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| 34. |
- Cronberg, Tobias
(författare)
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Ischemic Cell Death in the CNS - applications of a new in vitro model
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ischemic brain damage is a common cause of death and disability. A global ischemic insult is usually the result of a transient cardiac arrest while occlusion of cerebral blood vessels leads to focal ischemic lesions, commonly termed stroke. During the last decades our knowledge about the metabolic and cellular events leading to cell death following ischemia has expanded mainly due to experimental studies in vivo and in vitro. Important findings concerning the relevance of body temperature and blood glucose levels have been confirmed in humans. However, a vast number of pharmacological agents with protective effects in animal models of ischemia have failed in subsequent clinical trials. This illustrates that our knowledge of the mechanisms of ischemic cell death is still incomplete and that we need to question the models we use to mimic the human disorders. We have used the organotypic tissue culture from mouse hippocampus to establish a new model of in vitro ischemia (IVI). Similar to previous models we combine anoxia and aglycemia but in addition we apply a combination of ions similar to what is found in the brain extracellular fluid during ischemia. We found that the combination of a high potassium level (70mM), a low calcium level (0.3mM) and acidosis (pH 6.8) during IVI made the pattern of cell death more similar to what is found following global ischemia in vivo in that became more delayed and selective. A high level of glucose was found to increase cell death in contrast to what had previously been found in other cell culture models of ischemia but in similarity to what is found in vivo. While cell death following IVI could be completely prevented by the withdrawal of extracellular calcium during the insult or antagonists of glutamatergic NMDA-receptors, no effect of either was found in the hyperglycaemic IVI paradigm. On the other hand, intracellular calcium chelation prevented against cell death following hyperglycaemic IVI but not IVI. Inhibition of free radicals was ineffective in both paradigms. These findings illustrates that IVI and hyperglycaemic IVI induces two different patterns of cell death both of which may be important during ischemia in vivo. Intraischemic acidosis protected neurons in the CA3-subregion of hippocampus more than in CA1. NMDA-receptors in both regions were inhibited by acidosis but they recovered significantly slower in the CA3-region. This prolonged inhibition could explain the sparing of the CA3-neurons following IVI and global ischemia. The neuromodulator adenosine inhibits glutamate release through presynaptic A1-receptors. We used transgenic A1-receptor knock-out mice to study the importance of this receptor for the development of cell death following IVI and global ischemia in vivo. No effect of the knock-out was found in any of the two paradigms. The A1-receptor antagonist, 8-CPT increased damage in vivo but had no effect in vitro. This discrepancy between the models could be explained by a less importance of vesicular glutamate release in vitro or an undiscovered systemic side-effect of 8-CPT in vivo. The described models of IVI and hyperglycaemic IVI are well suited for further studies on the pathophysiology of cerebral ischemia using transgenic, pharmacological, electrophysiological and imaging techniques.
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| 35. |
- Cronberg, Tobias, et al.
(författare)
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Long-term neurological outcome after cardiac arrest and therapeutic hypothermia.
- 2009
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Ingår i: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 80, s. 1119-1123
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Tidskriftsartikel (refereegranskat)abstract
- AIM OF THE STUDY: To analyse the neurological status of survivors after cardiac arrest (CA) treated with hypothermia. METHODS: We prospectively included all patients with CA treated with hypothermia at intensive care units (ICU) in two university hospitals and one regional hospital. All adult survivors at 6 months after CA, n=48, were invited for neurological follow-up and 43 accepted. History, clinical status, ability testing and questionnaires were administered to screen for difficulties, including Assessment of Motor and Process Skills, Neurobehavioral Cognitive Status Examination, Frontal Lobe Assessment Battery, EQ-VAS quality of life scale, Skåne Sleep Index, Hospital Anxiety and Depression Rating Scale, Self-reported Montgomery and Astrand Depression Rating Scale, Global Deterioration Scale, Rivermead Behavioural Memory Test, and the Cerebral Performance Categories (CPC). RESULTS: No patient was found to be in a chronic vegetative state and all patients were living at home, one with extensive help. Thirty-six patients were in CPC1 at follow-up, and some degree of neurological sequelae was found in 40 patients, but was mild in all but 3. Three patients had no subjective complaints, nor could any deficits be detected. Initial defects improved over-time. Short-term memory loss, executive frontal lobe dysfunction along with mild depression and sleep rhythm disturbances were the most common findings. CONCLUSIONS: Mild cognitive impairment is common following hypothermia-treated cardiac arrest but has little effect on activities of daily living or quality of life.
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| 38. |
- Cronberg, Tobias, et al.
(författare)
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Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33 degrees C vs 36 degrees C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial
- 2015
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:6, s. 634-641
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.
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| 39. |
- Cronberg, Tobias, et al.
(författare)
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Neurological prognostication after cardiac arrest : Recommendations from the Swedish Resuscitation Council
- 2013
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 84:7, s. 867-872
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Tidskriftsartikel (refereegranskat)abstract
- Cardiopulmonary resuscitation is started in 5000 victims of out-of-hospital cardiac arrest in Sweden each year and the survival rate is approximately 10%. The subsequent development of a global ischaemic brain injury is the major determinant of the neurological prognosis for those patients who reach the hospital alive. Induced hypothermia is a recommended treatment after cardiac arrest and has been implemented in most Swedish hospitals.Recent studies indicate that induced hypothermia may affect neurological prognostication and previous international recommendations are therefore no longer valid when hypothermia is applied. An expert group from the Swedish Resuscitation Council has reviewed the literature and made recommendations taking into account the effects of induced hypothermia and concomitant sedation.A delayed neurological evaluation at 72h after rewarming is recommended for hypothermia treated patients. This evaluation should be based on several independent methods and the possibility of lingering pharmacological effects should be considered.
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| 40. |
- Cronberg, Tobias, et al.
(författare)
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Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.
- 2011
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Ingår i: Neurology. - 1526-632X. ; 77:7, s. 623-630
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma. METHODS: Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died. RESULTS: Six of the 17 patients (35%) with NSE levels <33 μg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening. CONCLUSIONS: NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.
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