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BACKGROUND: In patients resuscitated from cardiac arrest and displaying no ST-segment elevation on initial electrocardiogram (ECG), recent randomized trials indicated no benefits from early coronary angiography. How the results of such randomized studies apply to a real-world clinical context remains to be established. METHODS: We retrospectively analyzed a clinical database including all patients 18 yo or older admitted to our tertiary University Hospital from January 2017 to August 2020 after successful resuscitation of out-of-Hospital (OHCA) or In-Hospital (IHCA) cardiac arrest of presumed cardiac origin, and undergoing immediate coronary angiography, regardless of the initial rhythm and post-resuscitation ECG. The primary outcome of the study was survival at day 90 after cardiac arrest. Demographic data, characteristics of cardiac arrest, duration of resuscitation, laboratory values at admission, angiographic data and revascularization status were collected. Comparisons were performed according to the initial ECG (ST-segment elevation or not), and between survivors and non-survivors. Variables associated with the primary outcome were evaluated by univariate and multivariate regression analyses. RESULTS: We analyzed 147 patients (130 OHCA and 17 IHCA), including 67 with STEMI and 80 without STEMI (No STEMI). Immediate revascularization was performed in 65/67 (97%) STEMI and 15/80 (19%) no STEMI. Day 90 survival was significantly higher in STEMI (48/67, 72%) than no STEMI (44/80, 55%). In the latter patients, survival was not influenced by the revascularization status. In univariate and multivariate analyses, lower age, a shockable rhythm, shorter durations of no flow and low flow, and a lower initial blood lactate were associated with survival in both STEMI and no STEMI. In contrast, metabolic abnormalities, including lower initial plasma sodium and higher potassium were significantly associated with mortality only in the subgroup of no STEMI patients. CONCLUSIONS: Our results, obtained in a real-world clinical setting, indicate that an immediate coronary angiography is not associated with any survival advantage in patients resuscitated from cardiac arrest of presumed cardiac etiology without ST-segment elevation on initial ECG. Furthermore, we found that some early metabolic abnormalities may be associated with mortality in this population, which should deserve further investigation.
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Reanimação Cardiopulmonar , Angiografia Coronária , Parada Cardíaca Extra-Hospitalar , Intervenção Coronária Percutânea , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Parada Cardíaca Extra-Hospitalar/terapia , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/diagnóstico , Parada Cardíaca Extra-Hospitalar/diagnóstico por imagem , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Intervenção Coronária Percutânea/mortalidade , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Reanimação Cardiopulmonar/efeitos adversos , Reanimação Cardiopulmonar/mortalidade , Fatores de Risco , Bases de Dados Factuais , Valor Preditivo dos Testes , Eletrocardiografia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Medição de Risco , Parada Cardíaca/terapia , Parada Cardíaca/mortalidade , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Parada Cardíaca/etiologia , Idoso de 80 Anos ou maisRESUMO
Ex vivo lung perfusion (EVLP) may serve as a platform for the pharmacologic repair of lung grafts before transplantation (LTx). We hypothesized that EVLP could also permit nonpharmacologic repair through the induction of a heat shock response, which confers stress adaptation via the expression of heat shock proteins (HSPs). Therefore, we evaluated whether transient heat application during EVLP (thermal preconditioning [TP]) might recondition damaged lungs before LTx. TP was performed during EVLP (3 hours) of rat lungs damaged by warm ischemia by transiently heating (30 minutes, 41.5 °C) the EVLP perfusate, followed by LTx (2 hours) reperfusion. We also assessed the TP (30 minutes, 42 °C) during EVLP (4 hours) of swine lungs damaged by prolonged cold ischemia. In rat lungs, TP induced HSP expression, reduced nuclear factor κB and inflammasome activity, oxidative stress, epithelial injury, inflammatory cytokines, necroptotic death signaling, and the expression of genes involved in innate immune and cell death pathways. After LTx, heated lungs displayed reduced inflammation, edema, histologic damage, improved compliance, and unchanged oxygenation. In pig lungs, TP induced HSP expression, reduced oxidative stress, inflammation, epithelial damage, vascular resistance, and ameliorated compliance. Collectively, these data indicate that transient heat application during EVLP promotes significant reconditioning of damaged lungs and improves their outcomes after transplantation.
