The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury.

BACKGROUND: Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD+) production was identified after acute kidney injury (AKI), leading to the hypothesis that supplementation with NAM may increase the kidney NAD+ content, rescuing tryptophan pathways and subsequently improving kidney outcomes. METHODS: Urinary measurement of tryptophan and kynurenin using liquid chromatography-mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia-reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used. RESULTS: We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve [AUC] 0.82 [95% confidence interval (CI) 0.75-0.88] and 0.75 [0.68-0.83], respectively} and severe KDIGO Stages 2-3 AKI [AUC 0.71 (95% CI 0.6-0.81) and 0.66 (0.55-0.77), respectively]. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin-fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid-Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD+ kidney content. CONCLUSION: Notwithstanding the potential role of NAM supplementation in the setting of basal NAD+ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients.

French multicentre observational study on SARS-CoV-2 infections intensive care initial management: the FRENCH CORONA study.

AIM: Describing acute respiratory distress syndrome patterns, therapeutics management, and outcomes of ICU COVID-19 patients and indentifying risk factors of 28-day mortality. METHODS: Prospective multicentre, cohort study conducted in 29 French ICUs. Baseline characteristics, comorbidities, adjunctive therapies, ventilatory support at ICU admission and survival data were collected. RESULTS: From March to July 2020, 966 patients were enrolled with a median age of 66 (interquartile range 58-73) years and a median SAPS II of 37 (29-48). During the first 24 h of ICU admission, COVID-19 patients received one of the following respiratory supports: mechanical ventilation for 559 (58%), standard oxygen therapy for 228 (24%) and high-flow nasal cannula (HFNC) for 179 (19%) patients. Overall, 721 (75%) patients were mechanically ventilated during their ICU stay. Prone positioning and neuromuscular blocking agents were used in 494 (51%) and 460 (48%) patients, respectively. Bacterial co-infections and ventilator-associated pneumonia were diagnosed in 79 (3%) and 411 (43%) patients, respectively. The overall 28-day mortality was 18%. Age, pre-existing comorbidities, severity of respiratory failure and the absence of antiviral therapy on admission were identified as independent predictors of 28-day outcome. CONCLUSION: Severity of hypoxaemia on admission, older age (> 70 years), cardiovascular and renal comorbidities were associated with worse outcome in COVID-19 patients. Antiviral treatment on admission was identified as a protective factor for 28-day mortality. Ascertaining the outcomes of critically ill COVID-19 patients is crucial to optimise hospital and ICU resources and provide the appropriate intensity level of care.

Severe Respiratory and Hemodynamic Failures following Successful Spontaneous Pneumothorax Drainage.

Spontaneous pneumothorax is a frequent situation in respiratory medicine, and its treatment is based on conservative treatment or pleural drainage. Reexpansion pulmonary edema (REPE) is often a mild complication following pneumothorax drainage. We report here a severe case of unilateral REPE following spontaneous pneumothorax drainage associated with major pulmonary plasmatic leakage. The clinical presentation was severe and sudden with respiratory and circulatory failures. Initial resuscitation was mostly based on prone and head-down positioning in association to fluid expansion and mechanical ventilation. On the basis of this clinical case report, we strongly suggest to think about severe pulmonary reexpansion edema when respiratory and hemodynamic failures occur few hours after pneumothorax-related efficient pleural tube drainage.

Preoperative plasma fibrinogen level and transfusion in cardiac surgery: a biphasic correlation.

Coagulopathic bleeding is a serious complication of cardiac surgery. A very low preoperative plasma fibrinogen level (PFL) has been previously described as a risk factor for red blood cell (RBC) transfusion in the perioperative setting. Nevertheless, contradictory results have been published concerning preoperative fibrinogen infusion to decrease RBC transfusion. These results highlight the need for a better description of the relation between preoperative PFL and RBC transfusion. In this single-centre retrospective study, we showed that both high and low PFLs are associated with an increase in RBC transfusion. A pro-inflammatory preoperative status could be involved in the association between high PFL and the increase in RBC transfusion. This non-linear relation between PFL and RBC transfusion could explain the difficulty of decreasing postoperative bleeding using only an algorithm aimed at increasing preoperative PFL.

Patient blood management in elective bypass cardiac surgery: A 2-step single-centre interventional trial to analyse the impact of an educational programme and erythropoiesis stimulation on red blood cell transfusion.

Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. Perioperative patient blood management (PBM) is widely recommended in current practice guidelines. The aim of this protocol is to analyse the effect of a global perioperative PBM programme on the red blood cell (RBC) transfusion ratio, morbidities and rehabilitation score in elective cardiac surgery.This study is a prospective, single-centre trial with a 2-step protocol, A and B, as follows: A: non-drug intervention: the caregiver is given a blood management educational programme; B: drug intervention: systematic correction of perioperative iron, vitamin deficiencies, and anaemia. This study was designed to enrol 900 patients (500 in group A and 400 in group B) in a rolling period starting at anaesthesia consultation and ending 3 months after surgery. The primary objective was a 20% reduction in RBC transfusion after implementation of PBM programmes (protocol A + B) when compared to our previous transfusion ratio in the first half of 2018 (30.4% vs 38%). The secondary objectives were to evaluate the impact for each step of the study on the RBC transfusion rate, morbidity and the quality of postoperative rehabilitation.The strength of this study is its evaluation of the effect of a global PBM programme on RBC transfusion in cardiac surgery through a 2-step protocol. We aim to assess for the first time the impact of non-drug and drug interventions on RBC transfusion, comorbidities and delayed rehabilitation parameters. TRIALS REGISTRATIONS: ClinicalTrials.gov, NCT04040023: registered 29 July 2019.

Guidelines: Anaesthesia in the context of COVID-19 pandemic.

OBJECTIVES: The world is currently facing an unprecedented healthcare crisis caused by the COVID-19 pandemic. The objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the COVID-19 pandemic. METHODS: The group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas: (1) protection of staff and patients; (2) benefit/risk and patient information; (3) preoperative assessment and decision on intervention; (4) modalities of the preanaesthesia consultation; (5) specificity of anaesthesia and analgesia; (6) dedicated circuits and (7) containment exit type of interventions. RESULTS: The SFAR Guideline panel provides 51 statements on anaesthesia management in the context of COVID-19 pandemic. After one round of discussion and various amendments, a strong agreement was reached for 100% of the recommendations and algorithms. CONCLUSION: We present suggestions for how the risk of transmission by and to anaesthetists can be minimised and how personal protective equipment policies relate to COVID-19 pandemic context.

Aortic and innominate routes for transcatheter aortic valve implantation.

OBJECTIVES: This study aimed at evaluating the efficacy and safety of the transaortic approach for the transcatheter aortic valve implantation procedure using balloon-expandable and self-expanding devices. METHODS: From January 2012 to December 2016, the transaortic-transcatheter aortic valve implantation procedure was performed in 206 consecutive patients at the Rangueil University Hospital. All procedures were performed by a multidisciplinary heart team. The ascending aorta (27%) or innominate artery (73%) was exposed through a J-type manubriotomy. Events were adjudicated according to Valve Academic Research Consortium-2 criteria. RESULTS: Mean age and logistic European System for Cardiac Risk Evaluation II were 83.9 ± 6.7 years and 16.8% ± 10.8%, respectively. Balloon-expandable and self-expanding valves were implanted in 59.7% and 40.3% of patients, respectively. Device success rate was 98.1%. Thirty-day overall mortality, cardiovascular mortality, cerebrovascular event, myocardial infarction, and permanent pacemaker implantation rates were 5.3%, 4.4%, 1.5%, 1.0%, and 9.7%, respectively (1-year rates: 15.5%, 9.2%, 3.9%, 3.4%, and 10.2%, respectively). Life-threatening bleeding and major vascular complications (7.3% and 3.9%, respectively) were not related to the central access site in approximately half of the cases. Multivariable Cox regression analysis identified preoperative renal failure as an independent predictor of overall mortality (odds ratio, 2.82; 95% confidence interval, 1.73-4.59; P < .0001). At the 1-year follow-up, most patients had experienced improved functional status and 98.4% of them were free of moderate to severe paravalvular leak. CONCLUSIONS: In a higher-risk subgroup within the patient population receiving transcatheter aortic valve implantation, transaortic-transcatheter aortic valve implantation was successfully performed in 98.1% of cases, with high functional improvement and low rates of mortality and adverse events, especially neurologic complications.

