A reactive monocyte subset characterized by low expression of CD91 is expanded during sterile and septic inflammation.

OBJECTIVES: This study was undertaken to assess CD91 expression on monocytes and changes in monocyte subset distribution during acute tissue damage and bloodstream infection (BSI). METHODS: We investigated blood specimens from healthy individuals, trauma and cardiac surgery patients as a model of tissue damage, and patients with BSI, by flow cytometry using a panel of antibodies comprising CD45, HLA-DR, CD14, CD16 and CD91 for the identification of monocyte subsets. RESULTS: While infrequent in healthy subjects, CD91low/neg monocyte levels were markedly high in BSI, trauma and after cardiac surgery. This monocyte subset expanded up to 15-fold in both patient cohorts, whereas CD14+CD16+ inflammatory monocytes were multiplied by a factor of 5 only. CD14+CD91low monocytes displayed a significantly lower density of HLA-DR and markedly reduced expression of CD300e, compared to the other subsets. They also expressed high levels of myeloperoxidase and showed robust phagocytic and oxidative burst activity. CONCLUSIONS: Expansion of CD91low monocytes is a sensitive marker of acute inflammatory states of infectious and non-infectious etiology.

Virtual reality and hypnosis for anxiety and pain management in intensive care units: A prospective randomised trial among cardiac surgery patients.

BACKGROUND: Virtual reality and hypnosis are little studied in complex contexts, such as intensive care, where patients need significant physical and psychological assistance. OBJECTIVES: To compare and combine hypnosis and virtual reality benefits on anxiety and pain on patients before and after cardiac surgery. DESIGN: Prospective randomised controlled clinical trial. SETTING: The study was conducted in the University Hospital of Liege (Belgium) from October 2018 to January 2020. PATIENTS: One hundred patients (66 ±â€Š11.5 years; 24 women, 76 men) were included. Participants were adults undergoing cardiac surgery. Exclusion criteria: psychiatric diseases, claustrophobia, acrophobia, hearing loss, visual impairment, extreme fatigue, confusion surgery cancelled. INTERVENTIONS: Patients were randomly assigned to four arms (control; hypnosis; virtual reality; virtual reality hypnosis) and had 20 min of one of the techniques the day before and the day after surgery. MAIN OUTCOMES MEASURES: Anxiety, pain, fatigue, relaxation, physiological parameters, and opioid use were evaluated before and after each session. RESULTS: The main results did not show any significant differences between the groups. In all groups, anxiety decreased and pain increased from baseline to the postoperative day. Relaxation increased in all groups in the pre-operative (P < 0.0001) and postoperative period (P = 0.03). There were no significant differences for fatigue, physiological measures, or opioid use. CONCLUSION: As there were no significant differences between groups for the measured variables, we cannot affirm that one technique is better than another. Additional studies are required to compare and evaluate the cost-effectiveness of these techniques for critical care patients and caregivers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03820700. https://clinicaltrials.gov/ct2/show/NCT03820700. Retrospectively registered on 29 January 2019.

Machine learning identification of specific changes in myeloid cell phenotype during bloodstream infections.

The early identification of bacteremia is critical for ensuring appropriate treatment of nosocomial infections in intensive care unit (ICU) patients. The aim of this study was to use flow cytometric data of myeloid cells as a biomarker of bloodstream infection (BSI). An eight-color antibody panel was used to identify seven monocyte and two dendritic cell subsets. In the learning cohort, immunophenotyping was applied to (1) control subjects, (2) postoperative heart surgery patients, as a model of noninfectious inflammatory responses, and (3) blood culture-positive patients. Of the complex changes in the myeloid cell phenotype, a decrease in myeloid and plasmacytoid dendritic cell numbers, increase in CD14+CD16+ inflammatory monocyte numbers, and upregulation of neutrophils CD64 and CD123 expression were prominent in BSI patients. An extreme gradient boosting (XGBoost) algorithm called the "infection detection and ranging score" (iDAR), ranging from 0 to 100, was developed to identify infection-specific changes in 101 phenotypic variables related to neutrophils, monocytes and dendritic cells. The tenfold cross-validation achieved an area under the receiver operating characteristic (AUROC) of 0.988 (95% CI 0.985-1) for the detection of bacteremic patients. In an out-of-sample, in-house validation, iDAR achieved an AUROC of 0.85 (95% CI 0.71-0.98) in differentiating localized from bloodstream infection and 0.95 (95% CI 0.89-1) in discriminating infected from noninfected ICU patients. In conclusion, a machine learning approach was used to translate the changes in myeloid cell phenotype in response to infection into a score that could identify bacteremia with high specificity in ICU patients.