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Transplante de Pulmão , Ratos , Suínos , Animais , Pulmão , Reperfusão , Resposta ao Choque Térmico , Inflamação/patologia , PerfusãoRESUMO
OBJECTIVES: To evaluate the influence of vasoconstrictor agents (VCAs) on signs of vasoconstriction and bowel ischemia on MDCT detected in patients with non-occlusive mesenteric ischemia (NOMI). METHODS: This 8-year single-center retrospective study consecutively included all patients with histopathologically proven NOMI who underwent MDCT ≤ 48 h prior to surgical bowel resection. Two blinded radiologists jointly reviewed each examination for signs of bowel ischemia, abdominal organ infarct, mesenteric vessel size and regularity, and ancillary vascular findings. VCA administration (length and dosage), clinical and biochemical data, risk factors, and outcomes were retrieved from patients' medical records. Subgroup comparisons were performed. RESULTS: Ninety patients were included (59 males, mean age 65 years); 40 (44.4%) had received VCAs before MDCT. Overall mortality was 32% (n = 29), with no significant difference between the two groups. In patients treated with VCAs, the calibre of the superior mesenteric artery (SMA) was smaller (p = 0.032), and vasoconstriction of its branches tended to be more important (p = 0.096) than in patients not treated with VCAs. The presence and extent of bowel ischemia did not significantly correlate with VCA administration, but abdominal organ infarcts tended to be more frequent (p = 0.005) and involved more organs (p = 0.088). The VCA group had lower mean arterial pressure (p = 0.006) and lower hemoglobin levels (p < 0.001). Several biomarkers of organ failure and inflammation, differed significantly with VCA use, proving worse clinical condition. CONCLUSIONS: MDCT demonstrates more severe SMA vasoconstriction and tends to show increased abdominal organ infarcts after VCA administration in NOMI patients compared to NOMI patients not treated with VCAs. KEY POINTS: ⢠In critically ill patients with NOMI, MDCT demonstrates VCA support via increased vasoconstriction of the main SMA and its branches. ⢠VCA administration in NOMI patients tends to contribute to the development of organ infarcts, as shown on MDCT. ⢠An important degree of vasoconstriction in NOMI patients may indicate insufficient resuscitation and, thus, help clinicians in further patient management.
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Isquemia Mesentérica , Masculino , Humanos , Idoso , Isquemia Mesentérica/diagnóstico por imagem , Estudos Retrospectivos , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico , Tomografia Computadorizada por Raios X , Isquemia/diagnóstico por imagem , InfartoRESUMO
BACKGROUND: Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb® in cardiac arrest (CA) survivors at risk of PCAS. METHODS: In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 µg/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb® and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization. RESULTS: We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06). CONCLUSIONS: In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population. TRIAL REGISTRATION: NCT03523039, registered 14 May 2018.
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Parada Cardíaca Extra-Hospitalar , Síndrome Pós-Parada Cardíaca , Humanos , Citocinas , Projetos Piloto , Interleucina-6 , Parada Cardíaca Extra-Hospitalar/induzido quimicamenteRESUMO
BACKGROUND: The outcome of Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) in acute respiratory failure may be influenced by patient-related factors, center expertise and modalities of mechanical ventilation (MV) during ECMO. We determined, in a medium-size ECMO center in Switzerland, possible factors associated with mortality during VV-ECMO for acute respiratory failure of various etiologies. METHODS: We retrospectively analyzed all patients treated with VV-ECMO in our University Hospital from 2012 to 2019 (pre-COVID era). Demographic variables, severity scores, MV duration before ECMO, pre and on-ECMO arterial blood gases and respiratory variables were collected. The primary outcome was ICU mortality. Data were compared between survivors and non-survivors, and factors associated with mortality were assessed in univariate and multivariate analyses. RESULTS: Fifty-one patients (33 ARDS, 18 non-ARDS) were included. ICU survival was 49% (ARDS, 39%; non-ARDS 67%). In univariate analyses, a higher driving pressure (DP) at 24h and 48h on ECMO (whole population), longer MV duration before ECMO and higher DP at 24h on ECMO (ARDS patients), were associated with mortality. In multivariate analyses, ECMO indication, higher DP at 24h on ECMO and, in ARDS, longer MV duration before ECMO, were independently associated with mortality. CONCLUSIONS: DP on ECMO and longer MV duration before ECMO (in ARDS) are major, and potentially modifiable, factors influencing outcome during VV-ECMO.
