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Objectives: Though Human Leukocyte Antigen (HLA) matching benefits are demonstrated in renal transplantation, evidence in heart transplantation is lacking, and its clinical feasibility is uncertain. Posttransplantation anti-HLA antibodies are being increasingly studied in organ transplantation, with diverging conclusions between transplantated organs. Methods: We analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, acute rejection and chronic allograft vasculopathy in 309 patients receiving induction therapy and triple-drug immunosuppression. Results: The average number of HLA-A/B/DR mismatches between donor and recipient was 4.9 ± 1. The majority of mismatches was for Class I HLA-A/B with an average of 3.3, then for Class I HLA-DR with an average of 1.6. Overall, the HLA-A/-B/-DR mismatches had no influence on the cardiac allograft survival (p = 0.28). However, HLA-DR mismatches were negatively correlated to severe cellular and/or humoral allograft rejection (p = 0.04). Our analysis found anti-HLA antibodies in 27% of recipients, de novo anti-HLA antibodies in 16% of recipients, and donor-specific anti-HLA (DSA) antibodies in 8% of recipients. Furthermore, de novo DSA had no influence on the 5-year survival (78% with DSA vs. 92% without DSA; p = 0.49), which may be masked by the limited number of recipients in analysis By univariable analysis, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on severe cellular and/or humoral rejection or on chronic allograft vasculopathy. Conclusions: HLA-DR mismatch was negatively correlated to severe cellular and/or humoral allograft rejection but had no influence on cardiac allograft survival. In this study, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on cellular and/or humoral rejection or on chronic allograft vasculopathy. The results of this study add to the controversy on the impac

BACKGROUND: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. METHODS: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit's binding sites over time. RESULTS: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2-4.7) mg/L under ECMO and 2.5 (1.4-3.9) mg/L without ECMO (p = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. CONCLUSIONS: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard rat

Background: Voriconazole is one of the first‐line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. Methods: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit’s binding sites over time. Results: Sixty‐nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2–4.7) mg/L under ECMO and 2.5 (1.4–3.9) mg/L without ECMO (p = 0.58). Extensive inter‐and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. Conclusions: No significant ECMO‐effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.

Au cours de la pandémie liée au COVID-19, de nombreux patients ont été admis en unité de soins intensifs, mettant en exergue le travail d’une spécialité souvent peu ou mal connue du public. L’insuffisance respiratoire présentée par ces patients, et entrant dans le cadre de la définition de l’ARDS, a nécessité des techniques d’oxygénation et de ventilation non-invasive, invasive et dans les cas les plus sévères d’une assistance extra-corporelle. Ces traitements lourds, associés à des techniques de mobilisation compliquées (décubitus ventral) et aux autres traitements usuels de soins intensifs, chez un nombre important de patients simultanés et dont le pronostic était réservé, a généré une pression importante pour les équipes au lit du malade., [Management of patients with COVID-19-related respiratory failure at the intensive care unit] During the COVID-19 pandemic, many patients have been admitted to intensive care units, thereby highlighting the work of a medical specialty that is often little or poorly known to the public. In these patients, respiratory failure, falling within the definition of acute respiratory distress syndrome, had to be managed using non-invasive and invasive oxygenation and ventilation techniques, and in the most severe cases, using extracorporeal membrane oxygenation. These heavy treatments, combined with complicated mobilization techniques (prone position) and other usual intensive care treatments, had to be delivered simultaneously to a large number of patients with a guarded prognosis, which has put under significant pressure the bedside care teams.

Dear Editor, Skin rashes associated with COVID‐19 include eruptions induced by drugs prescribed for management of this infection. We report a case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with COVID‐19. [...]

