classification.13 Periventricular hyperintensity (PVH) was graded as absent (0), caps or pencil-thin lining (1), smooth halo (2) or irregular PVH affecting the deep white matter (3). Deep white matter
For the purpose of the analysis, the ADC values that had been measured symmetrically in either the cerebral or cerebellar hemispheres in the same patient were regarded as two measurements in the same region for each patient. Mixed effects models were used for repeated measurements of ADC.17 The estimated relationship between ADC and fluid balance/temperature was calculated in the
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mixed effects model. The nlme package in R (The R Foundation for Statistical Computing, Vienna, Austria) was used for linear mixed effects models, while SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) was used for P300 analyses. As regards SF-36, patient scores were compared with expected mean scores18 based on the Norwegian reference material in relation to gender and age.15 Numbers are presented as mean (SD) or median (low–high). A p-value of <0.05 was considered significant. For categorical covariates with more than two categories, both overall p-values for the covariate and p-values for individual contrasts are reported. 3. Results Ten patients were included in our study. Nine were discharged alive and survived to the follow-up examination. Essential prehospital data are presented in Table 1. The median age was 60 (22–75) years, and the median time from cardiac arrest until ROSC was 21 (5–40) min. They received different fluid loads during the first 24 h (ranges 4142–9158 ml). 3.1. Magnetic resonance imaging MRI was carried out on admission in nine patients, and in 10 patients after 96 h. The complete MRI-schedule was carried out in eight patients. There was a change in ADC during the observation period, significantly related to the temperature (p < 0.001) (Table 2). At 35 ◦ C, the ADC increased 1.7%/◦ C. None of the patients had lesions indicating acute ischemia on admission, but three patients developed lesions after the cooling-period (Table 3, Fig. 1). The mean score for chronic ischemia for all patients was 1.2 (1.3) for periventricular hyperintensity and 1.2 (0.6) for deep white matter hyperintensity. The chronic ischemia scores did not change over time in the individual patients. 3.2. EEG and event-related cognitive cortical response (P300) None of the EEGs showed signs of heavy encephalopathy and within group 3; there were none with marked pathology. Neurophysiologic responses are reported in Table 1. 3.3. Short Form-36, CPC and MMSE The neurophysiologic and cognitive performance tests were performed 22 (15–26) months (range) after the cardiac arrest. The Short Form-36 results are presented together with the expected scores and differences in Table 1. Our patients scored significantly better than the Norwegian controls15 as regards both bodily pain (p = 0.023) and mental health (p = 0.016). The other axes did not differ significantly from the expected values. The Cognitive Performance Category and Mini Mental Status Examination are presented in Table 1. 4. Discussion The most interesting result in our study is the lack of acute brain ischemia on admission, as evaluated by MRI. DWI has been reported to detect ischemic changes as early as 11 min after the onset of symptoms.19 Our results are therefore unexpected, as intervals between cardiac arrest and return of spontaneous circulation up to 40 min were included. The lack of initial brain damage in our patients may be attributed to early and efficient pre-hospital resuscitation. By only including patients with witnessed cardiac arrest of assumed cardiac origin, the chance of survival increased.20–22 Bystander CPR was initiated almost immediately, and ordinary ambulances as well as an anaesthesiologist-manned ambulance
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assisted the victims. The quality of CPR in out-of-hospital arrest is reported to be low, including differences in hands-off time during resuscitation.23 Our ambulance service has implemented a supraglottic airway device (laryngeal tube) as the primary airway management during CPR, as it is fast and easy to insert and permits continuous chest compressions.24 These factors may reduce the cerebral no-flow-time during resuscitation, leading to our results. Three patients with normal MRI on admission developed acute ischemic lesions after therapeutic hypothermia. Changes can be seen in different brain regions depending on the timing of imaging after CA and on the nature of the injury (primary hypoxia could, for example, be followed by ischemia).6 The cardiovascular status in our patients did not differ during the first 24 h between these patients and those with normal MRI after hypothermia.11 DWI changes induced by global hypoxic cerebral injury in humans may evolve slowly, with a peak reported after 2–4.5 days.8 Therefore, quantitative DWI with ADC measurements obtained between 49 and 108 h after the arrest appear to best differentiate survivors from those who die.8 This may explain why the results of the early MRI examination performed on admission appeared normal in our three patients, with lesions appearing on the second MRI examination. Out of these three patients with CPC 1 and 2, one died and two survived. The patient who died had an increasing number of DWI lesions between the second and third MRI examinations. Local anatomical differences in vascular supply and/or co-morbidity, e.g. chronic