Feasibility of extracorporeal membrane oxygenation cardiopulmonary resuscitation by low volume centers in Belgium.

OBJECTIVE: To assess the feasibility of delivering extracorporeal cardiopulmonary resuscitation (ECPR) in refractory out-of-hospital cardiac arrests (OHCA) by low volume extracorporeal membrane oxygenation (ECMO) centers and to explore pre-ECPR predictors of survival. METHODS: Between 2016 and 2020, we studied 21 ECPR patients admitted in 2 tertiary ECMO centers in Liège, Belgium. Our ECPR protocol was based on 6 prehospital criteria (no flow < 3 minutes, low flow < 60 minutes, initial shockable rhythm, end-tidal CO2 > 15 mmHg, age < 65 years, and absence of comorbidities). A dedicated training, prehospital checklist and call number for 24/7 ECMO team assistance were implemented. Hemodynamics and blood gases on admission also were assessed. RESULTS: Twenty-one (28%) out of 75 refractory OHCA patients referred were treated by ECPR, with a hospital survival rate of 43% (n = 9/21), comparable to ECPR results from the international extracorporeal life support organization registry. Transient return of spontaneous circulation before ECPR (89% in survivors vs 17% in non-survivors, P = 0.002) and higher initial serum bicarbonate (med [P25-P75] 14.0 [10.6-15.2] vs 7.5 [3.7-10.5] mmol/L, P = 0.019) or lower initial base deficit (14.9 [11.9-18.2] vs 21.6 [17.9-28.9] mmol/L, P = 0.039) were associated with a more favorable outcome. CONCLUSION: In low volume ECMO centers, the implementation of a specific ECPR protocol for refractory OHCA patients is feasible and provides potential clinical benefit. Highly selective inclusion criteria seem essential to select candidates for ECPR. Initial serum bicarbonate and base deficit integrating cumulative cell failure may be relevant pre-ECMO prognostic factors and require larger-scale evaluation.

Can hypnosis and virtual reality reduce anxiety, pain and fatigue among patients who undergo cardiac surgery: a randomised controlled trial.

BACKGROUND: Different non-pharmacological techniques, including hypnosis and virtual reality (VR) are currently used as complementary tools in the treatment of anxiety, acute and chronic pain. A new technique called virtual reality hypnosis (VRH), which encompasses a combination of both tools, is regularly used although its benefits and underlying mechanisms remain unknown to date. With the goal to improve our understanding of VRH combination effects, it is necessary to conduct randomised and controlled research trials in order to understand their clinical interest and potential benefits. METHODS: Patients (n = 100) undergoing cardiac surgery at the Liège University Hospital will be randomly assigned to one of four conditions (control, hypnosis, VR or VRH). Each patient will receive two sessions of one of the techniques: one the day before the surgery and one the day after. Physiological assessments will be made on the monitor and patients will rate their levels of anxiety, fatigue, pain, absorption and dissociation. DISCUSSION: This study will help to expand knowledge on the application of virtual reality, hypnosis and VRH in the specific context of cardiac and intensive care procedures, and the influence of these non-pharmacological techniques on patient's anxiety, fatigue, pain and phenomenological experience. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03820700. Date registered on 29 January 2019. Study recruitment date: October 6, 2018. Study anticipated completion date: December 28, 2020.

Volumetric capnography: lessons from the past and current clinical applications.

Dead space is an important component of ventilation-perfusion abnormalities. Measurement of dead space has diagnostic, prognostic and therapeutic applications. In the intensive care unit (ICU) dead space measurement can be used to guide therapy for patients with acute respiratory distress syndrome (ARDS); in the emergency department it can guide thrombolytic therapy for pulmonary embolism; in peri-operative patients it can indicate the success of recruitment maneuvers. A newly available technique called volumetric capnography (Vcap) allows measurement of physiological and alveolar dead space on a regular basis at the bedside. We discuss the components of dead space, explain important differences between the Bohr and Enghoff approaches, discuss the clinical significance of arterial to end-tidal CO2 gradient and finally summarize potential clinical indications for Vcap measurements in the emergency room, operating room and ICU.

