Mortality Attributable to Bloodstream Infections Caused by Different Carbapenem-Resistant Gram-Negative Bacilli: Results From a Nationwide Study in Italy (ALARICO Network).

BACKGROUND: Our aim was to analyze mortality attributable to carbapenem-resistant (CR) gram-negative bacilli (GNB) in patients with bloodstream infections (BSIs). METHODS: Prospective multicentric study including patients with GNB-BSI from 19 Italian hospitals (June 2018-January 2020). Patients were followed-up to 30 days. Primary outcomes were 30-day mortality and attributable mortality. Attributable mortality was calculated in the following groups: Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales, metallo-ß-lactamases (MBL)-producing Enterobacterales, CR-Pseudomonas aeruginosa (CRPA), CR-Acinetobacter baumannii (CRAB). A multivariable analysis with hospital fixed-effect was built to identify factors associated with 30-day mortality. Adjusted OR (aORs) were reported. Attributable mortality was calculated according to the DRIVE-AB Consortium. RESULTS: Overall, 1276 patients with monomicrobial GNB BSI were included: 723/1276 (56.7%) carbapenem-susceptible (CS)-GNB, 304/1276 (23.8%) KPC-, 77/1276 (6%) MBL-producing CRE, 61/1276 (4.8%) CRPA, and 111/1276 (8.7%) CRAB BSI. Thirty-day mortality in patients with CS-GNB BSI was 13.7% compared to 26.6%, 36.4%, 32.8% and 43.2% in patients with BSI by KPC-CRE, MBL-CRE, CRPA and CRAB, respectively (P < .001). On multivariable analysis, age, ward of hospitalization, SOFA score, and Charlson Index were factors associated with 30-day mortality, while urinary source of infection and early appropriate therapy resulted protective factors. Compared to CS-GNB, MBL-producing CRE (aOR 5.86, 95% CI 2.72-12.76), CRPA (aOR 1.99, 95% CI 1.48-5.95) and CRAB (aOR 2.65, 95% CI 1.52-4.61) were significantly associated with 30-day mortality. Attributable mortality rates were 5% for KPC-, 35% for MBL, 19% for CRPA, and 16% for CRAB. CONCLUSIONS: In patients with BSIs, carbapenem-resistance is associated with an excess of mortality, with MBL-producing CRE carrying the highest risk of death.

An integrated mathematical model of the human cardiopulmonary system: model development.

Several cardiovascular and pulmonary models have been proposed in the last few decades. However, very few have addressed the interactions between these two systems. Our group has developed an integrated cardiopulmonary model (CP Model) that mathematically describes the interactions between the cardiovascular and respiratory systems, along with their main short-term control mechanisms. The model has been compared with human and animal data taken from published literature. Due to the volume of the work, the paper is divided in two parts. The present paper is on model development and normophysiology, whereas the second is on the model's validation on hypoxic and hypercapnic conditions. The CP Model incorporates cardiovascular circulation, respiratory mechanics, tissue and alveolar gas exchange, as well as short-term neural control mechanisms acting on both the cardiovascular and the respiratory functions. The model is able to simulate physiological variables typically observed in adult humans under normal and pathological conditions and to explain the underlying mechanisms and dynamics.

An integrated mathematical model of the human cardiopulmonary system: model validation under hypercapnia and hypoxia.

A novel integrated physiological model of the interactions between the cardiovascular and respiratory systems has been in development for the past few years. The model has hundreds of parameters and variables representing the physical and physiological properties of the human cardiopulmonary system. It can simulate many dynamic states and scenarios. The description of the model and the results in normal resting conditions were presented in a companion paper (Albanese A, Cheng L, Ursino M, Chbat NW.Am J Physiol Heart Circ Physiol 310: 2016; doi:10.1152/ajpheart.00230.2014), where model predictions were compared against average population data from literature. However, it is also essential to test the model in abnormal or pathological conditions to prove its consistency. Hence, in this paper, we concentrate on testing the cardiopulmonary model under hypercapnic and hypoxic conditions, by comparing model's outputs to population-averaged cardiorespiratory data reported in the literature. The utility of this comprehensive model is demonstrated by testing the internal consistency of the simulated responses of a significant number of cardiovascular variables (heart rate, arterial pressure, and cardiac output) and respiratory variables (tidal volume, respiratory rate, minute ventilation, alveolar O2 and CO2 partial pressures) over a wide range of perturbations and conditions; namely, hypercapnia at 3-7% CO2 levels and hypoxia at 7-9% O2 levels with controlled CO2(isocapnic hypoxia) and without controlled CO2(hypocapnic hypoxia). Finally, a sensitivity analysis is performed to analyze the role of the main cardiorespiratory control mechanisms triggered by hypercapnia and hypoxia.

Heart-Lung Interactions During Mechanical Ventilation: Analysis via a Cardiopulmonary Simulation Model.

