Background: There is evidence that monocyte chemoattractant protein-1 (MCP-1) levels reflect the intensity of the inflammatory response in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) and have a predictive value for clinical outcomes. However, little is known about the effect of mild therapeutic hypothermia (MTH) on the inflammatory response in patients with CS complicating AMI. Therefore, we conducted a biomarker study to investigate the effect of MTH on MCP-1 levels in patients with CS complicating AMI. Methods: In the randomized mild hypothermia in cardiogenic shock (SHOCK-COOL) trial, 40 patients with CS complicating AMI were enrolled and assigned to MTH (33 ◦C) for 24 h or normothermia at a 1:1 ratio. Blood samples were collected at predefined time points at the day of admission/day 1, day 2 and day 3. Differences in MCP-1 levels between and within the MTH and normothermia groups were assessed. Additionally, the association of MCP-1 levels with the risk of all-cause mortality at 30 days was analyzed. Missing data were accounted for by multiple imputation as sensitivity analyses. Results: There were differences in MCP-1 levels over time between patients in MTH and normothermia groups (P for interaction = 0.013). MCP-1 levels on day 3 were higher than on day 1 in the MTH group (day 1 vs day 3: 21.2 [interquartile range, 0.25–79.9] vs. 125.7 [interquartile range, 87.3–165.4] pg/mL; p = 0.006) and higher than in the normothermia group at day 3 (MTH 125.7 [interquartile range, 87.3–165.4] vs. normothermia 12.3 [interquartile range, 0–63.9] pg/mL; p = 0.011). Irrespective of therapy, patients with higher levels of MCP-1 at hospitalization tended to have a decreased risk of all-cause mortality at 30 days (HR, 2.61; 95% CI 0.997–6.83; p = 0.051). Conclusions: The cooling phase of MTH had no significant effect on MCP-1 levels in patients with CS complicating AMI compared to normothermic control, whereas MCP-1 levels significantly increased after rewarming. Trial registration: NCT01890317.

