Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Caractérisation et modulation pharmacologique de la fonction ventriculaire gauche et du couplage contraction-relaxation par la mesure de la torsion et de la détorsion au cours de l’hypertension artérielle chronique

Chronic hypertension induces left ventricular (LV) hypertrophy, resulting in abnormalities in LV relaxation, passive stiffness and filling. The higher the heart rate, the more pronounced the LV diastolic dysfunction. Moreover, in the normal heart, there is a tight coupling between LV contraction and relaxation, implying that in case of preserved contraction-relaxation coupling during LV hypertrophy, there is no diastolic dysfunction without systolic dysfunction. Thus, the three main objectives of this thesis were to investigate 1) the LV function and contraction-relaxation coupling with LV twist and untwist, which represent LV myocardial deformation during systole and diastole, 2) the cellular mechanisms of the LV contraction-relaxation coupling and 3) the effects effects of heart rate reduction on LV twist and untwist in the context of chronic hypertension and LV hypertrophy. All experiments were conducted in a pig model of chronic hypertension and LV hypertrophy induced by four weeks of continuous angiotensin II infusion. Chronic angiotensin II infusion decreased LV twist and untwist but also delayed LV untwist in the cardiac cycle, whereas the LV ejection fraction was preserved. The contraction-relaxation coupling was preserved as illustrated by the strong relationship between LV twist and untwist. The contraction-relaxation coupling was also preserved at the level of cardiomyocytes. This implies that LV hypertrophy is associated with concomitant LV diastolic and systolic dysfunction despite preserved LV ejection fraction. Thus, LV diastolic dysfunction is always accompanied by LV systolic dysfunction, i.e., the discovery of LV diastolic dysfunction with preserved ejection fraction might imply the track of LV systolic dysfunction. At the cellular level, LV systolic and diastolic dysfunctions were associated to aberrant calcium handling with a remodelling of the type 2 ryanodine receptor calcium release channel (RyR2), i.e., PKA-hyperphosphorylation and depletion of calstabin 2 (FKBP12.6). RyR2 were leaky and hypersensitive to cytosolic calcium, during both the contraction and the relaxation phases. Since both LV systolic and diastolic dysfunctions were associated to leaky and hypersensitive RyR2 channels, it might suggest considering RyR2 as an integrator contributing to control contraction-relaxation coupling during chronic hypertension and LV hypertrophy. Finally, we investigated the effects of heart rate reduction induced by ivabradine, an If-channel blocker, which does not modify atrioventricular or LV conduction and is devoid of any intrinsic negative inotropic or lusitropic effects. In the context of chronic hypertension and LV hypertrophy, ivabradine improved both LV systolic and diastolic functions, as attested by the improvement in contraction and relaxation times, LV twist and untwist as well as LV filling. Heart-rate independent effects of ivabradine, i.e., pleiotropic effects, participate to its beneficial effect. However, the cellular mechanisms of these beneficial effects of ivabradine were not elucidated and require further investigations. In normal heart, when heart rate was reduced to a low level (approximately <60 beats/min) with