white matter ischemia, may explain the development of acute ischemic lesions, but this patient had no signs of chronic lesions, which could indicate poor perfusion. The two survivors both had a high score as regards chronic ischemic lesions. In deceased patients, Järnum and colleagues found large numbers of lesions with low diffusion values in the cortex of the occipital and parietal lobes.7 Choi et al. found that the mixed pattern of brain injury (the cortex and deep grey nuclei) on DWI performed within five days of cardiac arrest correlated well with an unfavourable outcome.5 These findings are supported by our results, as the patient who died developed acute ischemic lesions in the frontal, parietal, temporal and occipital cortex, and in the basal ganglia. No signs of acute ischemia were detected in this patient by MRI on admission, but the lesions were seen in DWI performed 32 and 96 h after cardiac arrest. In another study, it was observed that ADC changes were seen predominantly in the cortex and striatum within the first three days, whereas, in later DWI studies, the changes were restricted to cortical regions and subcortical white matter.6 Changes in the cerebellum were more evident during later imaging. We did not see any cerebellar lesions in our patients. The apparent diffusion coefficient (ADC) reflects the mass, temperature and viscosity of water molecules and is the result of Brownian movements. In acute ischemia, the diffusion is restricted, probably due to cytotoxic oedema and swollen cells, resulting in a decrease in ADC values. We classified ADC values below 0.6 × 10−3 mm2 as acute ischemia.12 This is a relevant cut-off level for patients treated with hypothermia after CA, since it was shown in another study that the percentage of brain volume that had a lower value than the ADC cut-off value of 0.65–0.7 × 10−3 mm2 differentiated between survivors and patients who died or remained vegetative.8 It should also be noted that a study in 2008 reported variability in ADC values in healthy brain tissue depending on the MRI coil systems, imagers, vendors and field strengths used,25 but these results need to be confirmed in a larger study designed to correct machine-dependent variations.26 This does not affect the interpretation of our longitudinal study in which all MRI examinations were performed using the same scanner and exactly the same protocol. Increased ADC may indicate vasogenic oedema, but we did not find any relationship between volume load and ADC during the first 24 h. This may be explained by an intact blood–brain barrier supported by the lack of acute brain ischemia on admis-
552 Table 1 Pre-hospital data presented with number of acute lesions detected by MRI/DWI in the acute/subacute phase. In addition, EEG-reactivity, P300 responses, Cognitive Performance Category, Mini Mental Status Examination and Short-Form 36 by followup examination, are included. Patient Clinical parameters
EEG P300 response times and amplitudes
Short Form-36 scores (expected)e
1
0 1b
3
4
61 VF 1 9 35 11 15 2 29 – 1b 3 2 1 +
2 65 VF 1 8 40 9 5 1 30 – 0 NA 0 0 1 2 +
45 VF 1 5 27 3 3 1 29 – 0 0 0 0 1 1 +
74 VF 1 5 11 1 1 1 30 – 0 0 0 2 1 3 +
422 428 434
367 369 369
361 365 362
365 367 367
3.3 3.6 2.8 518 98 29 90 (83) 50 (69) 84 (66) 45 (68) 45 (60) 25 (88) 67 (83) 80 (78)
7.2 8.8 10.2 325 100 8 85(82) 100 (67) 80 (71) 92 (69) 80 (64) 100 (89) 100 (79) 88 (81)
7.3 10.9 14.8 412 93 4 95 (91) 100 (87) 100 (80) 92 (80) 95 (66) 100 (88) 100 (89) 84 (81)
5
21.6 25.7 27.9 326 100 2 100 (76) 100 (53) 84 (71) 100 (67) 80 (64) 100 (83) 100 (69) 92 (83)
0
6 75 VF 8 8 13 2 1 1 29 – 0 0 2 1 2 + 361 358 372
16.6 23.9 28.0 322 97 5 55 (56) 0 (36) 62 (59) 35 (62) 20 (51) 100 (75) 67 (61) 88 (77)
0
5b
60 VF 4 6 35 4 0 4 – 31 12b 1 1 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
7
0
8 48 VF 0 3 5 1 0 1 30 – 0 0 2 2 3 + 308 306 319
3.1 3.9 5.1 342 98 8 80 (91) 25 (85) 72 (79) 52 (78) 50 (65) 100 (87) 100 (89) 80 (81)
0
9 73 VF 1 6 11 2 0 1 29 – 0 0 0 1 1 + 387 391 384
5.7 8.0 5.8 424 96 2 80 (78) 75 (56) 100 (73) 67 (68) 80 (65) 100(85) 67 (70) 96 (84)
VF – ventricular fibrillation, CA-CPR = time from arrest until CPR, CA-EMS = time from arrest until Emergency Medical Service present, CA-ROSC = time from arrest until ROSC, NA = not assessed. a 3, 32 and 96 h after the arrest. b The localisation of the lesions are presented in Table 3. c According to Fazekas’ classification.13 d Reactivity + = reactivity present. e Based on age and gender in a control population.15,18
0
10
1b
66 VF 3 8 20 2 1 1 28 – 2b 3 2 3 + 469 452 452
3.8 5.0 8.3 401 97 4 70 (83) 0 (67) 84 (73) 62 (70) 85 (65) 100 (89) 100 (78) 100 (82)
NA
22 VF 9 9 17 4 1 1 28 – NA 0 0 0 1 + 346 341 351 14.4 18.0 14.1 328 99 0 100 (94) 100 (89) 100 (85) 100 (84) 60 (61) 100 (88) 100 (82) 80 (77)
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MRI
Age (years) Primary cardiac rhythm CA-CPR (min) CA-EMS (min) CA-ROSC (min) No of shocks Adrenaline (mg) CPC MMSE Mortality (days) Number of acute ischemic lesionsa Chronic lesions PVHc Chronic lesions DWMHc EEG Reactivityd Time (ms) Frontal Central Parietal Amplitude (V) Frontal Central Parietal Motoric (ms) Correct hits (%) False hits (number) Physical functioning Role-physical Bodily pain General health Vitality Social functioning Role emotional Mental health
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Table 2 ADC (1 × 10−3 mm2 s−1 ) results in a mixed-effect model presented as estimates (SE) and descriptive temperature presented as the mean (SD).