Incidence and risk factors for early renal dysfunction after liver transplantation.

AIM: To determine renal dysfunction post liver transplantation, its incidence and risk factors in patients from a Belgian University Hospital. METHODS: Orthotopic liver transplantations performed from January 2006 until September 2012 were retrospectively reviewed (n = 187). Patients with no renal replacement therapy (RRT) before transplantation were classified into four groups according to their highest creatinine plasma level during the first postoperative week. The first group had a peak creatinine level below 12 mg/L, the second group between 12 and 20 mg/L, the third group between 20 and 35 mg/L, and the fourth above 35 mg/L. In addition, patients who needed RRT during the first week after transplantation were also classified into the fourth group. Perioperative parameters were recorded as risk factors, namely age, sex, body mass index (BMI), length of preoperative hospital stay, prior bacterial infection within one month, preoperative ascites, preoperative treatment with ß-blocker, angiotensin-converting enzyme inhibitor or non steroidal anti-inflammatory drugs, preoperative creatinine and bilirubin levels, donor status (cardiac death or brain death), postoperative lactate level, need for intraoperative vasopressive drugs, surgical revision, mechanical ventilation for more than 24 h, postoperative bilirubin and transaminase peak levels, postoperative hemoglobin level, amount of perioperative blood transfusions and type of immunosuppression. Univariate and multivariate analysis were performed using logistic ordinal regression method. Post hoc analysis of the hemostatic agent used was also done. RESULTS: There were 78 patients in group 1 (41.7%), 46 in group 2 (24.6%), 38 in group 3 (20.3%) and 25 in group 4 (13.4%). Twenty patients required RRT: 13 (7%) during the first week after transplantation. Using univariate analysis, the severity of renal dysfunction was correlated with presence of ascites and prior bacterial infection, preoperative bilirubin, urea and creatinine level, need for surgical revision, use of vasopressor, postoperative mechanical ventilation, postoperative bilirubin and urea, aspartate aminotransferase (ASAT), and hemoglobin levels and the need for transfusion. The multivariate analysis showed that BMI (OR = 1.1, P = 0.004), preoperative creatinine level (OR = 11.1, P < 0.0001), use of vasopressor (OR = 3.31, P = 0.0002), maximal postoperative bilirubin level (OR = 1.44, P = 0.044) and minimal postoperative hemoglobin level (OR = 0.059, P = 0.0005) were independent predictors of early post-liver transplantation renal dysfunction. Neither donor status nor ASAT levels had significant impact on early postoperative renal dysfunction in multivariate analysis. Absence of renal dysfunction (group 1) was also predicted by the intraoperative hemostatic agent used, independently of the extent of bleeding and of the preoperative creatinine level. CONCLUSION: More than half of receivers experienced some degree of early renal dysfunction after liver transplantation. Main predictors were preoperative renal dysfunction, postoperative anemia and vasopressor requirement.

[Is there a place for thrombin generation assay in routine clinical laboratory?]. / Quelle place pour le test de génération de thrombine au sein du laboratoire de biologie clinique ?

Laboratory diagnosis of coagulopathies primarily relies on assays selectively exploring either the extrinsic (PT), the intrinsic (aPTT) or the common (TT) pathway of the coagulation system. Although these tests are very useful to rapidly identify severe coagulation disorders or to monitor anticoagulant therapy, they only poorly correlate with the clinical manifestations. Global assays that evaluate the whole coagulation process could potentially more accurately reflect the hemorrhagic or thrombotic phenotype of an individual. Thrombin generation assay (TGA), first described in the 1950's, has been developed and automated in the 1990's. This technique is widely used in fundamental research but has yet failed to integrate clinical laboratories. In this article, we describe TGA and review its clinical applications. Laboratory aspects and technical issues will also be discussed.

Use of a pediatric oxygenator integrated in a veno-venous hemofiltration circuit to remove CO2: a case report in a severe burn patient with refractory hypercapnia.

Acute respiratory distress syndrome management is currently based on lung protective ventilation. Such strategy may lead to hypercapnic acidosis. We report a case of refractory hypercapnia in a severe burn adult, treated with simplified veno-venous extracorporeal carbon dioxide removal technique. We integrated a pediatric oxygenator in a continuous veno-venous hemofiltration circuit. This technique, used during at least 96h, was feasible, sure and efficient with carbon dioxide removal rate up to 32%.

Toward targeted early burn care: lessons from a European survey.