OBJECTIVES: To report current practices regarding mechanical ventilation in patients treated with extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) and their association with 6-month outcomes. METHODS: International, multi-center, prospective cohort study of patients undergoing ECMO for ARDS during a one-year period in 23 international intensive care units (ICUs). MEASUREMENTS AND MAIN RESULTS: We collected demographics, daily pre- and per-ECMO mechanical ventilation settings and use of adjunctive therapies, ICU- and 6-month-outcome data for 350 patients (median ± standard deviation pre-ECMO PaO2/FiO2 71±34 mmHg). Pre-ECMO use of prone positioning and neuromuscular blockers were 26% and 62%, respectively. Tidal volume (6.4±2.0 vs 3.7±2.0 ml/kg), plateau pressure (32±7 vs 24±7cmH2O), driving pressure (20±7 vs. 14±4 cmH2O), respiratory rate (26±8 vs 14±6 breaths/min) and mechanical power (26.1±12.7 vs. 6.6±4.8 J/min) were markedly reduced after ECMO initiation. Six-month survival was 61%. No association was found between ventilator settings during the first 2 days of ECMO and survival in multivariable analysis. A time-varying Cox model retained older age, higher fluid balance, higher lactate, and more need for renal replacement therapy along the ECMO course as being independently associated with 6-month mortality. A higher tidal volume and lower driving pressure (likely markers of static compliance improvement) across the ECMO course were also associated with better outcomes. CONCLUSION: Ultra-protective lung ventilation on ECMO was largely adopted across medium to high case-volume ECMO centers. In contrast with previous observations, mechanical ventilation settings during ECMO did not impact patients' prognosis in this context.

Dear Editor, Influenza affects between two and three million people worldwide each year, with complications responsible for a significant number of excess hospitalizations in intensive care units (ICUs) [1]. Since the newsworthy 2009 A(H1N1) pandemic (pdm), publications about influenza in ICUs remain scarce, with crucial outstanding issues on prognosis factors including the timing of antiviral treatments [2, 3, 4, 5]. Here, we present a multicenter prospective study of critically ill influenza-infected patients aimed to identify prognosis factors associated with death. [...]

OBJECTIVES: Cardiac transplantation using hearts from donors after circulatory death (DCD) is critically limited by the unavoidable warm ischaemia and its related unpredictable graft function. Inasmuch as hypothermic machine perfusion (MP) has been shown to improve heart preservation, we hypothesized that MP could enable the use of DCD hearts for transplantation. METHODS: We recovered 16 pig hearts following anoxia-induced cardiac arrest and cardioplegia. Grafts were randomly assigned to two different groups of 4-h preservation using either static cold storage (CS) or MP (Modified LifePort© System, Organ Recovery Systems©, Itasca, Il). After preservation, the grafts were reperfused ex vivo using the Langendorff method for 60 min. Energetic charge was quantified at baseline, post-preservation and post-reperfusion by measuring lactate and high-energy phosphate levels. Left ventricular contractility parameters were assessed both in vivo prior to ischaemia and ex vivo during reperfusion. RESULTS: Following preservation, the hearts that were preserved using CS exhibited higher lactate levels (57.1 ± 23.7 vs 21.4 ± 12.2 µmol/g; P < 0.001), increased adenosine monophosphate/adenosine triphosphate ratio (0.53 ± 0.25 vs 0.11 ± 0.11; P < 0.001) and lower phosphocreatine/creatine ratio (9.7 ± 5.3 vs 25.2 ± 11; P < 0.001) in comparison with the MP hearts. Coronary flow was similar in both groups during reperfusion (107 ± 9 vs 125 ± 9 ml/100 g/min heart; P = ns). Contractility decreased in the CS group, yet remained well preserved in the MP group. CONCLUSION: MP preservation of DCD hearts results in improved preservation of the energy and improved functional recovery of heart grafts compared with CS.

We report and discuss the case of a 51-year-old patient undergoing elective laparoscopic surgery for pheochromocytoma after 10 days of medical pre-treatment. After anaesthetic induction, a deep level of anaesthesia could not prevent the onset of repeated hypertensive peaks, followed by severe hypotensive periods. Once the surgical incision was made, the patient developed acute pulmonary oedema along with significant oxygen desaturation. The decision was made to stop the surgery and transfer the patient to the intensive care unit (ICU) for further support and management. Unfortunately, additional monitoring and symptomatic treatment did not help haemodynamic stabilisation. In the absence of any external stimulation or medical support, the oscillation of blood pressure (BP) continued with peaks every 20 minutes up to 300 mmHg systolic blood pressure (SBP) and falls down to 30 mmHg SBP. The patient also sustained two episodes of cardiac arrest from which he recovered. Facing this unmanageable situation, a decision was made after a multi-disciplinary discussion to go back to surgery in order to remove the source of adrenergic stimulation. Surgery by laparotomy was performed and catecholamine substitution was provided. Nevertheless, after tumour removal, BP dropped leading to a third cardiac arrest that was successfully managed. Following a 10-day stay in the ICU, the patient left with subsequent cardiac stabilisation and full recovery.