Position du problème. L’arrêt cardiaque extra-hospitalier (ACEH), dont la forme clinique la plus caricaturale correspond à la « mort subite », représenterait la première cause de mortalité à travers le monde. Malgré les améliorations apportées à leur prise en charge, le pronostic de ces patients demeure très péjoratif, y compris chez ceux qui ont bénéficié d’une réanimation initiale avec succès. En effet, la longue période d’ischémie suivie du phénomène de reperfusion secondaire au retour d’une activité circulatoire (RACS) est à l’origine d’une cascade de phénomènes physiopathologiques qui caractérisent le syndrome post-arrêt cardiaque. Plusieurs éléments thérapeutiques, telles que la reperfusion coronaire précoce et l’hypothermie thérapeutique, se sont développés ces dernières années afin de diminuer la morbi-mortalité importante observée dans cette situation. L’intérêt de ces interventions précoces sur le pronostic ultérieur demeure cependant débattu, car il a souvent été établi sur des sous-groupes de patients très sélectionnés. Objectif. L’objectif de ce travail était d’évaluer l’influence de ces interventions thérapeutiques précoces sur le devenir des patients victimes d’ACEH et admis vivants en service de réanimation. Méthode. Depuis 2000, une cohorte de patients survivants d’ACR et admis vivants en réanimation a été constituée dans un centre spécialisé. L’ensemble des caractéristiques démographiques, pré-hospitalières et hospitalières ont été analysées. L’analyse multivariée des facteurs pronostiques dans cette cohorte a utilisé principalement les méthodes de régression logistique. Résultats principaux. Entre 2003 et 2008, 435 patients ont été admis, ne présentaient pas d’étiologie extra-cardiaque évidente et ont bénéficié d’une coronarographie immédiate et systématique. Une lésion coronaire récente a été observée chez près de la moitié d’entre eux. Les moyens de détection d’une étiologie cardiaque sont extrêmement limités que ce soit par des modèles prédictifs simples utilisant des paramètres démographiques ou circonstancielles ou par des paramètres para-cliniques tels que l’électrocardiogramme ou les enzymes cardiaques. En effet, ces derniers possèdent des valeurs prédictives médiocres et ne peuvent être considérés comme outil de triage de ces patients. En revanche, la coronarographie immédiate et systématique (suivie d’une reperfusion coronaire si nécessaire) était associée de manière significative et indépendante à la survie hospitalière (OR ajusté= 2.06 (1.16-3.66)) et ceci quelque soit l’aspect électrocardiographique. Entre 2000 et 2009, 1145 patients ont été admis et 2/3 d’entre eux ont été traités par hypothermie thérapeutique. Parmi eux, 708/1145 (62%) avait initialement un rythme cardiaque choquable et 437/1145 (38%) présentait un rythme non choquable. Après ajustement sur les autres facteurs pronostiques, l’hypothermie thérapeutique avait un rôle protecteur sur le pronostic neurologique des patients à la sortie de réanimation dans le groupe présentant initialement un rythme choquable (OR ajusté= 1.90 (1.18-3.06)). En revanche, l’association entre le pronostic et l’intervention dans le groupe « non-choquable » n’était pas significative (OR ajusté=0.71 (0.37-1.36)). Parmi les facteurs susceptibles d’altérer le bénéfice lié à ce traitement, les complications infectieuses chez les patients traités par hypothermie thérapeutique s’avèrent courantes La plus fréquente est la pneumopathie précoce, dont l’apparition est associée de manière significative au traitement par hypothermie (OR ajusté= 1.90 (1.28-2.80)), mais son rôle sur le pronostic n’est pas démontré. / Background: Out-of-Hospital Cardiac Arrest (OHCA), usually clinically described as “sudden death”, is the leading worldwide cause of death. Despite recent improvements in management of OHCA, the prognosis of these patients remains very poor, even in those who benefitted from a successful initial resuscitation. During the period of ischemia following the Return of Spontaneous Circulation (ROSC), several pathophysiological phenomenons occur, characterizing the post cardiac arrest syndrome. Furthermore, different treatments, such as immediate coronary reperfusion or therapeutic hypothermia, are now implemented for the management of this syndrome in order to decrease the morbidities and the mortality involved during this period. However, the influence of these hospital interventions on prognosis is still debatable, since they have been assessed in very selected subgroups of patients.Objectives: The aim of our work was to assess the influence of these early interventions on the outcome of OHCA patients admitted alive in intensive care unit (ICU).Method: We set up an investigation cohort (starting in 2000) of OHCA patients, in whom a successful ROSC had been obtained and who were admitted alive in ICU. We gathered all demographic data, cardiac arrest circumstances, pre-hospital and hospital characteristics. We analyzed the different predictive factors of outcome using multivariate analysis, especially logistical regression.Results: Between 2003 and 2008, 435 patients without obvious extra-cardiac cause were included and benefited from an immediate and systematical coronary angiogram. We observed a recent lesion in nearly half of them. Detecting a cardiac etiology is very challenging even using simple predictive models including patient’s baseline characteristics and circumstances of the cardiac arrest. Moreover, other parameters, such as EKG patterns or cardiac biomarkers, did not seem helpful either. Indeed, these parameters had poor predictive values and consequently could not be considered as triage tools for these patients. Nevertheless, the immediate and systematical coronary angiogram, with percutaneous intervention if appropriate, was independently associated with an improvement of hospital survival (adjusted OR= 2.06 (1.16-3.66)), regardless of the EKG pattern.Between 2000 and 2009, 1145 patients were admitted and two third of them were treated with therapeutic hypothermia. Among them, 708/1145 (62%) had an initial shockable rhythm and 437/1145 (38%) presented a non shockable rhythm. On the one hand, after adjustment with other predictive factors, the therapeutic hypothermia significantly improved the good neurological outcome at ICU discharge (adjusted OR= 1.90 (1.18-3.06)). On the other hand, the influence of this intervention was not associated with prognosis on the “non-shockable” sub-group (adjusted OR=0.71 (0.37-1.36)). Among the undercurrent factors, which could minimize the benefit of this intervention, infectious complications in treated patients were common. The most frequent complication was early onset pneumonia, whose occurrence was significantly associated with hypothermia (adjusted OR= 1.90 (1.28-2.80)), even if its role on prognosis was not determined.Conclusions: Our findings support the international guidelines regarding the management of post-cardiac arrest, identifying the subgroups of patients who may benefit the most. These results encourage further prospective studies and randomized trials and bring helpful information in that way. Finally, ancillary analysis on an investigation cohort of hospital survivors suggests that protective