During the year 2011, a survey was performed to describe current practices throughout Europe regarding three critical issues of acute burn care, namely fluid resuscitation, nutrition, and burn wound excision strategy. Thirty-eight questionnaires returned by burn centres from 17 different European countries were analyzed. The survey shows that Parkland remains the most commonly used formula to determine fluid needs in adults. All respondent centers use urine output to guide fluid resuscitation. While early excision of deep burns is the rule among centers, burn depth assessment by laser Doppler imaging is used in only a few centers. Indirect calorimetry and Toronto formula to estimate energy requirements do not have unanimous backing from respondents. Current literature encourages clinicians to move forward targeted and individualized therapies using a bundle of basic and advanced hemodynamic parameters, indirect calorimetry, and laser Doppler imaging. The results of this study suggest that such an approach is not common yet, and reinforce the subsequent need for large clinical trials that would evaluate the impact of such guided therapies to provide recommendations with a significant level of evidence.

Persistent hypocoagulability in patients with septic shock predicts greater hospital mortality: impact of impaired thrombin generation.

PURPOSE: Sepsis induces hypercoagulability, hypofibrinolysis, microthrombosis, and endothelial dysfunction leading to multiple organ failure. However, not all studies reported benefit from anticoagulation for patients with severe sepsis, and time courses of coagulation abnormalities in septic shock are poorly documented. Therefore, the aim of this prospective observational cohort study was to describe the coagulation profile of patients with septic shock and to determine whether alterations of the profile are associated with hospital mortality. METHODS: Thirty-nine patients with septic shock on ICU admission were prospectively included in the study. From admission to day 7, analytical coagulation tests, thrombin generation (TG) assays, and thromboelastometric analyses were performed and tested for association with survival. RESULTS: Patients with septic shock presented on admission prolongation of prothrombin time, activated partial thromboplastin time (aPTT), increased consumption of most procoagulant factors as well as both delay and deficit in TG, all compatible with a hypocoagulable state compared with reference values (P < 0.001). Time courses revealed a persistent hypocoagulability profile in non-survivors as compared with survivors. From multiple logistic regression, prolonged aPTT (P = 0.007) and persistence of TG deficit (P = 0.024) on day 3 were strong predictors of mortality, independently from disease severity scores, disseminated intravascular coagulation score, and standard coagulation tests on admission. CONCLUSIONS: Patients with septic shock present with hypocoagulability at the time of ICU admission. Persistence of hypocoagulability assessed by prolonged aPTT and unresolving deficit in TG on day 3 after onset of septic shock is associated with greater hospital mortality.

Relevance of nitric oxide for myocardial remodeling.

Endogenous myocardial nitric oxide (NO) may modulate the transition from adaptive to maladaptive remodeling leading to heart failure. In rodent models of pressure overload or myocardial infarction, the three NO synthase (NOS) isoforms were shown to play a neutral, protective, or even adverse role in myocardial remodeling, depending on the quantity of NO produced, the location of each NOS and their regulators, the prevailing oxidant stress and resultant NO/oxidant balance, as well as NOS coupling/dimerization. Beside neuronal NOS and--in specific conditions--inducible NOS isoforms, endothelial NOS (eNOS) exerts cardioprotective effects on pressure-overload, ischemia/reperfusion, and myocardial infarction-induced myocardial remodeling, provided the enzyme remains in a coupled state. Besides its effects on excitation-contraction coupling in response to stretch, eNOS acts as an "endogenous beta-blocker" by restoring the sympathovagal balance, opposing excessive hypertrophy as well as promoting vasodilatation and neoangiogenesis, thereby contributing to tissue repair. As eNOS was also shown to mediate the beneficial effects of cardiovascular drugs commonly used in patients with heart failure, strategies to increase its expression and/or coupled catalytic activity in the myocardium offer new therapeutic avenues for the treatment of this disease.

Nitric oxide and the heart: update on new paradigms.

The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with the help of experiments using genetic deletion or overexpression of the three nitric oxide synthase (NOS) isoforms in cardiomyocytes. Contrary to the effects of exogenous, pharmacologic NO donors, signaling by endogenous NO is restricted to intracellular effectors co-localized with NOS in specific subcellular compartments. This both ensures coordinate signaling by the three NOS isoforms on different aspects of the cardiomyocyte function and helps to reconcile previous apparently contradictory observations based on the use of non-isoform-specific NOS inhibitors. This review will emphasize the role of NOS on excitation-contraction coupling in the normal and diseased heart. Endothelial NOS and neuronal NOS contribute to maintain an adequate balance between adrenergic and vagal input to the myocardium and participate in the early and late phases of the Frank-Starling adaptation of the heart. At the early phases of cardiac diseases, inducible NOS reinforces these effects, which may become maladaptive as disease progresses.

