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1.
Lancet ; 404(10453): 659-669, 2024 Aug 17.
Article in English | MEDLINE | ID: mdl-39153816

ABSTRACT

BACKGROUND: Increased protein provision might ameliorate muscle wasting and improve long-term outcomes in critically ill patients. The aim of the PRECISe trial was to assess whether higher enteral protein provision (ie, 2·0 g/kg per day) would improve health-related quality of life and functional outcomes in critically ill patients who were mechanically ventilated compared with standard enteral protein provision (ie, 1·3 g/kg per day). METHODS: The PRECISe trial was an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in five Dutch hospitals and five Belgian hospitals. Inclusion criteria were initiation of invasive mechanical ventilation within 24 h of intensive care unit (ICU) admission and an expected duration of invasive ventilation of 3 days or longer. Exclusion criteria were contraindications for enteral nutrition, moribund condition, BMI less than 18 kg/m2, kidney failure with a no dialysis code, or hepatic encephalopathy. Patients were randomly assigned to one of four randomisation labels, corresponding with two study groups (ie, standard or high protein; two labels per group) in a 1:1:1:1 ratio through an interactive web-response system. Randomisation was done via random permuted-block randomisation in varying block sizes of eight and 12, stratified by centre. Participants, care providers, investigators, outcome assessors, data analysts, and the independent data safety monitoring board were all blinded to group allocation. Patients received isocaloric enteral feeds that contained 1·3 kcal/mL and 0·06 g of protein/mL (ie, standard protein) or 1·3 kcal/mL and 0·10 g of protein/mL (ie, high protein). The study-nutrition intervention was limited to the time period during the patient's ICU stay in which they required enteral feeding, with a maximum of 90 days. The primary outcome was EuroQoL 5-Dimension 5-level (EQ-5D-5L) health utility score at 30 days, 90 days, and 180 days after randomisation, adjusted for baseline EQ-5D-5L health utility score. This trial was registered with ClinicalTrials.gov (NCT04633421) and is closed to new participants. FINDINGS: Between Nov 19, 2020, and April 14, 2023, 935 patients were randomly assigned. 335 (35·8%) of 935 patients were female and 600 (64·2%) were male. 465 (49·7%) of 935 were assigned to the standard protein group and 470 (50·3%) were assigned to the high protein group. 430 (92·5%) of 465 patients in the standard protein group and 419 (89·1%) of 470 patients in the high protein group were assessed for the primary outcome. The primary outcome, EQ-5D-5L health utility score during 180 days after randomisation (assessed at 30 days, 90 days, and 180 days), was lower in patients allocated to the high protein group than in those allocated to the standard protein group, with a mean difference of -0·05 (95% CI -0·10 to -0·01; p=0·031). Regarding safety outcomes, the probability of mortality during the entire follow-up was 0·38 (SE 0·02) in the standard protein group and 0·42 (0·02) in the high protein group (hazard ratio 1·14, 95% CI 0·92 to 1·40; p=0·22). There was a higher incidence of symptoms of gastrointestinal intolerance in patients in the high protein group (odds ratio 1·76, 95% CI 1·06 to 2·92; p=0·030). Incidence of other adverse events did not differ between groups. INTERPRETATION: High enteral protein provision compared with standard enteral protein provision resulted in worse health-related quality of life in critically ill patients and did not improve functional outcomes during 180 days after ICU admission. FUNDING: Netherlands Organisation for Healthcare Research and Development and Belgian Health Care Knowledge Centre.


Subject(s)
Critical Illness , Dietary Proteins , Enteral Nutrition , Quality of Life , Humans , Male , Female , Critical Illness/therapy , Belgium , Double-Blind Method , Middle Aged , Netherlands , Enteral Nutrition/methods , Aged , Dietary Proteins/administration & dosage , Recovery of Function , Respiration, Artificial , Intensive Care Units
2.
Clin Chem Lab Med ; 62(7): 1438-1449, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38278526

ABSTRACT

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.