Centrum semiovale Nc.lentiformis Cerebellum Temperature (◦ C) a b
On admission (3 h after CA)
Day 1 (32 h after CA)
p-Valuea
Day 4 (96 h after CA)
0.701 (0.016) 0.711 (0.016) 0.807 (0.016) 34.4 (1.2)
0.704 (0.017) 0.721 (0.017) 0.813 (0.017) 35.6 (1.5)
0.84 0.52 0.69
0.752 (0.016) 0.780 (0.016) 0.842 (0.016) 37.1 (0.25)
p-Valueb p = 0.001 p < 0.001 p = 0.020
Overall p-value p = 0.002 p < 0.001 p < 0.001
Contrast between admission and day 1. Contrast between admission and day 4.
Table 3 Location and number of acute ischemic lesions, which developed after hypothermia in three patients. Patient 1 6
9
MRI (h)
Number of acute ischemic lesions
Location
32 96 32
1 1 5
96
12
32 96
1 2
Left frontal white matter (watershed) Left frontal white matter (watershed) Left frontal and temporoparietal cortex (watershed) + bilat caudate and lentiform nuclei Bilateral frontal, parietal, temporal and occipital cortex + bilat caudate and lentiform nuclei Left lentiform nucleus Left lentiform nucleus + right frontal white matter (watershed)
Fig. 1. A 60-year-old man with a 35-min cardiac arrest (CPR after 4 min.) who died after 31 days. MRI on admission shows no acute ischemic lesions on the DWI (A) or ADC map (D). DWI (B) at 32 h shows high signal intensity in the bilateral caudate and lentiform nuclei and in the left temporoparietal and frontal (not in this section) cortical watershed regions with low signal on the ADC map (E) in corresponding regions. DWI (C) at 96 h shows progression, with extensive bilateral cortical lesions with high signal intensity and corresponding ADC map (F).
sion, or the minimal difference in temperature between the first and second MRIs. As the difference between admission and day 4 was significant, temperature may be important. However, we did not record the brain temperature, but the temperature in the
urinary bladder. The temperature co-variation between these sites was found to be delayed during rapid, profound hypothermia.27,28 The lower rate of cooling/heating used in our setting may result in a good agreement between temperatures in the brain and the urinary
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bladder. The observed change in ADC as a function of temperature supports the results from animal studies.29,30 For prognostic data collection, the clinically relevant time window for performing DWI starts after re-warming the patient for around 36 h to avoid the lower temperature affecting the ADC values.8 The auditory evoked P300 potential reflects the response in the cortex recorded at different sites. The shorter latency and higher the amplitude of the response, the better. Tiainen and colleagues reported significantly higher amplitude in a cardiac arrest population treated with therapeutic hypothermia compared with normothermia (7.91 vs. 4.99 V).31 Our results are even higher, emphasising the good outcome. Witnessed out-of-hospital cardiac arrest (OHCA) combined with ventricular fibrillation has an increased survival rate and a better neurological outcome compared with non-shockable rhythms.32–34 Since all our patients are in this favourable group, a good outcome was expected. However, it is remarkable that the patients score better for bodily pain and mental health than the general population. This may be related to psychological aspects and the relief of survival. The degree of chronic illness may also affect the self-reported quality of life, but we have no data to support this. A Danish study using SF-36 also reported a better score for bodily pain, although not significantly different to the normal population.35 This is also supported by a study using the Nottingham Health Profile.36 MMSE is a screening tool for cognitive dysfunction, but it is not sensitive to cognitive disorders such as mild dementia.37 Highly educated patients may achieve good scores even though they have disorders detected by more sophisticated tests.38 We did not adjust for level of education, but it is surprising to detect outstanding scores for MMSE and CPC in spite of prolonged resuscitation of up to 40 min. One limitation of our study is the different time span of followup after discharge. However, we believed it to be more important that the patients had sufficient time to achieve their potentials for rehabilitation. Moreover, the MRI protocol applied to the intensive care patients was demanding, and a larger number of patients would have been desirable. MRI may not be appropriate for all comatose cardiac arrest patients, such as patients with hemodynamic instability or other contraindications (e.g. a pacemaker, IABP). More longitudinal MRI/DWI studies of CA patients treated with hypothermia are needed in order to further assess the effect of hypothermia and to separate the effect of initial hypoxia from events potentially occurring during treatment. 5. Conclusion MRI performed in an early phase after cardiac arrest has limitations, as MRI performed after 24 and 96 h revealed ischemic lesions not detectable on admission. ADC was related to the core temperature, and not to the volume distributed intravenously. Follow-up neurophysiologic tests and self-reported quality of life were good. Funding Bård E. Heradstveit is a fellow research of the Regional Centre for Emergency Medical Research and Development (RAKOS, Stavanger/Norway). The RAKOS had no influence of the topic, study design nor interpretation of the data. Conflict of interest There are no commercial relations involving any of the authors that might pose a conflict of interest in connection with this manuscript.
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Out-of-hospital cardiopulmonary resuscitation: a population-based Norwegian study of incidence and survival. Eur J Emerg Med 1999;6:323–30. 21. Fairbanks RJ, Shah MN, Lerner EB, Ilangovan K, Pennington EC, Schneider SM. Epidemiology and outcomes of out-of-hospital cardiac arrest in Rochester, New York. Resuscitation 2007;72:415–24. 22. Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. The brain resuscitation clinical trial I and II study groups. Crit Care Med 1995;23:18–25. 23. Wik L, Kramer-Johansen J, Myklebust H, et al. Quality of cardiopulmonary resuscitation during out-of-hospital cardiac arrest. JAMA 2005;293:299–304. 24. Wiese CH, Semmel T, Muller JU, Bahr J, Ocker H, Graf BM. The use of the laryngeal tube disposable (LT-D) by paramedics during out-of-hospital resuscitation-an observational study concerning ERC guidelines 2005. Resuscitation 2009;80:194–8. 25. Sasaki M, Yamada K, Watanabe Y, et al. Variability in absolute apparent diffusion coefficient values across different platforms may be substantial: a multivendor, multi-institutional comparison study. Radiology 2008;249:624–30. 26. Galanaud D, Puybasset L. Cardiac arrest – has the time of MRI come? Crit Care 2010;14:135.