ivabradine, LV twist was not affected but LV diastolic function was altered as suggested by decreased LV untwist parameters and increased LV end-diastolic pressure. Investigation of contraction-relaxation coupling during decompensation from stable LV hypertrophy remains a goal to achieve.L’hypertension artérielle chronique induit une hypertrophie ventriculaire gauche, à l’origine d’une dysfonction diastolique caractérisée par des troubles de la relaxation, de la compliance et du remplissage ventriculaires gauches, le tout aggravé par toute augmentation de la fréquence cardiaque. Le couplage contraction-relaxation physiologique implique, en cas de préservation dans ce contexte d’hypertrophie ventriculaire gauche, que cette dysfonction diastolique s’accompagne d’une dysfonction systolique. Ainsi, ce travail de thèse s’est attaché (1) à caractériser la fonction ventriculaire gauche et le couplage contraction-relaxation à l’aide de la mesure de la torsion et la détorsion, (2) à étudier les mécanismes cellulaires impliqués dans le couplage contraction-relaxation et (3) à explorer les effets d’une stratégie thérapeutique visant à réduire la fréquence cardiaque sur la torsion et la détorsion du ventricule gauche dans un modèle d’hypertension artérielle chronique et d’hypertrophie ventriculaire induites chez le porc chroniquement instrumenté par la perfusion continue d’angiotensine II pendant 28 jours. A J28, la torsion et la détorsion étaient diminuées et la détorsion également retardée au sein du cycle cardiaque, alors que la fraction d’éjection ventriculaire gauche était préservée. Le couplage contraction-relaxation était préservé, tant au niveau du ventricule gauche qu’à l’échelon cardiomyocytaire, suggérant que toute dysfonction diastolique devrait faire rechercher une dysfonction systolique. A J28, ces anomalies fonctionnelles s’accompagnaient d’une diminution de l’expression de la SERCA2a et de sa protéine régulatrice le phospholamban. Des anomalies du récepteur de la ryanodine de type 2 étaient aussi observées avec son hyperphosphorylation et la dissociation de sa protéine régulatrice calstabine 2, à l’origine de fuites calciques systoliques et diastoliques. Ce dernier pourrait ainsi jouer un rôle clé dans la préservation du couplage contraction-relaxation et représenter l’intégrateur entre les anomalies ventriculaire gauche systolique et diastolique observées. Enfin, la réduction pharmacologique de la fréquence cardiaque à J28 par l’ivabradine, un inhibiteur sélectif des canaux If, permettait d’améliorer, en partie par des effets fréquence-indépendants dont les mécanismes cellulaires restent à élucider, tant les anomalies ventriculaire gauche diastolique que systolique, avec une amélioration des temps de contraction et de relaxation isovolumiques, de la torsion et de la détorsion ainsi que du remplissage du ventricule gauche. En l’absence d’hypertrophie ventriculaire gauche, la réduction de la fréquence cardiaque à des valeurs inférieures à 60 batt/min s’accompagnait d’un effet délétère fréquence-dépendant, à l’origine d’une altération isolée de la fonction diastolique caractérisée par une diminution de la détorsion du ventricule gauche et une augmentation de la pression télédiastolique ventriculaire gauche. La caractérisation de la fonction ventriculaire gauche et l’étude du couplage contraction-relaxation par la mesure de la torsion et de la détorsion en cas de décompensation cardiaque restent à déterminer