Subject(s)
Inflammation , Monocytes , Sepsis , Adult , Aged , Female , Humans , Male , Middle Aged , Flow Cytometry , HLA-DR Antigens/metabolism , Monocytes/metabolism , Monocytes/immunology , NADPH Oxidase 2/metabolism , Receptors, Complement 3b , Receptors, IgG/metabolism , Receptors, IgG/blood , Sepsis/blood , Sepsis/immunology
3.
Eur J Anaesthesiol ; 39(1): 58-66, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34783683

ABSTRACT

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.


Subject(s)
Cardiac Surgical Procedures , Hypnosis , Virtual Reality , Adult , Anxiety/diagnosis , Anxiety/epidemiology , Anxiety/therapy , Cardiac Surgical Procedures/adverse effects , Female , Humans , Intensive Care Units , Male , Pain Management , Phobic Disorders , Prospective Studies
4.
Sci Rep ; 11(1): 20288, 2021 10 13.
Article in English | MEDLINE | ID: mdl-34645893

ABSTRACT

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.


Subject(s)
Myeloid Cells/metabolism , Sepsis/physiopathology , Adult , Aged , Algorithms , Area Under Curve , Bacteremia/diagnosis , Biomarkers/metabolism , Critical Care , Dendritic Cells/cytology , Female , Flow Cytometry , GPI-Linked Proteins/metabolism , Granulocytes/cytology , Humans , Immunophenotyping , Inflammation , Intensive Care Units , Interleukin-3 Receptor alpha Subunit/metabolism , Lipopolysaccharide Receptors/metabolism , Machine Learning , Macrophages/cytology , Male , Middle Aged , Monocytes/cytology , Phenotype , ROC Curve , Receptors, IgG/metabolism
5.
J Am Coll Emerg Physicians Open ; 2(3): e12484, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34189521

ABSTRACT

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.

6.
Trials ; 21(1): 330, 2020 Apr 15.
Article in English | MEDLINE | ID: mdl-32293517

ABSTRACT

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.


Subject(s)
Anxiety/prevention & control , Cardiac Surgical Procedures/psychology , Hypnosis/methods , Pain/prevention & control , Virtual Reality Exposure Therapy/methods , Adult , Aged , Aged, 80 and over , Belgium/epidemiology , Cardiac Surgical Procedures/adverse effects , Case-Control Studies , Fatigue/prevention & control , Feasibility Studies , Female , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Prospective Studies , Virtual Reality
7.
Crit Care ; 20(1): 184, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27334879

ABSTRACT

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.


Subject(s)
Capnography/methods , Capnography/standards , Respiratory Dead Space/physiology , Capnography/trends , Humans , Intensive Care Units/organization & administration , Pulmonary Embolism/diagnosis , Respiration, Artificial/methods , Respiration, Artificial/standards , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/therapy , Thrombolytic Therapy , Ventilation-Perfusion Ratio/physiology , Ventilator Weaning/trends
8.
World J Transplant ; 6(1): 220-32, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-27011921

ABSTRACT

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.

9.
Ann Biol Clin (Paris) ; 73(2): 137-49, 2015.
Article in French | MEDLINE | ID: mdl-25847735

ABSTRACT

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.


Subject(s)
Blood Coagulation Disorders/diagnosis , Blood Coagulation Tests/methods , Diagnostic Tests, Routine/methods , Thrombin/metabolism , Blood Coagulation Disorders/blood , Blood Coagulation Tests/statistics & numerical data , Clinical Laboratory Services/standards , Diagnostic Tests, Routine/statistics & numerical data , Humans , Partial Thromboplastin Time/methods , Partial Thromboplastin Time/statistics & numerical data , Thrombin/analysis
10.
Burns ; 40(7): e57-60, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24685066

ABSTRACT

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%.