B.E. Heradstveit et al. / Resuscitation 82 (2011) 549–555 27. Akata T, Setoguchi H, Shirozu K, Yoshino J. Reliability of temperatures measured at standard monitoring sites as an index of brain temperature during deep hypothermic cardiopulmonary bypass conducted for thoracic aortic reconstruction. J Thorac Cardiovasc Surg 2007;133:1559–65. 28. Stone JG, Young WL, Smith CR, et al. Do standard monitoring sites reflect true brain temperature when profound hypothermia is rapidly induced and reversed? Anesthesiology 1995;82:344–51. 29. Hasegawa Y, Latour LL, Sotak CH, Dardzinski BJ, Fisher M. Temperature dependent change of apparent diffusion coefficient of water in normal and ischemic brain of rats. J Cereb Blood Flow Metab 1994;14:383–90. 30. Yenari MA, Onley D, Hedehus M, et al. Diffusion- and perfusion-weighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under conditions of mild hypothermia. Brain Res 2000;885: 208–19. 31. Tiainen M, Poutiainen E, Kovala T, Takkunen O, Happola O, Roine RO. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke 2007;38:2303–8.
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32. Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-ofhospital cardiac arrest in Europe. Resuscitation 2005;67:75–80. 33. Olasveengen TM, Samdal M, Steen PA, Wik L, Sunde K. Progressing from initial non-shockable rhythms to a shockable rhythm is associated with improved outcome after out-of-hospital cardiac arrest. Resuscitation 2009;80:24–9. 34. Rea TD, Eisenberg MS, Sinibaldi G, White RD. Incidence of EMS-treated out-ofhospital cardiac arrest in the United States. Resuscitation 2004;63:17–24. 35. Bro-Jeppesen J, Kjaergaard J, Horsted TI, et al. The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest. Resuscitation 2009;80:171–6. 36. Sunnerhagen KS, Johansson O, Herlitz J, Grimby G. Life after cardiac arrest; a retrospective study. Resuscitation 1996;31:135–40. 37. Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 1992;40:922–35. 38. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993;269:2386–91.
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Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
Repeated magnetic resonance imaging and cerebral performance after cardiac arrest—A pilot study Bård E. Heradstveit a,∗ , Elna-Marie Larsson b , Håvard Skeidsvoll c , Stig-Morten Hammersborg a,d , Tore Wentzel-Larsen e , Anne Berit Guttormsen a,d , Jon-Kenneth Heltne a,d a
Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway Department of Radiology, Uppsala University Hospital, Uppsala, Sweden Department of Neurology, Section of Neurophysiology, Haukeland University Hospital, Bergen, Norway d Section for Anaesthesiology and Intensive Care, Dept of Surgical Sciences, University of Bergen, Bergen, Norway e Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway b c
a r t i c l e
i n f o
Article history: Received 21 October 2010 Received in revised form 22 December 2010 Accepted 17 January 2011
Keywords: Cardiac arrest Magnetic resonance imaging Cerebral performance Prognosis Therapeutic hypothermia Outcome
a b s t r a c t Aim of the study: Prognostication may be difficult in comatose cardiac arrest survivors. Magnetic resonance imaging (MRI) is potentially useful in the prediction of neurological outcome, and it may detect acute ischemia at an early stage. In a pilot setting we determined the prevalence and development of cerebral ischemia using serial MRI examinations and neurological assessment. Methods: Ten witnessed out-of-hospital cardiac arrest patients were included. MRI was carried out approximately 2 h after admission to the hospital, repeated after 24 h of therapeutic hypothermia and 96 h after the arrest. The images were assessed for development of acute ischemic lesions. Neurophysiological and cognitive tests as well as a self-reported quality-of-life questionnaire, Short Form-36 (SF-36), were administered minimum 12 months after discharge. Results: None of the patients had acute cerebral ischemia on MRI at admission. Three patients developed ischemic lesions after therapeutic hypothermia. There was a change in the apparent diffusion coefficient, which significantly correlated with the temperature (p < 0.001). The neurophysiological tests appeared normal. The patients scored significantly better on SF 36 than the controls as regards both bodily pain (p = 0.023) and mental health (p = 0.016). Conclusions: MRI performed in an early phase after cardiac arrest has limitations, as MRI performed after 24 and 96 h revealed ischemic lesions not detectable on admission. ADC was related to the core temperature, and not to the volume distributed intravenously. Follow-up neurophysiologic tests and self-reported quality of life were good. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among resuscitated CA patients treated in an intensive care unit (ICU), approximately 50% regain consciousness, while the remaining 50% remain comatose until they die.1 The results of computed tomography (CT) performed early after cardiac arrest are most often normal, and thus of limited value.2 Magnetic resonance imaging (MRI) using diffusion-weighted imaging (DWI) may detect acute brain ischemia at an early stage.3,4 However, only a few DWI studies have been published of cardiac arrest patients treated with hypothermia, and they usually include only
A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.01.018. ∗ Corresponding author. Tel.: +47 55976850. E-mail address: [email protected] (B.E. Heradstveit). 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2011.01.018
a single MRI examination several days after the insult.5–8 They found that an increased number of lesions, especially in the parietal lobe and deep grey nuclei, were associated with worse outcome. Reports are lacking on MRI of the brain on admission to hospital, and on the influence of pre-hospital cardiac life support. A favourable outcome for the patient may not be revealed until therapeutic hypothermia and sedation have been terminated. The cell-protecting mechanisms during therapeutic hypothermia9 indicate a potential influence on ischemic changes in the brain tissue after the cardiac arrest. This has not previously been evaluated by repeated MRI examinations with DWI in the same patients. We have prospectively studied serial MRI examinations of the brain during the first 96 h after the return of spontaneous circulation (ROSC) and assessed the neurological outcome after discharge.