Regulation of the mammalian heart function by nitric oxide.

The mammalian heart expresses all three isoforms of nitric oxide synthases (NOS) in diverse cell types of the myocardium. Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart. They also attenuate the beta1-/beta2-adrenergic increase in inotropy and chronotropy, and reinforce the pre- and post-synaptic vagal control of cardiac contraction. By doing so, the NOS protect the heart against excessive stimulation by catecholamines, just as an "endogenous beta-blocker". In the ischemic and failing myocardium, induced iNOS further reinforces this effect, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and infarcted heart, but its role (compensatory or deleterious) is less clear. In addition to their direct regulation of contractility, the NOS modulate oxygen consumption, substrate utilization, sensitivity to apoptosis, hypertrophy and regenerative potential, all of which illustrate the pleiotropic effects of this radical on the cardiac cell biology.

Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction.

BACKGROUND: In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium. METHODS AND RESULTS: We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the alpha-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold) NOS3 overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32, P<0.001); an attenuation of the beta-adrenergic positive inotropic response (isoproterenol, 10(-7) mol/L: 62.1+/-7.8% versus 90.8+/-8.0% of maximum Ca2+ response; n=10 to 17; P<0.05); a potentiation of the muscarinic negative chronotropic response (carbamylcholine, 3.10(-8) mol/L: -63.9+/-14% versus -27.7+/-5.6% of basal rate; n=8 to 10; P<0.05), confirmed by telemetry in vivo; and an attenuation of the accentuated antagonism of beta-adrenergically stimulated contraction (-14.6+/-1.5% versus -3.5+/-1.5; n=7 to 11; P<0.05). Cardiomyocyte NOS inhibition reversed all 4 effects (P<0.05). CONCLUSIONS: Moderate overexpression of NOS3, targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte NOS3 may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.

Prognosis of hematologic malignancies does not predict intensive care unit mortality.

OBJECTIVE: To evaluate the correlation between specific prognosis of hematologic malignancies on the one hand and intensive care unit and hospital mortality in critically ill patients with hematologic malignancies on the other hand. DESIGN: Observational study during a 10-yr period. SETTING: A 22-bed medical-surgical intensive care unit. PATIENTS: A total of 84 consecutive patients with nonterminal hematologic malignancies with medical complications requiring intensive care. INTERVENTIONS: None. MEASUREMENTS: Demographic factors, acute physiology and organ dysfunction scores, microbiology, therapeutic support, and hematologic factors data on admission and during the intensive care unit stay were collected, together with mortality follow-up. Based on specific-disease prognostic factors and related published survival curves, the prognosis of hematologic malignancies was assessed and defined as good, intermediate, or poor according to a 3-yr survival probability of >50%, 20-50%, or <20%, respectively. MAIN RESULTS: Prognosis of hematologic malignancies does not predict intensive care unit or hospital mortality and almost reaches significance for 6-mo mortality (53%, 71%, and 84% rate for patients with good, intermediate, and poor prognosis, respectively, p =.058), but it determines long-term survival (p =.008). Intensive care unit, hospital, and 6-mo overall mortality rates were 38%, 61%, and 75%, respectively. Using multivariate analysis, intensive care unit mortality was best predicted on admission by respiratory failure and fungal infection, whereas hospital mortality was predicted by the number of organ failures, the bone marrow transplant status, and the presence of fungal infection. The Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II had no prognostic value, whereas the difference of the Multiple Organ Dysfunction Score between at the time of admission and at day 5 allowed quick prediction of hospital mortality. Diseases with the poorest 6-mo prognosis were acute myeloid leukemia and non-Hodgkin lymphoma. CONCLUSION The severity of the underlying hematologic malignancies does not influence intensive care unit or hospital mortality. Short-term prognosis is exclusively predicted by acute organ dysfunctions and by a pathogen's aggressiveness. Therefore, reluctance to admit patients with nonterminal hematologic malignancies to the intensive care unit based only on the prognosis of their underlying hematologic malignancy does not seem justified.