This chapter describes the history of mechanical circulatory, available paracorporeal or implantable systems, indications for mechanical circulatory support, patient selection and management, complications and future perspectives.

A 19-year-old man was admitted with acute dyspnoea. Physical examination revealed subcutaneous emphysema in the cervical and thoracic area. This was further confirmed by the total body computed tomography that also demonstrated mediastinal emphysema. Epidural pneumatosis of the thoracis spine was also evident. There was no history of trauma, but well of a recent oral ecstasy consumption during a techno rave party, associated with intense dancing and jumping. Clinical course was favourable with conservative therapy.

Introduction: The improved outcomes of third-generation continuous-flow left ventricular assist devices (CF-LVAD) in bridge-to-transplant and the high attrition rate among patients awaiting an allograft have raised the question whether CF-LVADs are better than the waiting list for transplant eligible patients. Hypothesis: we assessed the hypothesis that survival after LVAD is improved compared to waiting list in adult patients listed in UNOS status II. Methods: We identified all patients >18 years of age in the Organ Procurement and Transplantation Network (OPTN) database listed for their first heart transplant in the US in UNOS status II with no mechanical circulatory support at time of listing and not candidates to multi-organ transplant between January 2011 and March 2014. Of 2468 patients listed during the study period, 208 patients received a third-generation CF-LVAD. CF-LVAD and NO-LVAD patients were then matched 1:2 by mean of the closest-neighbor Propensity Score and survival of the matched groups was estimated with the Kaplan-Meier method. Results: One hundred and ninety CF-LVAD patients were PS-matched with 380 NO-LVAD patients. The matched groups were similar for several baseline characteristics (p=ns). In the CF-LVAD subgroup, 158 patients (83.2%) were transplanted, 21 (11.1%) were still on support and on the list, and 11 patients (5.8%) died or were delisted. In the NO-LVAD group, 314 patients (82.6%) were transplanted, 48 (12.6%) were still on the list and 18 patients (4.7%) died or were delisted. Freedom from death or delisting with CF-LVAD was 80.5% versus 85.5% of NO-LVAD patients at 18 months postoperatively (p=0.4). Cumulative survival considering also the post-transplant period was similar in the two groups at 24 months since listing (80.4% CF-LVAD versus 79.4% NO-LVAD, p=0.3). Conclusions: In conclusion, heart transplant candidates listed in status II and supported with CF-LVAD have shown a similar survival on the waiting list compared to candid

Nous rapportons le cas d’une patiente de 49 ans ayant développé un syndrome d’encéphalopathie postérieure réversible (PRES) 7 jours après transplantation cardiaque. La symptomatologie, l’imagerie caractéristique et les hypothèses pathophysiologiques de cette entité sont discutés à la lumière de la littérature récente.

OBJECTIVES: Studies have emphasized the importance of normal fibrinogen concentrations in surgical patients. The primary hypothesis of this study was that fibrinogen levels significantly decrease in on-pump coronary artery bypass graft (CABG) surgery versus off-pump coronary artery bypass graft (OPCAB) surgery. The second objective was to show that ROTEM (TEM International, GmbH, Munich, Germany) rapidly detects these abnormalities compared with standard tests. DESIGN: A prospective, nonrandomized study. SETTING: A university hospital. PARTICIPANTS: Forty-two and 62 patients in the CABG and OPCAB groups, respectively, undergoing first-time bypass surgery were included. INTERVENTIONS: CABG versus OPCAB surgery. MEASUREMENTS AND MAIN RESULTS: Routine coagulation tests and ROTEM values were measured before anesthesia (T0), after the first dose of heparin (T1), after protamine (T2), upon intensive care unit arrival (T3), and 4 hours postoperatively (T4). The outcome measures were followed until 4 hours postoperatively. Fibrinogen concentrations were significantly lower in the CABG versus the OPCAB group at T2 (170 ± 44 v 243 ± 73 mg/dL, p < 0.001) and T3 (179 ± 42 v 232 ± 68 mg/dL, p < 0.001). This was confirmed by significantly lower FIBTEM maximal clot firmness values at T2 (9 ± 4 v 14 ± 5 mm, p < 0.001) and T3 (9 ± 4 v 13 ± 6 mm, p < 0.001). In the CABG group, patients received significantly more transfusions of all blood products except fresh frozen plasma. CONCLUSIONS: Fibrinogen concentration significantly decreases after cardiopulmonary bypass. ROTEM helps in its fast detection.