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2. Materials and methods
hyperintensity (DWMH) was graded as absent (0), punctuate foci (1), confluence of foci (2) and large confluent areas (3).
2.1. Ethics 2.6. Neurophysiological tests and cognitive performance The study was approved by the Regional Committees for Medical Research Ethics, the Data Inspectorate, the Directorate for Health and Social Affairs and the Norwegian Medicines Agency. Deferred consent was used, and patients’ families had an opportunity to withdraw patients from the study at any time. All patients included were informed about the study when they were able to receive the information, and they signed a written informed consent form. 2.2. Study population and environment The study was carried out on 10 patients with witnessed outof-hospital cardiac arrest of cardiac aetiology (using the Utstein style definition10 ) between September 2005 and March 2007 at Haukeland University Hospital (Bergen, Norway). The patients were cooled and included in a fluid study, described elsewhere.11 All patients had to be provided with advanced medical life support within 15 min, gained return of spontaneous circulation within 60 min and still be comatose upon arrival at the hospital. Patients strongly in need of nursing before the arrest, suffering a primary coagulopathy or given >2000 ml of fluid upon admittance were excluded. 2.3. MRI MRI was performed after cardiac intervention and if the patient did not have an intra-aortic-balloon pump (IABP). Repeated MRI was scheduled after 24 and 96 h. The MRI examinations were performed at 1.5 T with morphological sequences including T2weighted fluid attenuated inversion recovery images (FLAIR). Diffusion-weighted imaging (DWI) was added to the protocol and performed using single-shot spin-echo echo planar imaging (SE EPI) with diffusion gradients in three directions, b-values 0 and 1000 mm2 /s, repetition time (TR) 3200 ms, echo time (TE) 94 ms, slice thickness 5 mm, matrix 128 × 128, three averages. Twenty to 23 slices were obtained to cover the brain, and the scan time was approximately 1 min.
At least 12 months after the cardiac arrest, the fully conscious patients were invited to a follow-up test consisting of auditory evoked potential (P300), Mini Mental Status Examination (MMSE), Short Form-36 (SF-36) and CPC (Cognitive Performance Category). 2.7. Electroencephalogram (EEG) The EEG was recorded using a 21-channel digital recorder in a standardised manner according to the International 10-20 System (Nervus Taugagreining, Iceland), evaluated by experienced neurophysiologists and categorised into normal (1), abnormal (2) and slightly pathological (3). The EEG was recorded in a quiet room for 20 min, during which the patients, on request, performed opening/closing of the eyes, hyperventilation, flash light stimulation, testing number memory, and, finally, there was also a quiet period during which the patient was left alone. Reactivity of the EEG was assessed as a change in background and the dominant ␣-activity following stimulation. 2.8. Event-related cognitive cortical evoked response (P300) In a silent room, the patients, lying comfortably on a couch with their eyes closed, were presented with two different tones through earphones, the same sound on each side. The tones had different pitches (1000 Hz or 2000 Hz), appeared at random intervals of 1–3 s and lasted for an equal length of time, but the tone with the highest pitch was only heard 20% of the time. The patient was instructed to ignore the frequently presented tone, but when the infrequent tone appeared he was to press a button with the dominant hand. This marked the patient’s motor reaction time, and also gave information about correct or wrong response. The cerebral cortical responses were recorded from three positions along the midline (Fz, Cz and Pz according to the International 10-20 System). Eye artefact was controlled for and the analysis time was 1 s. Amplitude and latency of the cortical response were measured together with the motor reaction time (Keypoint, Dantec, Denmark).