Characterization and pharmacological modulation of the left ventricular function and contraction-relaxation coupling by measuring twist and untwist during chronic arterial hypertension

L’hypertension artérielle chronique induit une hypertrophie ventriculaire gauche, à l’origine d’une dysfonction diastolique caractérisée par des troubles de la relaxation, de la compliance et du remplissage ventriculaires gauches, le tout aggravé par toute augmentation de la fréquence cardiaque. Le couplage contraction-relaxation physiologique implique, en cas de préservation dans ce contexte d’hypertrophie ventriculaire gauche, que cette dysfonction diastolique s’accompagne d’une dysfonction systolique. Ainsi, ce travail de thèse s’est attaché (1) à caractériser la fonction ventriculaire gauche et le couplage contraction-relaxation à l’aide de la mesure de la torsion et la détorsion, (2) à étudier les mécanismes cellulaires impliqués dans le couplage contraction-relaxation et (3) à explorer les effets d’une stratégie thérapeutique visant à réduire la fréquence cardiaque sur la torsion et la détorsion du ventricule gauche dans un modèle d’hypertension artérielle chronique et d’hypertrophie ventriculaire induites chez le porc chroniquement instrumenté par la perfusion continue d’angiotensine II pendant 28 jours. A J28, la torsion et la détorsion étaient diminuées et la détorsion également retardée au sein du cycle cardiaque, alors que la fraction d’éjection ventriculaire gauche était préservée. Le couplage contraction-relaxation était préservé, tant au niveau du ventricule gauche qu’à l’échelon cardiomyocytaire, suggérant que toute dysfonction diastolique devrait faire rechercher une dysfonction systolique. A J28, ces anomalies fonctionnelles s’accompagnaient d’une diminution de l’expression de la SERCA2a et de sa protéine régulatrice le phospholamban. Des anomalies du récepteur de la ryanodine de type 2 étaient aussi observées avec son hyperphosphorylation et la dissociation de sa protéine régulatrice calstabine 2, à l’origine de fuites calciques systoliques et diastoliques. Ce dernier pourrait ainsi jouer un rôle clé dans la préservation du couplage contraction-relaxation et représenter l’intégrateur entre les anomalies ventriculaire gauche systolique et diastolique observées. Enfin, la réduction pharmacologique de la fréquence cardiaque à J28 par l’ivabradine, un inhibiteur sélectif des canaux If, permettait d’améliorer, en partie par des effets fréquence-indépendants dont les mécanismes cellulaires restent à élucider, tant les anomalies ventriculaire gauche diastolique que systolique, avec une amélioration des temps de contraction et de relaxation isovolumiques, de la torsion et de la détorsion ainsi que du remplissage du ventricule gauche. En l’absence d’hypertrophie ventriculaire gauche, la réduction de la fréquence cardiaque à des valeurs inférieures à 60 batt/min s’accompagnait d’un effet délétère fréquence-dépendant, à l’origine d’une altération isolée de la fonction diastolique caractérisée par une diminution de la détorsion du ventricule gauche et une augmentation de la pression télédiastolique ventriculaire gauche. La caractérisation de la fonction ventriculaire gauche et l’étude du couplage contraction-relaxation par la mesure de la torsion et de la détorsion en cas de décompensation cardiaque restent à déterminer.Chronic hypertension induces left ventricular (LV) hypertrophy, resulting in abnormalities in LV relaxation, passive stiffness and filling. The higher the heart rate, the more pronounced the LV diastolic dysfunction. Moreover, in the normal heart, there is a tight coupling between LV contraction and relaxation, implying that in case of preserved contraction-relaxation coupling during LV hypertrophy, there is no diastolic dysfunction without systolic dysfunction. Thus, the three main objectives of this thesis were to investigate 1) the LV function and contraction-relaxation coupling with LV twist and untwist, which represent LV myocardial deformation during systole and diastole, 2) the cellular mechanisms of the LV contraction-relaxation coupling and 3) the effects effects of heart rate reduction on LV twist and untwist in the context of chronic hypertension and LV hypertrophy. All experiments were conducted in a pig model of chronic hypertension and LV hypertrophy induced by four weeks of continuous angiotensin II infusion. Chronic angiotensin II infusion decreased LV twist and untwist but also delayed LV untwist in the cardiac cycle, whereas the LV ejection fraction was preserved. The contraction-relaxation coupling was preserved as illustrated by the strong relationship between LV twist and untwist. The contraction-relaxation coupling was also preserved at the level of cardiomyocytes. This implies that LV hypertrophy is associated with concomitant LV diastolic and systolic dysfunction despite preserved LV ejection fraction. Thus, LV diastolic dysfunction is always accompanied by LV systolic dysfunction, i.e., the discovery of LV diastolic dysfunction with preserved ejection fraction might imply the track of LV systolic dysfunction. At the cellular level, LV systolic and diastolic dysfunctions were associated to aberrant calcium handling with a remodelling of the type 2 ryanodine receptor calcium release channel (RyR2), i.e., PKA-hyperphosphorylation and depletion of calstabin 2 (FKBP12.6). RyR2 were leaky and hypersensitive to cytosolic calcium, during both the contraction and the relaxation phases. Since both LV systolic and diastolic dysfunctions were associated to leaky and hypersensitive RyR2 channels, it might suggest considering RyR2 as an integrator contributing to control contraction-relaxation coupling during chronic hypertension and LV hypertrophy. Finally, we investigated the effects of heart rate reduction induced by ivabradine, an If-channel blocker, which does not modify atrioventricular or LV conduction and is devoid of any intrinsic negative inotropic or lusitropic effects. In the context of chronic hypertension and LV hypertrophy, ivabradine improved both LV systolic and diastolic functions, as attested by the improvement in contraction and relaxation times, LV twist and untwist as well as LV filling. Heart-rate independent effects of ivabradine, i.e., pleiotropic effects, participate to its beneficial effect. However, the cellular mechanisms of these beneficial effects of ivabradine were not elucidated and require further investigations. In normal heart, when heart rate was reduced to a low level (approximately <60 beats/min) with ivabradine, LV twist was not affected but LV diastolic function was altered as suggested by decreased LV untwist parameters and increased LV end-diastolic pressure. Investigation of contraction-relaxation coupling during decompensation from stable LV hypertrophy remains a goal to achieve