This thesis explores physiological changes occurring after acute brain injury. The first two chapters focus on traumatic brain injury (TBI), a significant cause of disability and death worldwide. I discuss the evidence behind current management of secondary brain injury with emphasis on partial brain oxygen tension (PbtO2) and intracranial pressure (ICP). The second chapter describes a subgroup analysis of the effect of hypothermia on ICP and PbtO2 in 17 patients enrolled to the Eurotherm3235 trial. There was a mean decrease in ICP of 4.1 mmHg (n=9, p < 0.02) and a mean decrease in PbtO2 (7.8 ± 3.1 mmHg (p < 0.05)) in the hypothermia group that was not present in controls. The findings support previous studies in demonstrating a decrease in ICP with hypothermia. Decreased PbtO2 could partially explain worse outcomes seen in the hypothermia group in the Eurotherm3235 trial. Further analysis of PbtO2 and ICP guided treatment is needed. The third chapter focuses on delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH), another form of acute brain injury that causes significant morbidity and mortality. I include a background of alpha-calcitonin gene-related peptide (αCGRP), a potential treatment of DCI, along with results from a systematic review and meta-analysis of nine experimental models investigating αCGRP. The meta-analysis demonstrates a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated with αCGRP compared with controls (p < 0.0005, 95% CI 23.7 to 57.9). Neurobehavioural scores were reported in four publications and showed a Physiological responses to brain tissue hypoxia and blood flow after acute brain injury standardised mean difference of 1.31 in favour of αCGRP (CI -0.49 to 3.12). I conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in animal studies but note that there is insufficient evidence to determine its effect on functional outcomes. A review of previous trials of αCGRP administration in humans is included, in addition to an original retrospective analysis of CSF concentrations of αCGRP in humans. Enzyme-linked immunosorbent assay of CSF (n = 22) was unable to detect αCGRP in any sample, which contrasts with previous studies and was likely secondary to study methodology. Finally, I summarise by discussing a protocol I designed for a dose-toxicity study involving the intraventricular administration of αCGRP to patients with aSAH and provide some recommendations for future research. This protocol was based upon the systematic review and was submitted to the Medical Research Council's DPFS funding stream during the PhD.

The controlled lowering of core body temperature to 32°C to 34°C is defined as therapeutic hypothermia (TH). Therapeutic hypothermia has been shown to improve neurological outcome and survival in unconscious patients successfully resuscitated after cardiac arrest. Brain temperature is important for cerebral protection therefore methods for primarily cooling the brain have also been explored. This thesis focuses on the likelihood that intranasal cooling can induce, maintain and control cerebral hypothermia. The method uses bilaterally introduced intranasal balloons circulated with cold saline. Selective brain cooling induced with this method was effectively accomplished in pigs with normal circulation while no major disturbances in systemic circulation or physiological variables were recorded. The temperature gradients between brain and body could be maintained for at least six hours. Intranasal balloon catheters were used for therapeutic hypothermia initiation and maintenance during and after successful resuscitation in pigs. Temperature reduction was also obtained by combined intranasal cooling and intravenous ice-cold fluids with possible additional benefits in terms of physiologic stability after cardiac arrest. Rewarming was possible via the intranasal balloons. In these studies brain temperature was recorded invasively by temperature probes inserted in the brain. The fast changes in pig’s brain temperature could also be tracked by a non-invasive method. High-spatial resolution magnetic resonance spectroscopic imaging (MRSI) without internal reference showed a good association with direct invasive temperature monitoring. In addition the mapping of temperature changes during brain cooling was also possible. In awake and unsedated volunteers subjected to intranasal cooling brain temperature changes were followed by two MR techniques. Brain cooling was shown by the previously calibrated high-spatial resolution MRSI and by the phase-mapping method. Intranasal cooling reduced body temperature slightly. The volunteers remained alert during cooling, the physiological parameters stable, and no shivering was reported.

No description available.

Therapeutic hypothermia (TH) is the only clinically used intervention that suppresses nearly all manifestations of ischemia-reperfusion injury after cardiac arrest. Experimental models has proven that exogenous antioxidants have positive impact on ischemia-reperfusion injury and it is able to prevent it as well. Results in this thesis are based on application of high dosages of N-acetylcystein (NAC) on ischemia-reperfusion injury after experimental cardiac arrest in a porcine model. It was used as a form of monoteraphy or in combination with TH. During the experiment animals were randomized into 5 groups: administration of NAC and TH (group A), administration of NAC during cardiac arrest (group B), induction of TH (group C), without any intervention (group D) and administration of NAC after return of spontaneous circulation (group E). We were not able to confirm additive effect of NAC in combination with TH. Administration of NAC during cardiac arrest led to statistically important reduction of oxidative stress but in the same time anafylactic reaction led to higher mortality in group B and changes in hemodynamical parameters in group E. Key words: Therapeutic hypothermia, cardiac arrest, N-acetylcysteine, ischemia-reperfusion injury, cardiopulmonary resuscitation, oxidative stress, oxygen radicals