Heart-lung interaction mechanisms are generally not well understood. Mechanical ventilation, for example, accentuates such interactions and could compromise cardiac activity. Thereby, assessment of ventilation-induced changes in cardiac function is considered an unmet clinical need. We believe that mathematical models of the human cardiopulmonary system can provide invaluable insights into such cardiorespiratory interactions. In this article, we aim to use a mathematical model to explain heart-lung interaction phenomena and provide physiologic hypotheses to certain contradictory experimental observations during mechanical ventilation. To accomplish this task, we highlight three model components that play a crucial role in heart-lung interactions: 1) pericardial membrane, 2) interventricular septum, and 3) pulmonary circulation that enables pulmonary capillary compression due to lung inflation. Evaluation of the model's response under simulated ventilation scenarios shows good agreement with experimental data from the literature. A sensitivity analysis is also presented to evaluate the relative impact of the model's highlighted components on the cyclic ventilation-induced changes in cardiac function.

Neurobrucellosis associated with syndrome of inappropriate antidiuretic hormone with resultant diabetes insipidus and hypothyroidism.

Neurological involvement of the central nervous system in brucellosis is uncommon. We describe a rare case of meningoencephalitis due to Brucella melitensis infection, associated with the syndrome of inappropriate antidiuretic hormone secretion and leading to diabetes insipidus and hypothyroidism. Neurobrucellosis, although rare, should be considered in cases of neurological disease of unknown etiology.

Effects of septum and pericardium on heart-lung interactions in a cardiopulmonary simulation model.

Mechanical heart-lung interactions are often overlooked in clinical settings. However, their impact on cardiac function can be quite significant. Mechanistic physiology-based models can provide invaluable insights into such cardiorespiratory interactions, which occur not only under external mechanical ventilatory support but in normal physiology as well. In this work, we focus on the cardiac component of a previously developed mathematical model of the human cardiopulmonary system, aiming to improve the model's response to the intrathoracic pressure variations that are associated with the respiratory cycle. Interventricular septum and pericardial membrane are integrated into the existing model. Their effect on the overall cardiac response is explained by means of comparison against simulation results from the original model as well as experimental data from literature.

End-inspiratory occlusion in the presence of intrinsic PEEP.

Typical modern mechanical ventilators offer the clinician the possibility of automatically performing end-inspiratory occlusion maneuvers. The static conditions induced by such maneuvers are indeed favorable to estimating patient's respiratory mechanics in terms of total resistance (R) and elastance (E). These are parameters of wide clinical interest. However, in the presence of intrinsic PEEP, the standard formula used to compute E via the occlusion maneuver is known to be inaccurate. In this paper we propose an alternative method for the estimation of E via the occlusion maneuver that eliminates the bias by leveraging concepts derived from physiological modeling of the respiratory system dynamics. The proposed method is also capable of accounting for respiratory efforts triggering the breath, and hence can be applied in both passive and spontaneously breathing conditions.

Patient emulator: a tool for testing mechanical ventilation therapies.

Several modes of mechanical ventilation are clinically available. The differences among them in terms of efficacy and patient outcomes are not clear yet. Testing and comparison of mechanical ventilation modes via human or animal trials is a very challenging and costly process. In this paper, we present the patient emulator (PE), a novel system that can be used as a platform for in-silico testing of mechanical ventilation therapies. The system is based on a large-scale integrated mathematical model of the human cardiopulmonary system interfaced with a physical ventilator via a controlled piston-cylinder actuator. The performance of the proposed PE is demonstrated by simulating a realistic pressure support ventilation step protocol. The PE-simulated patient's response is then compared against averaged data from 33 human subjects. The agreement between the simulated data and their experimental counterparts shows the potential of the proposed PE to be used as a substitute for or in addition to conventional animal and human trials.

Noninvasive Estimation of Respiratory Mechanics in Spontaneously Breathing Ventilated Patients: A Constrained Optimization Approach.

This paper presents a method for breath-by-breath noninvasive estimation of respiratory resistance and elastance in mechanically ventilated patients. For passive patients, well-established approaches exist. However, when patients are breathing spontaneously, taking into account the diaphragmatic effort in the estimation process is still an open challenge. Mechanical ventilators require maneuvers to obtain reliable estimates for respiratory mechanics parameters. Such maneuvers interfere with the desired ventilation pattern to be delivered to the patient. Alternatively, invasive procedures are needed. The method presented in this paper is a noninvasive way requiring only measurements of airway pressure and flow that are routinely available for ventilated patients. It is based on a first-order single-compartment model of the respiratory system, from which a cost function is constructed as the sum of squared errors between model-based airway pressure predictions and actual measurements. Physiological considerations are translated into mathematical constraints that restrict the space of feasible solutions and make the resulting optimization problem strictly convex. Existing quadratic programming techniques are used to efficiently find the minimizing solution, which yields an estimate of the respiratory system resistance and elastance. The method is illustrated via numerical examples and experimental data from animal tests. Results show that taking into account the patient effort consistently improves the estimation of respiratory mechanics. The method is suitable for real-time patient monitoring, providing clinicians with noninvasive measurements that could be used for diagnosis and therapy optimization.

Cardiorespiratory adaptation to breath-holding in air: Analysis via a cardiopulmonary simulation model.