OBJECTIVE: Preliminary data showed an increase in endogenous erythropoietin (EPO) concentrations after acute normovolemic hemodilution (ANH) in patients undergoing coronary artery bypass graft (CABG) surgery. Numerous studies have shown the organ protective properties of EPO. The aim of this study was to investigate the cardioprotective effects of these increased EPO concentrations that resulted from ANH during cardiac surgery. DESIGN: A prospective, randomized, blind study. SETTING: A university hospital. PARTICIPANTS: A total of 93 patients undergoing isolated CABG surgery with or without cardiopulmonary bypass (CPB). INTERVENTIONS: Subjects with CPB were randomized into the control (C) or ANH group. Those in the off-pump coronary artery bypass group underwent no treatment. In the ANH group, a precalculated amount of blood was withdrawn and replaced by colloids after the induction of anesthesia. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were recorded intra- and postoperatively. Troponin concentrations were measured as a routine parameter postoperatively. Upon intensive care unit arrival, the EPO levels were higher in the ANH group than in the C group. There was no significant difference between the troponin values of the C and the ANH groups at 4 hours postoperatively. CONCLUSIONS: In patients undergoing CABG surgery on CPB, an increase in endogenous EPO concentrations in the physiologic range has no cardioprotective effects.

Background: Central Pulse Wave Velocity (PWV) is considered to be the gold standard measurement of arterial stiffness. In healthy subjects, cardiovascular risk factors such as age, hypertension, diabetes and end-stage renal disease are associated with increased central (Carotid-Femoral) and peripheral (Femoral-Ankle) PWV. However, little is known about PWV in patients with peripheral arterial disease and pathological Ankle-Brachial Index (ABI). The aim of this study was to study central and peripheral PWV in a population with various degree of peripheral arterial disease. Methods: Central and peripheral PWV were measured in sixty-two hospitalized patients. Half were admitted for symptomatic peripheral vascular disease and the remainder for cardiac or carotid disease. The population was classified on basis of the Framingham-derived risk score for claudicants and on the ABI. For all patients, PWV was assessed on electrocardiogram-ultrasonographic images acquired at the four following sites: carotid, radial, femoral and tibial arteries. Results: Carotid-Femoral PWV increased significantly with the Framingham-derived global risk score (p < 0.0001) but Femoral-Ankle PWV did not. With respect to the Ankle-Brachial Index, Carotid-Femoral and Femoral-Ankle PWV significantly increased (p = 0.05 and p = 0.02 respectively) with the severity of peripheral arterial scoring. Conclusions: These results confirm that central PWV is the best indicator of general atherosclerosis, even in the presence of peripheral arterial disease. Both central and peripheral PWV can be considered as indicators of the severity of peripheral vascular disease. © 2011 Association for Research into Arterial Structure and Physiology.

Refractory hypercapnia with severe acidosis appeared in a 67-year-old man who presented with lung fibrosis and a left pneumothorax as delayed complications of bleomycin chemotherapy for advanced grade lymphoma. Due to failure of noninvasive ventilation using a high-flow nasal cannula oxygen system, the patient was mechanically ventilated with two ventilators at different settings, after intubation with a double-lumen tube. As he had a poor haematological prognosis, extracorporeal membranous oxygenation was not considered. To remove some amount of carbon dioxide, we used a simplified method based on a veno-venous hemofiltration circuit coupled to a paediatric oxygenator and an air/oxygen blender. The efficacy on carbon dioxide removal was modest, with a percentage of CO2 total extraction ranging from 10.5 to 20.4%, but the system was immediately available, well tolerated and not very expensive.