The optimal time between clinical brain death diagnosis and confirmation using CT angiography: a retrospective study.

BACKGROUND: In several countries, a computed tomography angiography (CTA) is used to confirm brain death (BD). A six­hour interval is recommended between clinical diagnosis and CTA acquisition despite the lack of strong evidence to support this interval. The aim of this study was to determine the optimal timing for CTA in the confirmation of BD. METHODS: This retrospective observational study enrolled all adult patients admitted between January 2009 and December 2013 to the intensive care units of a French university hospital with clinically diagnosed BD and at least one CTA performed as a confirmatory test. The CTAs were identified as conclusive (e.g. yielding confirmation of BD) or inconclusive (e.g. showing persistent brain circulation). RESULTS: One hundred and four patients (sex ratio M/F 1.8; age 55 years [41­64]) underwent 117 CTAs. CTAs confirmed cerebral circulatory arrest in 94 cases yielding a sensitivity of 80%. Inconclusive CTAs were performed earlier than conclusive ones (2 hours [1­3] vs. 4 hours [2­9], P=0.03) and were associated with decompressive craniectomy (5 cases [23%] vs. 6 cases [7%], P=0.05) and the failure to complete full neurological examination (5 cases [23%] vs. 4 cases [5%], P=0.02). Six hours after BD clinical diagnosis, the proportion of conclusive CTA was only 51%, with progressive increase overtime with more than 80% of conclusive CTA after 12 hours. CONCLUSIONS: A 12­hour interval might be appropriate in order to limit the risk of inconclusive CTAs.

Acute Bradykinin Receptor Blockade During Hemorrhagic Shock in Mice Prevents the Worsening Hypotensive Effect of Angiotensin-Converting Enzyme Inhibitor.

OBJECTIVES: Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice. DESIGN: In vivo study. SETTING: University research unit. SUBJECTS: C57/Bl6 mice. INTERVENTIONS: The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure. MEASUREMENTS AND MAIN RESULTS: During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups. CONCLUSIONS: During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.

Doppler renal resistive index for early detection of acute kidney injury after major orthopaedic surgery: a prospective observational study.

BACKGROUND: Postoperative acute kidney injury (AKI) is a cause of morbidity and mortality. Its diagnosis requires better markers than variations in diuresis or postoperative serum creatinine. OBJECTIVES: The aim of this study was to evaluate the accuracy of Doppler renal resistive index for early detection of AKI after hip or knee arthroplasty. DESIGN: A prospective observational study. SETTING: A single-centre study in a university hospital. PATIENTS: Fifty men and women older than 65 years, requiring hip or knee replacement with at least two perioperative AKI risk factors, including diabetes, arteritis, chronic heart or renal dysfunction, and prescription of angiotensin-converting enzyme (ACE) inhibitors. Exclusion criteria were poor abdominal echogenicity, arrhythmia, respiratory failure or agitation. INTERVENTION: Renal resistive index was measured preoperatively and in the postanaesthesia care unit. RESULTS: Sixteen patients presented with AKI in the postoperative period. Resistive index was increased in this group in both the preoperative [0.72 (0.69 to 0.73) vs. 0.66 (0.58 to 0.71); P = 0.01] and postoperative periods [0.75 (0.71 to 0.75) vs. 0.67 (0.62 to 0.72); P = 0.0001]. Resistive index evaluated by ROC curves and AUC to detect AKI was 0.862 [95% confidence interval (95% CI) 0.735 to 0.943]. The most accurate cut-off value was a postoperative resistive index of 0.705 (sensitivity = 94%, specificity = 71%, LR+ = 3.19 and LR- = 0.09). The grey area between 0.705 and 0.73, corresponding to the inconclusive zone, included 26% (13/50) of all the patients. CONCLUSION: Postoperative resistive index appears to be effective for early detection of AKI after major orthopaedic surgery. Resistive index can be measured in the postoperative care unit in patients at risk of AKI. TRIAL REGISTRATION NUMBER: 29-0512.

Hnf-1ß transcription factor is an early hif-1α-independent marker of epithelial hypoxia and controls renal repair.