Subject(s)
Burns/complications , Hemofiltration/methods , Hypercapnia/therapy , Oxygenators , Respiratory Distress Syndrome/complications , Smoke Inhalation Injury/complications , Extracorporeal Circulation , Hemofiltration/instrumentation , Humans , Hypercapnia/etiology , Male , Middle Aged , Severity of Illness Index
11.
J Burn Care Res ; 35(4): e234-9, 2014.
Article in English | MEDLINE | ID: mdl-24419142

ABSTRACT

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.


Subject(s)
Burn Units , Burns/therapy , Practice Patterns, Physicians'/statistics & numerical data , Calorimetry, Indirect , Dissection , Europe/epidemiology , Fluid Therapy , Humans , Laser-Doppler Flowmetry , Nutrition Assessment , Resuscitation/methods , Resuscitation/statistics & numerical data , Surveys and Questionnaires
12.
Intensive Care Med ; 38(8): 1326-35, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22735856

ABSTRACT

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.


Subject(s)
Blood Coagulation Disorders/mortality , Hospital Mortality , Shock, Septic/mortality , Thrombin/metabolism , Aged , Anticoagulants/therapeutic use , Antithrombin III/analysis , Blood Coagulation Factors/analysis , Female , Fibrin/metabolism , Humans , Intensive Care Units , Logistic Models , Longitudinal Studies , Male , Middle Aged , Partial Thromboplastin Time , Prospective Studies , Protein C/analysis , Prothrombin Time
13.
Curr Heart Fail Rep ; 4(1): 18-25, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17386181

ABSTRACT

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.


Subject(s)
Myocardium/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism , Ventricular Remodeling , Adrenergic beta-Antagonists/pharmacology , Animals , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Myocardial Contraction/drug effects , Myocardial Ischemia/metabolism , Myocardial Ischemia/physiopathology , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Vasodilator Agents/pharmacology , Ventricular Remodeling/drug effects
14.
Ann N Y Acad Sci ; 1047: 173-82, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16093495

ABSTRACT

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.


Subject(s)
Myocardium/chemistry , Nitric Oxide Synthase/analysis , Nitric Oxide/physiology , Electrophysiology , Heart Diseases/enzymology , Heart Diseases/etiology , Humans , Models, Biological , Myocardium/enzymology , Nitric Oxide Synthase/metabolism
15.
Article in English | MEDLINE | ID: mdl-15985381

ABSTRACT

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.


Subject(s)
Heart/physiology , Nitric Oxide Synthase/chemistry , Nitric Oxide/metabolism , Animals , Catecholamines/metabolism , Diastole , Humans , Models, Biological , Muscles/metabolism , Myocardial Contraction , Myocardial Infarction/metabolism , Myocardium/metabolism , Nitric Oxide Synthase/metabolism , Protein Isoforms , Receptors, Adrenergic, beta/metabolism , Signal Transduction , Systole
16.
Circulation ; 110(17): 2666-72, 2004 Oct 26.
Article in English | MEDLINE | ID: mdl-15492314

ABSTRACT

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.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Myocardial Contraction , Myocytes, Cardiac/enzymology , Nitric Oxide Synthase/genetics , Animals , Caveolae/chemistry , Caveolin 3 , Caveolins/analysis , Gene Expression , Isoproterenol/antagonists & inhibitors , Mice , Mice, Transgenic , Muscarinic Agonists/pharmacology , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Neural Inhibition , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Vagus Nerve/physiology
17.
Crit Care Med ; 30(10): 2260-70, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12394954

ABSTRACT

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.


Subject(s)
Hematologic Neoplasms/mortality , APACHE , Adult , Female , Hematologic Neoplasms/complications , Hematologic Neoplasms/therapy , Hospital Mortality , Humans , Intensive Care Units , Male , Middle Aged , Multivariate Analysis , Prognosis , Risk Factors , Severity of Illness Index , Survival Analysis
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