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COVID-19 , Oxigenação por Membrana Extracorpórea , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Humanos , Estudos Retrospectivos , Gasometria , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/terapiaRESUMO
Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) or reduced (HFrEF) ejection fraction, which increases the pulsatile afterload of the right ventricle (RV) by reducing pulmonary artery (PA) compliance. In a subset of patients, progressive remodeling of the pulmonary circulation resulted in a pre-capillary phenotype of PH, with elevated pulmonary vascular resistance (PVR) further increasing the RV afterload, eventually leading to RV-PA uncoupling and RV failure. The primary therapeutic objective in PH-LHD is to reduce left-sided pressures through the appropriate use of diuretics and guideline-directed medical therapies for heart failure. When pulmonary vascular remodeling is established, targeted therapies aiming to reduce PVR are theoretically appealing. So far, such targeted therapies have mostly failed to show significant positive effects in patients with PH-LHD, in contrast to their proven efficacy in other forms of pre-capillary PH. Whether such therapies may benefit some specific subgroups of patients (HFrEF, HFpEF) with specific hemodynamic phenotypes (post- or pre-capillary PH) and various degrees of RV dysfunction still needs to be addressed.
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Insuficiência Cardíaca , Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/complicações , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Volume Sistólico , Circulação Pulmonar/fisiologia , HemodinâmicaRESUMO
Background: High-risk Pulmonary Embolism (PE) has an ominous prognosis and requires emergent reperfusion therapy, primarily systemic thrombolysis (ST). In deteriorating patients or with contraindications to ST, Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) may be life-saving, as supported by several retrospective studies. However, due to the heterogeneous clinical presentation (refractory shock, resuscitated cardiac arrest (CA) or refractory CA), the real impact of VA-ECMO in high-risk PE remains to be fully determined. In this study, we present our centre experience with VA-ECMO for high-risk PE. Method: From 2008 to 2020, we analyzed all consecutive patients treated with VA-ECMO for high-risk PE in our tertiary 35-bed intensive care unit (ICU). Demographic variables, types of reperfusion therapies, indications for VA-ECMO (refractory shock or refractory CA requiring extra-corporeal cardiopulmonary resuscitation, ECPR), hemodynamic variables, initial arterial blood lactate and ICU complications were recorded. The primary outcome was ICU survival, and secondary outcome was hospital survival. Results: Our cohort included 18 patients (9F/9M, median age 57 years old). VA-ECMO was indicated for refractory shock in 7 patients (2 primary and 5 following resuscitated CA) and for refractory CA in 11 patients. Eight patients received anticoagulation only, 9 received ST, and 4 underwent surgical embolectomy. ICU survival was 1/11 (9%) for ECPR vs 3/7 (42%) in patients with refractory shock (p = 0.03, log-rank test). Hospital survival was 0/11 (0%) for ECPR vs 3/7 for refractory shock (p = 0.01, log-rank test). Survivors and Non-survivors had comparable demographic and hemodynamic variables, pulmonary obstruction index, and amounts of administered vasoactive drugs. Pre-ECMO lactate was significantly higher in non-survivors. Massive bleeding was the most frequent complication in survivors and non-survivors, and was the direct cause of death in 3 patients, all treated with ST. Conclusions: VA-ECMO for high-risk PE has very different outcomes depending on the clinical context. Furthermore, VA-ECMO was associated with significant bleeding complications, with more severe consequences following systemic thrombolysis. Future studies on VA-ECMO for high-risk PE should therefore take into account the distinct clinical presentations and should determine the best strategy for reperfusion in such circumstances.