2.4. DWI analysis Apparent diffusion coefficient (ADC) maps were calculated using the scanner software. ADC was measured in six reproducible regions of interest (ROI) (three in each hemisphere) in all MRI examinations using a picture archiving and communications system (PACS) workstation. The ROIs were manually positioned by an experienced neuroradiologist in the centrum semiovale (a circular ROI area measuring approximately 100 mm2 ), lentiform nucleus (a triangular freehand ROI area measuring 220–240 mm2 ) and mid-cerebellar hemisphere (a circular ROI area measuring 250–270 mm2 ). In addition, qualitative evaluation of the cortex, the subcortical grey matter and the white matter was performed by visual inspection of DWI and ADC maps and the total number of acute ischemic lesions was noted. ADC was measured in these lesions, and only lesions containing regions with ADC values below 0.6 × 10 −3 mm2 were classified as acute ischemia.12
2.9. Quality of life, Mini Mental Status Examination and cognitive performance The patients were presented with the SF-36 (standard version 1.0) one week before the tests. The SF-36 was chosen due to high sensitivity in cardiac patients.14 The SF-36 was evaluated by a physician, before a Mini Mental Status Examination (MMSE) was performed. The SF-36 scores were compared with expected scores, based on a historic control of a normal population.15 A Cognitive Performance Category (CPC) was assigned by the physician at the end of the consultation.16 The CPC score is a five-category scale: 1 = conscious and alert with normal cerebral function; 2 = conscious and alert with moderate cerebral function; 3 = conscious with severe cerebral disability; 4 = comatose or in persistent vegetative state; 5 = dead. 2.10. Statistics
2.5. FLAIR images and analyses of white matter Chronic ischemic/degenerative white matter lesions were evaluated with regard to number and appearance according to Fazekas’s classification.13 Periventricular hyperintensity (PVH) was graded as absent (0), caps or pencil-thin lining (1), smooth halo (2) or irregular PVH affecting the deep white matter (3). Deep white matter
For the purpose of the analysis, the ADC values that had been measured symmetrically in either the cerebral or cerebellar hemispheres in the same patient were regarded as two measurements in the same region for each patient. Mixed effects models were used for repeated measurements of ADC.17 The estimated relationship between ADC and fluid balance/temperature was calculated in the
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mixed effects model. The nlme package in R (The R Foundation for Statistical Computing, Vienna, Austria) was used for linear mixed effects models, while SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) was used for P300 analyses. As regards SF-36, patient scores were compared with expected mean scores18 based on the Norwegian reference material in relation to gender and age.15 Numbers are presented as mean (SD) or median (low–high). A p-value of <0.05 was considered significant. For categorical covariates with more than two categories, both overall p-values for the covariate and p-values for individual contrasts are reported. 3. Results Ten patients were included in our study. Nine were discharged alive and survived to the follow-up examination. Essential prehospital data are presented in Table 1. The median age was 60 (22–75) years, and the median time from cardiac arrest until ROSC was 21 (5–40) min. They received different fluid loads during the first 24 h (ranges 4142–9158 ml). 3.1. Magnetic resonance imaging MRI was carried out on admission in nine patients, and in 10 patients after 96 h. The complete MRI-schedule was carried out in eight patients. There was a change in ADC during the observation period, significantly related to the temperature (p < 0.001) (Table 2). At 35 ◦ C, the ADC increased 1.7%/◦ C. None of the patients had lesions indicating acute ischemia on admission, but three patients developed lesions after the cooling-period (Table 3, Fig. 1). The mean score for chronic ischemia for all patients was 1.2 (1.3) for periventricular hyperintensity and 1.2 (0.6) for deep white matter hyperintensity. The chronic ischemia scores did not change over time in the individual patients. 3.2. EEG and event-related cognitive cortical response (P300) None of the EEGs showed signs of heavy encephalopathy and within group 3; there were none with marked pathology. Neurophysiologic responses are reported in Table 1. 3.3. Short Form-36, CPC and MMSE The neurophysiologic and cognitive performance tests were performed 22 (15–26) months (range) after the cardiac arrest. The Short Form-36 results are presented together with the expected scores and differences in Table 1. Our patients scored significantly better than the Norwegian controls15 as regards both bodily pain (p = 0.023) and mental health (p = 0.016). The other axes did not differ significantly from the expected values. The Cognitive Performance Category and Mini Mental Status Examination are presented in Table 1. 4. Discussion The most interesting result in our study is the lack of acute brain ischemia on admission, as evaluated by MRI. DWI has been reported to detect ischemic changes as early as 11 min after the onset of symptoms.19 Our results are therefore unexpected, as intervals between cardiac arrest and return of spontaneous circulation up to 40 min were included. The lack of initial brain damage in our patients may be attributed to early and efficient pre-hospital resuscitation. By only including patients with witnessed cardiac arrest of assumed cardiac origin, the chance of survival increased.20–22 Bystander CPR was initiated almost immediately, and ordinary ambulances as well as an anaesthesiologist-manned ambulance