Exercise capacity is improved in patients supported with continuous flow rotary blood pumps (RP). The aim of this study was to investigate the mechanisms underlying this improvement. Ten patients implanted with a RP underwent cardiopulmonary exercise testing (CPET) at 6 months after surgery with hemodynamic and metabolic measurements (RP group). A group of 10 matched heart failure patients were extracted from our heart transplant database, and the results of their last CPET before transplantation were used for comparison (heart failure [HF] group). Peak VO(2) was significantly higher in RP than in HF patients (15.8 ± 6.2 vs. 10.9 ± 3 mL O(2)/kg.min) reaching 52 ± 16% of their predicted peak VO(2). The total output measured by a Swan-Ganz catheter increased from 5.6 ± 1.6 to 9.2 ± 1.8 L/min in the RP group and was significantly higher at rest and at peak exercise than in the HF group, whose output increased from 3.5 ± 0.4 to 5.6 ± 1.6 L/min. In the RP group, the estimated pump flow increased from 5.3 ± 0.4 to 6.2 ± 0.8, whereas the native cardiac output increased from 0.0 ± 0.5 to 3 ± 1.7 L/min. Cardiac output at peak exercise was inversely correlated with age (r = -0.86, P = 0.001) and mean pulmonary artery pressure (r = -0.75, P = 0.012). Maximal exercise capacity is improved in patients supported by RP as compared to matched HF patients and reaches about 50% of the expected values. Both a spontaneous increase of pump flow at constant pump speed and an increase of the native cardiac output contribute to total flow elevation. These findings may suggest that an automatic pump speed adaptation during exercise would further improve the exercise capacity. This hypothesis should be examined.

Extracorporeal membrane oxygenation (ECMO) is a technique that provides support to selected patients with severe respiratory failure. During the 2009 H1N1 influenza infection outbreak, ECMO was used with a good impact on survival for pregnant women, who are at higher risk of H1N1 influenza infection. However, there is little information about the survival of fetus post-ECMO therapy in the literature. We present a case report of a pregnant patient with severe adult respiratory distress syndrome secondary to 2009 H1N1 influenza treated with ECMO. The outcome was good both for the mother and her fetus. At 1-year follow-up, her child had no neurological or clinical abnormalities. We conclude that ECMO can be used safely during pregnancy with a good neurological and clinical outcome for the fetus.

BACKGROUND: The true relevance of allosensitization in patients benefiting from left ventricular assist device (LVAD) as bridge to transplant (BTT) is still debated. Available registry data referred to numerous devices precluding LVAD-specific analysis. Therefore, we studied all patients with Novacor LVAD prior to transplantation. METHODS: From 1985 to 2006, 37 Novacor LVADs were implanted as BTT, with 30 patients surviving to transplantation (81%). Post-LVAD sensitization was determined for anti-HLA-class I and class II IgGs. Study endpoints were overall survival and/or graft loss, > or =3A cellular rejection and chronic allograft vasculopathy (CAV). The results from LVAD patients were compared to non-LVAD primary heart transplant recipients (n=318). RESULTS: After LVAD insertion, 5 out of 27 patients available for analysis developed anti-HLA antibodies (18.5%). The mean anti-HLA titer after Novacor LVAD implantation was 14% [SD 31]. Actuarial 5- and 10-year patient/graft survival for LVAD and non-LVAD transplant recipients were 73% and 55%, and 70% and 55%, respectively (p=NS). Overall prevalence of rejection > or =3A was 23.3 % (LVAD group) and 18.9% (non-LVAD group) (p=NS). At follow-up, the respective incidence of CAV was 8% (LVAD group) and 32.4% (non-LVAD group) (p<0.01). However, mean follow-up was significantly different for LVAD and non-LVAD patients, 46 vs 90 months (p<0.001). CONCLUSION: In this study, allosensitization occurred infrequently after Novacor LVAD implantation. Secondly, analysis of outcome variables shows that Novacor-LVAD BTT patients can anticipate similar survival to non-LVAD patients, thus minimizing the impact of allosensitization after LVAD implantation.