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BACKGROUND: COVID-19 related acute respiratory distress syndrome (ARDS) has specific characteristics compared to ARDS in other populations. Proning is recommended by analogy with other forms of ARDS, but few data are available regarding its physiological effects in this population. This study aimed to assess the effects of proning on oxygenation parameters (PaO2/FiO2 and alveolo-arterial gradient (Aa-gradient)), blood gas analysis, ventilatory ratio (VR), respiratory system compliance (CRS) and estimated dead space fraction (VD/VT HB). We also looked for variables associated with treatment failure. METHODS: Retrospective monocentric study of intubated COVID-19 ARDS patients managed with an early intubation, low to moderate positive end-expiratory pressure and early proning strategy hospitalized from March 6 to April 30 2020. Blood gas analysis, PaO2/FiO2, Aa-gradient, VR, CRS and VD/VT HB were compared before and at the end of each proning session with paired t-tests or Wilcoxon tests (p < 0.05 considered as significant). Proportions were assessed using Fischer exact test or Chi square test. RESULTS: Forty-two patients were included for a total of 191 proning sessions, median duration of 16 (5-36) hours. Considering all sessions, PaO2/FiO2 increased (180 [148-210] vs 107 [90-129] mmHg, p < 0.001) and Aa-gradient decreased (127 [92-176] vs 275 [211-334] mmHg, p < 0.001) with proning. CRS (36.2 [30.0-41.8] vs 32.2 [27.5-40.9] ml/cmH2O, p = 0.003), VR (2.4 [2.0-2.9] vs 2.3 [1.9-2.8], p = 0.028) and VD/VT HB (0.72 [0.67-0.76] vs 0.71 [0.65-0.76], p = 0.022) slightly increased. Considering the first proning session, PaO2/FiO2 increased (186 [165-215] vs 104 [94-126] mmHg, p < 0.001) and Aa-gradient decreased (121 [89-160] vs 276 [238-321] mmHg, p < 0.001), while CRS, VR and VD/VT HB were unchanged. Similar variations were observed during the subsequent proning sessions. Among the patients who experienced treatment failure (defined as ICU death or need for extracorporeal membrane oxygenation), fewer expressed a positive response in terms of oxygenation (defined as increase of more than 20% in PaO2/FiO2) to the first proning (67 vs 97%, p = 0.020). CONCLUSION: Proning in COVID-19 ARDS intubated patients led to an increase in PaO2/FiO2 and a decrease in Aa-gradient if we consider all the sessions together, the first one or the 4 subsequent sessions independently. When considering all sessions, CRS increased and VR and VD/VT HB only slightly increased.
Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Humanos , Adulto , Estudos Retrospectivos , Decúbito Ventral , Respiração Artificial , COVID-19/terapia , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/terapiaRESUMO
BACKGROUND: According to international guidelines, neuroprognostication in comatose patients after cardiac arrest (CA) is performed using a multimodal approach. However, patients undergoing extracorporeal membrane oxygenation (ECMO) may have longer pharmacological sedation and show alteration in biological markers, potentially challenging prognostication. Here, we aimed to assess whether routinely used predictors of poor neurological outcome also exert an acceptable performance in patients undergoing ECMO after CA. METHODS: This observational retrospective study of our registry includes consecutive comatose adults after CA. Patients deceased within 36 h and not undergoing prognostic tests were excluded. Veno-arterial ECMO was initiated in patients < 80 years old presenting a refractory CA, with a no flow < 5 min and a low flow ≤ 60 min on admission. Neuroprognostication test performance (including pupillary reflex, electroencephalogram, somatosensory-evoked potentials, neuron-specific enolase) toward mortality and poor functional outcome (Cerebral Performance Categories [CPC] score 3-5) was compared between patients undergoing ECMO and those without ECMO. RESULTS: We analyzed 397 patients without ECMO and 50 undergoing ECMO. The median age was 65 (interquartile range 54-74), and 69.8% of patients were men. Most had a cardiac etiology (67.6%); 52% of the patients had a shockable rhythm, and the median time to return of an effective circulation was 20 (interquartile range 10-28) minutes. Compared with those without ECMO, patients receiving ECMO had worse functional outcome (74% with CPC scores 3-5 vs. 59%, p = 0.040) and a nonsignificant higher mortality (60% vs. 47%, p = 0.080). Apart from the neuron-specific enolase level (higher in patients with ECMO, p < 0.001), the presence of prognostic items (pupillary reflex, electroencephalogram background and reactivity, somatosensory-evoked potentials, and myoclonus) related to unfavorable outcome (CPC score 3-5) in both groups was similar, as was the prevalence of at least any two such items concomitantly. The specificity of each these variables toward poor outcome was between 92 and 100% in both groups, and of the combination of at least two items, it was 99.3% in patients without ECMO and 100% in those with ECMO. The predictive performance (receiver operating characteristic curve) of their combination toward poor outcome was 0.822 (patients without ECMO) and 0.681 (patients with ECMO) (p = 0.134). CONCLUSIONS: Pending a prospective assessment on a larger cohort, in comatose patients after CA, the performance of prognostic factors seems comparable in patients with ECMO and those without ECMO. In particular, the combination of at least two poor outcome criteria appears valid across these two groups.