L'encéphalopathie hypoxique ischémique néonatale (EHI) reste la cause principale de mortalité chez le nouveau-né à terme. Un tiers des survivants vont développer des séquelles neurologiques, dont la paralysie cérébrale (PC), l'épilepsie et un retard intellectuel. Afin d'améliorer leur pronostic, ces nouveau-nés sont soumis à l'hypothermie thérapeutique (HT) qui débute au plus tard 6 heures après la naissance, pour une durée totale de 72 heures, suivie d'un réchauffement graduel (0.5°C/h). Il a été démontré que cette thérapie à effet neuroprotecteur diminue considérablement l'étendue des lésions cérébrales et la fréquence des séquelles neurologiques. Or, des études animales suggèrent que l'hypothermie sans sédation avec opioïdes n'est pas bénéfique. Selon les observations qui ont été réalisées, les porcelets traités avec la thérapie, mais sans l’administration d’analgésique ont manifesté des signes d’instabilités et de tremblements exagérés. On ignorait jusqu’à présent dans quelle mesure ces résultats tirés des expérimentations animales pouvaient être généralisables au nouveau-né. Ainsi, mon projet de maîtrise vise à mieux comprendre les facteurs qui risquent de compromettre les effets bénéfiques de la thérapie de refroidissement, dans le but d’optimiser la neuroprotection et d’améliorer le développement des nourrissons atteints d’EHI. Nous avons comme objectif principal d’évaluer l’association entre les doses d’opioïdes consommées pendant l’HT, le degrée de tremblement, et l’évolution de l’index de discontinuité à l’EEG au fil des 72h de l’HT, du réchauffement et jusqu’à 12 heures post-HT. Pour répondre à l’objectif, nous avons conduit une étude chez 21 nouveau-nés avec EHI soumis à l’HT, et dont les principaux résultats ont montré des associations significatives entre les fortes doses d’opioïdes administrés à l’enfant (r = - 0.493, p = 0.023), les frissons réduits pendant l’HT (r = 0.513, p = 0.017) et l’amélioration du rythme cérébrale d’EEG. Ces résultats sont décrits de manière plus approfondie dans le Chapitre 2 qui présente la version de l’article soumis à la revue Journal of Pediatrics, et le Chapitre 3 qui présente un retour sur la littérature à la lumière de nos trouvailles. Quant au Chapitre 4, nous y élaborons les possibilités de perspectives futures et les retombées cliniques de nos résultats. À long terme, nous espérons que nos travaux permettront l’ouverture d’une nouvelle piste d’amélioration de la neuroprotection, en favorisant systématiquement une meilleure prise en charge de la douleur et du stress induit par le refroidissement. / Neonatal hypoxic-ischemic encephalopathy (HIE) remains the leading cause of death and mortality in the term infant. A third of the survivors will develop neurological sequelae including cerebral palsy (CP), epilepsy and mental retardation. In order to improve their prognosis, these newborns undergo therapeutic hypothermia (TH), which begins no later than 6 hours after birth, maintained for a total duration of 72 hours and followed by gradual rewarming (0.5°C/h). This neuroprotective therapy has been shown to significantly decrease the extent of brain injury and the frequency of neurological sequelae. Results from animal studies revealed that ongoing hypothermia without proper anesthesia is not beneficial. Based on the observations that have been reported, piglets treated with TH with no analgesics have shown signs of instability and excessive tremors. Until now, the extent to which these results from animal experiments could be generalized to the newborn remained unknown. Thus, the purpose of my master’s project was to better understand the clinical factors that may compromise the beneficial effects of TH, in an attempt to optimize neuroprotection and improve the neurological outcome of HIE infants. Our main objective was to assess the associations between opioid doses consumed during TH, shivering recorded during TH, and the evolution of EEG discontinuity index over the course of TH, rewarming and up to 12 hours post-TH. To meet the objective, we conducted a study in 21 newborns with HIE undergoing TH, and the results have shown significant associations between high doses of opioid administered (r = - 0.493, p = 0.023), reduced shivering stress (r = 0.513, p = 0.017) and improved EEG background activity. The key findings of the study are described in more detail in Chapter 2, which presents the original manuscript submitted for publication to the “Journal of Pediatrics”, and Chapter 3, which presents a review of the literature in light of our results. In Chapter 4, we discuss future perspectives and the clinical significance of our results. At last, we hope that our study will open up new avenues for improving neuroprotection, by systematically promoting a better management of pain and cooling-induced stress.

Successful cardiopulmonary resuscitation is the first step to rescue life during cardiac arrest. High mortality even after successful restoration of spontaneous circulation is substantially caused by patophysiological process associated with ischemia-reperfusion injury and it is widely called post-cardiac arrest syndrome (PCAS). There are many patophysiological mechanisms involved in the development and progress of this syndrom; the key role seems to play oxidative stress, triggering the activation cascade of systemic inflammatory reaction. In our study we have tested different possibilities of influencing the post-cardiac arrest syndrom. In the first experimental study we have compared the effect of mild therapeutic hypothermia with controlled normothermia on PCAS in a porcine model of cardiac arrest. In the second study we have compared in the same model the protective effects of mild therapeutic hypothermia, administration of nitric oxide and ischemic postconditioning. Results of the first experiment have revealed that mild therapeutic hypotermia is superior in the resuscitability, maintenance of blood pressure, oxidative stress suppression and organ damage protection than controlled normothermia. In the second experiment we have shown that neither nitric oxide administration, nor ischemic...

It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB). In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM. The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM. The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only. In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.

No description available.