Évaluation de la formation des internes au niveau basique en échographie cardiaque transthoracique en réanimation à l'aide d'une grille de notation

L'échographie cardiaque transthoracique (ETT) est actuellement recommandée pour la prise en charge des patients de réanimation en insuffisance circulatoire aiguë. Néanmoins, aucun outil d'évaluation ne permet de s'assurer de façon standardisée et reproductible que les compétences nécessaires à la pratique de l'ETT en réanimation appelées niveau basique en ETT ont été acquises. Dans cette étude prospective, nous avons évalué la pertinence d'une grille de notation permettant de juger de l'acquisition de ce niveau basique chez 16 internes en réanimation. Après une formation théorique et pratique à l'ETT, les internes étaient évalués à l'aide de la grille de notation dédiée par deux experts en échographie cardiaque lors de la réalisation d'une ETT à un (M1), trois (M3) et six (M6) mois. La grille de notation proposée dans cette étude permettait d'une part de juger de l'acquisition du niveau basique en ETT en réanimation par les internes et d'autre part d'évaluer leur capacité à proposer, à partir des données de leur échographie cardiaque, un diagnostic et une prise en charge thérapeutique de l'insuffisance circulatoire aiguë adaptés.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Current Advances in Lung Ultrasound in COVID-19 Critically Ill Patients: A Narrative Review

Lung ultrasound (LUS) has a relatively recent democratization due to the better availability and training of physicians, especially in intensive care units. LUS is a relatively cheap and easy-to-learn and -use bedside technique that evaluates pulmonary morphology when using simple algorithms. During the global COVID-19 pandemic, LUS was found to be an accurate tool to quickly diagnose, triage and monitor patients with COVID-19 pneumonia. This paper aims to provide a comprehensive review of LUS use during the COVID-19 pandemic. The first section of our work defines the technique, the practical approach and the semeiotic signs of LUS examination. The second section exposed the COVID-19 pattern in LUS examination and the difference between the differential diagnosis patterns and the well-correlation found with computer tomography scan findings. In the third section, we described the utility of LUS in the management of COVID-19 patients, allowing an early diagnosis and triage in the emergency department, as the monitoring of pneumonia course (pneumonia progression, alveolar recruitment, mechanical ventilation weaning) and detection of secondary complications (pneumothorax, superinfection). Moreover, we describe the usefulness of LUS as a marker of the prognosis of COVID-19 pneumonia in the fourth section. Finally, the 5th part is focused on describing the interest of the LUS, as a non-ionized technique, in the management of pregnant COVID-19 women

Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review

The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field

Post-resuscitation shock: recent advances in pathophysiology and treatment

A post-resuscitation shock occurs in 50–70% of patients who had a cardiac arrest. It is an early and transient complication of the post-resuscitation phase, which frequently leads to multiple-organ failure and high mortality. The pathophysiology of post-resuscitation shock is complex and results from the whole-body ischemia–reperfusion process provoked by the sequence of circulatory arrest, resuscitation manoeuvers and return of spontaneous circulation, combining a myocardial dysfunction and sepsis features, such as vasoplegia, hypovolemia and endothelial dysfunction. Similarly to septic shock, the hemodynamic management of post-resuscitation shock is based on an early and aggressive hemodynamic management, including fluid administration, vasopressors and/or inotropes. Norepinephrine should be considered as the first-line vasopressor in order to avoid arrhythmogenic effects of other catecholamines and dobutamine is the most established inotrope in this situation. Importantly, the optimal mean arterial pressure target during the post-resuscitation shock still remains unknown and may probably vary according to patients. Mechanical circulatory support by extracorporeal membrane oxygenation can be necessary in the most severe patients, when the neurological prognosis is assumed to be favourable. Other symptomatic treatments include protective lung ventilation with a target of normoxia and normocapnia and targeted temperature management by avoiding the lowest temperature targets. Early coronary angiogram and coronary reperfusion must be considered in ST-elevation myocardial infarction (STEMI) patients with preserved neurological prognosis although the timing of coronary angiogram in non-STEMI patients is still a matter of debate. Further clinical research is needed in order to explore new therapeutic opportunities regarding inflammatory, hormonal and vascular dysfunction.SCOPUS: re.jinfo:eu-repo/semantics/publishe