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Encéfalo , Coma , Oxigenação por Membrana Extracorpórea , Parada Cardíaca , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Coma/etiologia , Coma/fisiopatologia , Coma/terapia , Eletroencefalografia , Feminino , Parada Cardíaca/complicações , Humanos , Masculino , Fosfopiruvato Hidratase/metabolismo , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .
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Artérias/fisiopatologia , Dióxido de Carbono/análise , Veias/fisiopatologia , Humanos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , PrognósticoRESUMO
BACKGROUND: High levels of arterial oxygen pressures (PaO2) have been associated with increased mortality in extracorporeal cardiopulmonary resuscitation (ECPR), but there is limited information regarding possible mechanisms linking hyperoxia and death in this setting, notably with respect to its hemodynamic consequences. We aimed therefore at evaluating a possible association between PaO2, circulatory failure and death during ECPR. METHODS: We retrospectively analyzed 44 consecutive cardiac arrest (CA) patients treated with ECPR to determine the association between the mean PaO2 over the first 24 h, arterial blood pressure, vasopressor and intravenous fluid therapies, mortality, and cause of deaths. RESULTS: Eleven patients (25%) survived to hospital discharge. The main causes of death were refractory circulatory shock (46%) and neurological damage (24%). Compared to survivors, non survivors had significantly higher mean 24 h PaO2 (306 ± 121 mmHg vs 164 ± 53 mmHg, p < 0.001), lower mean blood pressure and higher requirements in vasopressors and fluids, but displayed similar pulse pressure during the first 24 h (an index of native cardiac recovery). The mean 24 h PaO2 was significantly and positively correlated with the severity of hypotension and the intensity of vasoactive therapies. Patients dying from circulatory failure died after a median of 17 h, compared to a median of 58 h for patients dying from a neurological cause. Patients dying from neurological cause had better preserved blood pressure and lower vasopressor requirements. CONCLUSION: In conclusion, hyperoxia is associated with increased mortality during ECPR, possibly by promoting circulatory collapse or delayed neurological damage.
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Reanimação Cardiopulmonar/efeitos adversos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Parada Cardíaca/complicações , Hiperóxia/etiologia , Choque/etiologia , Feminino , Parada Cardíaca/mortalidade , Parada Cardíaca/terapia , Mortalidade Hospitalar , Humanos , Hiperóxia/mortalidade , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Estudos RetrospectivosRESUMO
PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.
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Lesão Pulmonar Aguda/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/virologia , Animais , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/enzimologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3-AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3-AB: 1 hour WI + 3 hours EVLP + 3-AB (1 mg. mL-1 ) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin-6 and 10 (IL-6, IL-10) in BAL and plasma. 3-AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3-AB also attenuated the IL-6/IL-10 ratio in BAL and plasma, supporting an improved balance between pro- and anti-inflammatory mediators. Thus, 3-AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.