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assisted the victims. The quality of CPR in out-of-hospital arrest is reported to be low, including differences in hands-off time during resuscitation.23 Our ambulance service has implemented a supraglottic airway device (laryngeal tube) as the primary airway management during CPR, as it is fast and easy to insert and permits continuous chest compressions.24 These factors may reduce the cerebral no-flow-time during resuscitation, leading to our results. Three patients with normal MRI on admission developed acute ischemic lesions after therapeutic hypothermia. Changes can be seen in different brain regions depending on the timing of imaging after CA and on the nature of the injury (primary hypoxia could, for example, be followed by ischemia).6 The cardiovascular status in our patients did not differ during the first 24 h between these patients and those with normal MRI after hypothermia.11 DWI changes induced by global hypoxic cerebral injury in humans may evolve slowly, with a peak reported after 2–4.5 days.8 Therefore, quantitative DWI with ADC measurements obtained between 49 and 108 h after the arrest appear to best differentiate survivors from those who die.8 This may explain why the results of the early MRI examination performed on admission appeared normal in our three patients, with lesions appearing on the second MRI examination. Out of these three patients with CPC 1 and 2, one died and two survived. The patient who died had an increasing number of DWI lesions between the second and third MRI examinations. Local anatomical differences in vascular supply and/or co-morbidity, e.g. chronic white matter ischemia, may explain the development of acute ischemic lesions, but this patient had no signs of chronic lesions, which could indicate poor perfusion. The two survivors both had a high score as regards chronic ischemic lesions. In deceased patients, Järnum and colleagues found large numbers of lesions with low diffusion values in the cortex of the occipital and parietal lobes.7 Choi et al. found that the mixed pattern of brain injury (the cortex and deep grey nuclei) on DWI performed within five days of cardiac arrest correlated well with an unfavourable outcome.5 These findings are supported by our results, as the patient who died developed acute ischemic lesions in the frontal, parietal, temporal and occipital cortex, and in the basal ganglia. No signs of acute ischemia were detected in this patient by MRI on admission, but the lesions were seen in DWI performed 32 and 96 h after cardiac arrest. In another study, it was observed that ADC changes were seen predominantly in the cortex and striatum within the first three days, whereas, in later DWI studies, the changes were restricted to cortical regions and subcortical white matter.6 Changes in the cerebellum were more evident during later imaging. We did not see any cerebellar lesions in our patients. The apparent diffusion coefficient (ADC) reflects the mass, temperature and viscosity of water molecules and is the result of Brownian movements. In acute ischemia, the diffusion is restricted, probably due to cytotoxic oedema and swollen cells, resulting in a decrease in ADC values. We classified ADC values below 0.6 × 10−3 mm2 as acute ischemia.12 This is a relevant cut-off level for patients treated with hypothermia after CA, since it was shown in another study that the percentage of brain volume that had a lower value than the ADC cut-off value of 0.65–0.7 × 10−3 mm2 differentiated between survivors and patients who died or remained vegetative.8 It should also be noted that a study in 2008 reported variability in ADC values in healthy brain tissue depending on the MRI coil systems, imagers, vendors and field strengths used,25 but these results need to be confirmed in a larger study designed to correct machine-dependent variations.26 This does not affect the interpretation of our longitudinal study in which all MRI examinations were performed using the same scanner and exactly the same protocol. Increased ADC may indicate vasogenic oedema, but we did not find any relationship between volume load and ADC during the first 24 h. This may be explained by an intact blood–brain barrier supported by the lack of acute brain ischemia on admis-
552 Table 1 Pre-hospital data presented with number of acute lesions detected by MRI/DWI in the acute/subacute phase. In addition, EEG-reactivity, P300 responses, Cognitive Performance Category, Mini Mental Status Examination and Short-Form 36 by followup examination, are included. Patient Clinical parameters
EEG P300 response times and amplitudes
Short Form-36 scores (expected)e
1
0 1b
3
4
61 VF 1 9 35 11 15 2 29 – 1b 3 2 1 +
2 65 VF 1 8 40 9 5 1 30 – 0 NA 0 0 1 2 +
45 VF 1 5 27 3 3 1 29 – 0 0 0 0 1 1 +
74 VF 1 5 11 1 1 1 30 – 0 0 0 2 1 3 +
422 428 434
367 369 369
361 365 362
365 367 367
3.3 3.6 2.8 518 98 29 90 (83) 50 (69) 84 (66) 45 (68) 45 (60) 25 (88) 67 (83) 80 (78)
7.2 8.8 10.2 325 100 8 85(82) 100 (67) 80 (71) 92 (69) 80 (64) 100 (89) 100 (79) 88 (81)
7.3 10.9 14.8 412 93 4 95 (91) 100 (87) 100 (80) 92 (80) 95 (66) 100 (88) 100 (89) 84 (81)
5
21.6 25.7 27.9 326 100 2 100 (76) 100 (53) 84 (71) 100 (67) 80 (64) 100 (83) 100 (69) 92 (83)
0
6 75 VF 8 8 13 2 1 1 29 – 0 0 2 1 2 + 361 358 372
16.6 23.9 28.0 322 97 5 55 (56) 0 (36) 62 (59) 35 (62) 20 (51) 100 (75) 67 (61) 88 (77)
0
5b
60 VF 4 6 35 4 0 4 – 31 12b 1 1 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
7
0
8 48 VF 0 3 5 1 0 1 30 – 0 0 2 2 3 + 308 306 319
3.1 3.9 5.1 342 98 8 80 (91) 25 (85) 72 (79) 52 (78) 50 (65) 100 (87) 100 (89) 80 (81)
0
9 73 VF 1 6 11 2 0 1 29 – 0 0 0 1 1 + 387 391 384
5.7 8.0 5.8 424 96 2 80 (78) 75 (56) 100 (73) 67 (68) 80 (65) 100(85) 67 (70) 96 (84)
VF – ventricular fibrillation, CA-CPR = time from arrest until CPR, CA-EMS = time from arrest until Emergency Medical Service present, CA-ROSC = time from arrest until ROSC, NA = not assessed. a 3, 32 and 96 h after the arrest. b The localisation of the lesions are presented in Table 3. c According to Fazekas’ classification.13 d Reactivity + = reactivity present. e Based on age and gender in a control population.15,18
0
10
1b
66 VF 3 8 20 2 1 1 28 – 2b 3 2 3 + 469 452 452
3.8 5.0 8.3 401 97 4 70 (83) 0 (67) 84 (73) 62 (70) 85 (65) 100 (89) 100 (78) 100 (82)
NA
22 VF 9 9 17 4 1 1 28 – NA 0 0 0 1 + 346 341 351 14.4 18.0 14.1 328 99 0 100 (94) 100 (89) 100 (85) 100 (84) 60 (61) 100 (88) 100 (82) 80 (77)
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MRI
Age (years) Primary cardiac rhythm CA-CPR (min) CA-EMS (min) CA-ROSC (min) No of shocks Adrenaline (mg) CPC MMSE Mortality (days) Number of acute ischemic lesionsa Chronic lesions PVHc Chronic lesions DWMHc EEG Reactivityd Time (ms) Frontal Central Parietal Amplitude (V) Frontal Central Parietal Motoric (ms) Correct hits (%) False hits (number) Physical functioning Role-physical Bodily pain General health Vitality Social functioning Role emotional Mental health
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Table 2 ADC (1 × 10−3 mm2 s−1 ) results in a mixed-effect model presented as estimates (SE) and descriptive temperature presented as the mean (SD).