Epithelial repair following acute kidney injury (AKI) requires epithelial-mesenchyme-epithelial cycling associated with transient re-expression of genes normally expressed during kidney development as well as activation of growth factors and cytokine-induced signaling. In normal kidney, the Hnf-1ß transcription factor drives nephrogenesis, tubulogenesis and epithelial homeostasis through the regulation of epithelial planar cell polarity and expression of developmental or tubular segment-specific genes. In a mouse model of ischemic AKI induced by a 2-hours hemorrhagic shock, we show that expression of this factor is tightly regulated in the early phase of renal repair with a biphasic expression profile (early down-regulation followed by transient over-expression). These changes are associated to tubular epithelial differentiation as assessed by KSP-cadherin and megalin-cubilin endocytic complex expression analysis. In addition, early decrease in Hnf1b expression is associated with the transient over-expression of one of its main target genes, the suppressor of cytokine signaling Socs3, which has been shown essential for renal repair. In vitro, hypoxia induced early up-regulation of Hnf-1ß from 1 to 24 hours, independently of the hypoxia-inducible factor Hif-1α. When prolonged, hypoxia induced Hnf-1ß down-regulation while normoxia led to Hnf-1ß normalization. Last, Hnf-1ß down-regulation using RNA interference in HK-2 cells led to phenotype switch from an epithelial to a mesenchyme state. Taken together, we showed that Hnf-1ß may drive recovery from ischemic AKI by regulating both the expression of genes important for homeostasis control during organ repair and the state of epithelial cell differentiation.

Type 2 diabetes mellitus in mice aggravates the renal impact of hemorrhagic shock.

The objectives of this study were to determine whether type 2 diabetic mice would exhibit a more severe renal impact of hemorrhagic shock (HS) based on a recently described model of acute kidney injury and to determine the impact of HS on renal responses to hypoxia. We induced HS or sham procedure in type 2 diabetic and obese db/db mice. Creatininemia, glomerular filtration rate, urine output, histologic injury score, and kidney inductible molecule 1 mRNA were used to investigate the renal impact of HS. Tissular hypoxia and its impact were quantified using pimonidazole immunostaining and mRNA of hypoxic inducible factor, vascular endothelial growth factor receptors 1 and 2, Tie-2, endothelial nitric oxide synthase, and inducible nitric oxide synthase. Diabetic mice exhibiting mild diabetic nephropathy express hypoxic signals at baseline. The renal impact of HS was more severe in diabetic mice, with a worsening of tissular hypoxia and an altered response to hypoxia. Furthermore, endothelial nitric oxide synthase was highly overexpressed in diabetic shocked mice when compared with nondiabetic shocked mice. Renal impact of HS in type 2 diabetic mice is more intense than in nondiabetic ones. Preexisting hypoxia during diabetes could result in a renal preconditioning that modifies endothelial and tissular responses to acute kidney injury.

Patent foramen ovale appearance with association of left ventricular assist device and mechanical ventilation.

We report on a 62-year-old man referred to the cardiac intensive care unit less than 24 hours after anterior ST-segment elevated myocardial infarction. The patient developed cardiogenic shock requiring elective intubation, vasopressor, and inotropic support. Emergency coronary angiography, revascularization, and insertion of an intraaortic balloon pump were performed. Nevertheless, the hemodynamic situation remained unstable, and a left ventricular assist device (LVAD) was inserted. Severe hypoxemia occurred several minutes after initiating the Impella Recover LD/LP 5.0 (Abiomed, Danvers, MA). Transesophageal echocardiography allowed diagnosis of patent foramen ovale. The shunt resulted from abnormal left-to-right pressure gradient due to left ventricular unloading and increased right ventricular afterload induced by mechanical ventilation. Transesophageal echocardiography was used to regulate both LVAD output and positive end-expiratory pressure settings to optimize oxygen transport. Because patent foramen ovale is common in humans, transesophageal echocardiography should be performed systematically after LVAD insertion.

Lethal hemorrhagic alveolitis after adenovirus pneumonia in a lung transplant recipient.

Viral infections are frequent and severe in lung transplant recipients. They frequently occur during the first year after transplantation. We report on a rare case of bilateral adenovirus necrotizing pneumonia with a diffuse alveolar hemorrhage, 4 years after bilateral lung transplantation. The medical evolution was lethal in 72 hours because of respiratory, renal, and cardiac failure. Considering this case and the growing evidence on the severity of adenoviral infections, we call for controlled studies and therapeutic recommendations.