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Circulação Extracorpórea , Transplante de Pulmão , Animais , Benzamidas , Pulmão , Transplante de Pulmão/efeitos adversos , Perfusão , RatosRESUMO
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-saving technology that provides transient respiratory and circulatory support for patients with profound cardiogenic shock or refractory cardiac arrest. Among its potential complications, VA-ECMO may adversely affect lung function through various pathophysiological mechanisms. The interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response which may increase pulmonary vascular permeability and promote the sequestration of polymorphonuclear neutrophils within the lung parenchyma. Also, VA-ECMO increases the afterload of the left ventricle (LV) through reverse flow within the thoracic aorta, resulting in increased LV filling pressure and pulmonary congestion. Furthermore, VA-ECMO may result in long-standing pulmonary hypoxia, due to partial shunting of the pulmonary circulation and to reduced pulsatile blood flow within the bronchial circulation. Ultimately, these different abnormalities may result in a state of persisting lung inflammation and fibrotic changes with concomitant functional impairment, which may compromise weaning from VA-ECMO and could possibly result in long-term lung dysfunction. This review presents the mechanisms of lung damage and dysfunction under VA-ECMO and discusses potential strategies to prevent and treat such alterations.
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Oxigenação por Membrana Extracorpórea , Fenômenos Fisiológicos Respiratórios , Humanos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Isquemia/etiologia , Isquemia/fisiopatologia , Tecido Parenquimatoso/lesões , Tecido Parenquimatoso/fisiopatologiaRESUMO
Vasopressin (AVP) is a posterior pituitary hormone initially known for its antidiuretic actions. In this article, we recall the biochemical and pharmacological characteristics of the AVP and its analogues. Currently, its main indication in critical care medicine is vasoplegic shock in view of its vasopressive properties. This strong vasopressive activity is related to the activation of V1 receptors located in the vascular smooth muscle. The scientific evidence of the AVP therapy, and its potential benefits versus norepinephrine in vasoplegic shock, is reviewed in this article. Similarly, we present the other indications of vasopressin in the critical patient, based on recent studies and international guidelines.
La vasopressine (AVP) est une hormone post-hypophysaire connue initialement pour ses effets antidiurétiques. Dans cet article de synthèse, nous rappelons les particularités biochimiques et pharmacologiques de l'AVP et de ses analogues. De nos jours, sa principale indication en médecine intensive est le choc vasoplégique, eu égard à ses propriétés vasopressives qui sont liées à l'activation des récepteurs V1 du muscle lisse des vaisseaux sanguins, résultant en une puissante vasoconstriction. L'évidence scientifique de l'apport de l'AVP, et de ses bénéfices potentiels par rapport à la noradrénaline dans le choc vasoplégique, est revue en détail dans cet article. De même, nous présentons les autres indications de la vasopressine chez le patient en état critique, sur la base des études récentes et les recommandations des sociétés savantes.
Assuntos
Arginina Vasopressina/metabolismo , Arginina Vasopressina/uso terapêutico , Estado Terminal , Vasoplegia/tratamento farmacológico , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Norepinefrina/uso terapêutico , Receptores de Vasopressinas/metabolismoRESUMO
Poly(ADP-ribose) polymerase (PARP) is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. In mice subjected to cecal ligation and puncture (CLP) organ injury markers, circulating and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. In U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1-10 mg/kg i.p.) improved multiorgan dysfunction. Olaparib treatment reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. In the spleen, the number of CD4+ and CD8+ lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatment. Treg but not Th17 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animals received olaparib. The Th17/Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identified a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatment selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. In contrast to males, in female mice olaparib did not have significant protective effects in CLP. In aged mice olaparib exerted beneficial effects that were less pronounced than the effects obtained in young adult males. In in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1-100 µM) inhibited PARP activity, protected against the loss of cell viability, preserved NAD+ levels and improved cellular bioenergetics. In none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on nuclear or mitochondrial DNA integrity. In conclusion, olaparib improves organ function and extends survival in septic shock. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of septic shock.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Ceco , Citocinas/sangue , DNA/efeitos dos fármacos , Reposicionamento de Medicamentos , Feminino , Humanos , Ligadura , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Contagem de Linfócitos , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Punções , Sepse/sangue , Sepse/imunologia , Sepse/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Células U937RESUMO
BACKGROUND: Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. METHODS: We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care (n = 15) or CytoSorb® HA (n = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors' activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). RESULTS: Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors' adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. CONCLUSIONS: CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. TRIAL REGISTRATION: ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.