Centrum semiovale Nc.lentiformis Cerebellum Temperature (◦ C) a b
On admission (3 h after CA)
Day 1 (32 h after CA)
p-Valuea
Day 4 (96 h after CA)
0.701 (0.016) 0.711 (0.016) 0.807 (0.016) 34.4 (1.2)
0.704 (0.017) 0.721 (0.017) 0.813 (0.017) 35.6 (1.5)
0.84 0.52 0.69
0.752 (0.016) 0.780 (0.016) 0.842 (0.016) 37.1 (0.25)
p-Valueb p = 0.001 p < 0.001 p = 0.020
Overall p-value p = 0.002 p < 0.001 p < 0.001
Contrast between admission and day 1. Contrast between admission and day 4.
Table 3 Location and number of acute ischemic lesions, which developed after hypothermia in three patients. Patient 1 6
9
MRI (h)
Number of acute ischemic lesions
Location
32 96 32
1 1 5
96
12
32 96
1 2
Left frontal white matter (watershed) Left frontal white matter (watershed) Left frontal and temporoparietal cortex (watershed) + bilat caudate and lentiform nuclei Bilateral frontal, parietal, temporal and occipital cortex + bilat caudate and lentiform nuclei Left lentiform nucleus Left lentiform nucleus + right frontal white matter (watershed)
Fig. 1. A 60-year-old man with a 35-min cardiac arrest (CPR after 4 min.) who died after 31 days. MRI on admission shows no acute ischemic lesions on the DWI (A) or ADC map (D). DWI (B) at 32 h shows high signal intensity in the bilateral caudate and lentiform nuclei and in the left temporoparietal and frontal (not in this section) cortical watershed regions with low signal on the ADC map (E) in corresponding regions. DWI (C) at 96 h shows progression, with extensive bilateral cortical lesions with high signal intensity and corresponding ADC map (F).
sion, or the minimal difference in temperature between the first and second MRIs. As the difference between admission and day 4 was significant, temperature may be important. However, we did not record the brain temperature, but the temperature in the
urinary bladder. The temperature co-variation between these sites was found to be delayed during rapid, profound hypothermia.27,28 The lower rate of cooling/heating used in our setting may result in a good agreement between temperatures in the brain and the urinary
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bladder. The observed change in ADC as a function of temperature supports the results from animal studies.29,30 For prognostic data collection, the clinically relevant time window for performing DWI starts after re-warming the patient for around 36 h to avoid the lower temperature affecting the ADC values.8 The auditory evoked P300 potential reflects the response in the cortex recorded at different sites. The shorter latency and higher the amplitude of the response, the better. Tiainen and colleagues reported significantly higher amplitude in a cardiac arrest population treated with therapeutic hypothermia compared with normothermia (7.91 vs. 4.99 V).31 Our results are even higher, emphasising the good outcome. Witnessed out-of-hospital cardiac arrest (OHCA) combined with ventricular fibrillation has an increased survival rate and a better neurological outcome compared with non-shockable rhythms.32–34 Since all our patients are in this favourable group, a good outcome was expected. However, it is remarkable that the patients score better for bodily pain and mental health than the general population. This may be related to psychological aspects and the relief of survival. The degree of chronic illness may also affect the self-reported quality of life, but we have no data to support this. A Danish study using SF-36 also reported a better score for bodily pain, although not significantly different to the normal population.35 This is also supported by a study using the Nottingham Health Profile.36 MMSE is a screening tool for cognitive dysfunction, but it is not sensitive to cognitive disorders such as mild dementia.37 Highly educated patients may achieve good scores even though they have disorders detected by more sophisticated tests.38 We did not adjust for level of education, but it is surprising to detect outstanding scores for MMSE and CPC in spite of prolonged resuscitation of up to 40 min. One limitation of our study is the different time span of followup after discharge. However, we believed it to be more important that the patients had sufficient time to achieve their potentials for rehabilitation. Moreover, the MRI protocol applied to the intensive care patients was demanding, and a larger number of patients would have been desirable. MRI may not be appropriate for all comatose cardiac arrest patients, such as patients with hemodynamic instability or other contraindications (e.g. a pacemaker, IABP). More longitudinal MRI/DWI studies of CA patients treated with hypothermia are needed in order to further assess the effect of hypothermia and to separate the effect of initial hypoxia from events potentially occurring during treatment. 5. Conclusion MRI performed in an early phase after cardiac arrest has limitations, as MRI performed after 24 and 96 h revealed ischemic lesions not detectable on admission. ADC was related to the core temperature, and not to the volume distributed intravenously. Follow-up neurophysiologic tests and self-reported quality of life were good. Funding Bård E. Heradstveit is a fellow research of the Regional Centre for Emergency Medical Research and Development (RAKOS, Stavanger/Norway). The RAKOS had no influence of the topic, study design nor interpretation of the data. Conflict of interest There are no commercial relations involving any of the authors that might pose a conflict of interest in connection with this manuscript.
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