Assuntos
Ponte Cardiopulmonar/efeitos adversos , Citocinas/efeitos adversos , Hemofiltração/instrumentação , Adulto , Idoso , Idoso de 80 Anos ou mais , Ponte Cardiopulmonar/métodos , Quimiocina CCL2/análise , Quimiocina CCL2/sangue , Citocinas/sangue , Citocinas/metabolismo , Feminino , Hemofiltração/métodos , Hemofiltração/normas , Humanos , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-1alfa/análise , Interleucina-1alfa/sangue , Interleucina-1beta/análise , Interleucina-1beta/sangue , Interleucina-2/análise , Interleucina-2/sangue , Interleucina-4/análise , Interleucina-4/sangue , Interleucina-5/análise , Interleucina-5/sangue , Interleucina-6/análise , Interleucina-6/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Projetos Piloto , Complicações Pós-Operatórias/prevenção & controle , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: The use of automated (oscillometric) blood pressure (BP) devices is not validated in atrial fibrillation (AF) patients. OBJECTIVES: To assess the reliability of three oscillometric BP devices, and the agreement with invasive arterial blood pressure(IBP) in AF patients. METHODS: 48 AF patients with randomized sequences of 10 consecutive BP measurements with two pairs of devices: (1) OmronR7™(wrist) and OmronHEM907™(arm); (2) OmronR7™ and Microlife WatchBPhome(arm). Reliability and agreement of each device were assessed by the intra-class correlation coefficient (ICC) for the continuous BP measurements and Bland & Altman methodology, respectively. In 10 additional AF patients, 10 consecutive measurements with IBP and OmronHEM907™, and IBP and Microlife WatchBPhome were performed. RESULTS: The OmronR7™ was not able to obtain any BP Readings. Arm devices presented better ICC for systolicBP(SBP) than for diastolicBP(DBP) (Omron HEM907™:0.94 [0.90; 0.97] vs. 0.77 [0.67; 0.89]; Microlife WatchBPhome:0.92 [0.88; 0.96] vs.0.79 [0.69; 0.89]).The correlation coefficient between Microlife WatchBPhome and IBP computed using the average of repeated measurements from two to ten measurements improved up to the third and remained stable afterwards. The agreement between IBP and SBP, and IBP and DBP, was moderate as illustrated by a wide limit of agreement [-24; 26](SBP) and [-15;17](DBP) for Microlife WatchBPHome, respectively and [-30; 13](SBP) and [-7; 15](DBP) for OmronHEM907. CONCLUSIONS: BP measurement using the two arm oscillometric devices achieved a high reliability for SBP. The agreement between IBP and arm devices was low but using the average of three consecutive measurements improved the results substantially.
Assuntos
Fibrilação Atrial/diagnóstico , Determinação da Pressão Arterial/métodos , Pressão Sanguínea/fisiologia , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/patologia , Feminino , Humanos , MasculinoRESUMO
Despite the benefit of the drugs acting on neuro-humoral activation and cardiac resynchronization therapy, some patients will end in a severe refractory form of heart failure: advanced heart failure. The only therapeutic options with a positive impact on mortality and quality of life are heart transplantation and permanent left ventricular assist device (LVAD). The significant technological improvements of the past 20 years lead to a reduction of the complications associated with these devices, which now allow their use not only during the waiting period preceding heart transplantation (bridge to transplant), but also as a durable therapeutic option (destination therapy).
Malgré le bénéfice des médicaments agissant sur l'activation neuro-humorale et de la thérapie de resynchronisation, certains patients vont évoluer vers une forme sévère et réfractaire d'insuffisance cardiaque : l'insuffisance cardiaque avancée (ICA). Les seules options thérapeutiques de l'ICA ayant démontré un impact favorable sur la survie et la qualité de vie sont la transplantation cardiaque et l'implantation d'un dispositif d'assistance ventriculaire gauche permanent (LVAD, Left Ventricular Assist Device). Les importantes améliorations technologiques des vingt dernières années ont permis de réduire significativement les complications associées à ces dispositifs, permettant non seulement leur utilisation dans l'attente du greffe cardiaque (bridge to transplant), mais aussi comme option thérapeutique définitive (destination therapy).