Apnea via breath-holding (BH) in air induces cardiorespiratory adaptation that involves the activation of several reflex mechanisms and their complex interactions. Hence, the effects of BH in air on cardiorespiratory function can become hardly predictable and difficult to be interpreted. Particularly, the effect on heart rate is not yet completely understood because of the contradicting results of different physiological studies. In this paper we apply our previously developed cardiopulmonary model (CP Model) to a scenario of BH with a twofold intent: (1) further validating the CP Model via comparison against experimental data; (2) gaining insights into the physiological reasoning for such contradicting experimental results. Model predictions agreed with published experimental animal and human data and indicated that heart rate increases during BH in air. Changes in the balance between sympathetic and vagal effects on heart rate within the model proved to be effective in inverting directions of the heart rate changes during BH. Hence, the model suggests that intra-subject differences in such sympatho-vagal balance may be one of the reasons for the contradicting experimental results.

Constrained optimization for noninvasive estimation of work of breathing.

This paper presents a technique for noninvasive estimation of respiratory muscle effort (also known as work of breathing, WOB) in mechanically ventilated patients. Continual and real-time assessment of the patient WOB is desirable, as it helps the clinician make decisions about increasing or decreasing mechanical respiratory support. The technique presented is based on a physiological model of the respiratory system, from which a cost function is constructed as the sum of squared errors between model-based airway pressure predictions and actual measurements. Quadratic programming methods are used to minimize this cost function. An experimental example on animal data shows the effectiveness of the technique.

Real-time noninvasive estimation of intrapleural pressure in mechanically ventilated patients: a feasibility study.

A method for real-time noninvasive estimation of intrapleural pressure in mechanically ventilated patients is proposed. The method employs a simple first-order lung mechanics model that is fitted in real-time to flow and pressure signals acquired non-invasively at the opening of the patient airways, in order to estimate lung resistance (RL), lung compliance (CL) and intrapleural pressure (Ppl) continuously in time. Estimation is achieved by minimizing the sum of squared residuals between measured and model predicted airway pressure using a modified Recursive Least Squares (RLS) approach. Particularly, two different RLS algorithms, namely the conventional RLS with Exponential Forgetting (EF-RLS) and the RLS with Vector-type Forgetting Factor (VFF-RLS), are considered in this study and their performances are first evaluated using simulated data. Simulations suggest that the conventional EF-RLS algorithm is not suitable for our purposes, whereas the VFF-RLS method provides satisfactory results. The potential of the VFF-RLS based method is then proved on experimental data collected from a mechanically ventilated pig. Results show that the method provides continuous estimated lung resistance and compliance in normal physiological ranges and pleural pressure in good agreement with invasive esophageal pressure measurements.

Myocarditis and cardiomyopathy HIV associated.

Heart muscle involvement associated with human immunodeficiency virus (HIV) infection may present as myocarditis, dilated cardiomyopathy or as isolated left or right ventricular dysfunction. Histopathological and ultra structural findings with different degrees of cardiac-chamber dilation have been described and an important role of the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 has been suggested. We present a case of myocarditis in a 47-year-old woman with HIV associated cardiomyopathy, focussing attention on heart muscle involvement in HIV disease.

Mephedrone (4-methylmethcathinone; 'meow meow'): chemical, pharmacological and clinical issues.

BACKGROUND: Recently, those substances deriving from the active ingredient of the Khat plant, cathinone, have been rising in popularity. Indeed, 4-methylmethcathinone (mephedrone; 'meow meow' and others) has been seen by some as a cheaper alternative to other classified recreational drugs. AIMS: We aimed here at providing a state-of-the-art review on mephedrone history and prevalence of misuse, chemistry, pharmacology, legal status, product market appearance, clinical/management and related fatalities. METHODS: Because of the limited evidence, some of the information here presented has been obtained from user reports/drug user-orientated web sites. The most common routes for mephedrone recreational use include insufflation and oral ingestion. It elicits stimulant and empathogenic effects similar to amphetamine, methylamphetamine, cocaine and MDMA. Due to its sympathomimetic actions, mephedrone may be associated with a number of both physical and psychopathological side effects. Recent preliminary analysis of recent UK data carried out in 48 related cases have provided positive results for the presence of mephedrone at postmortem. DISCUSSION AND CONCLUSIONS: Within the UK, diffusion of mephedrone may have been associated with an unprecedented combination of a particularly aggressive online marketing policy and a decreasing availability/purity of both ecstasy and cocaine. Mephedrone has been recently classified in both the UK and in a number of other countries as a measure to control its availability. Following this, a few other research psychoactives have recently entered the online market as yet unregulated substances that may substitute for mephedrone. Only international collaborative efforts may be able to tackle the phenomenon of the regular offer of novel psychoactive drugs.

Revelation of Brugada electrocardiographic pattern during a febrile state.

The prevalence of the Brugada-type ECG and its natural history are still unclear. The Brugada syndrome is usually identified by a characteristic Brugada-type ECG that consists of ST elevation of a coved type in the precordial leads V1 to V3 and ventricular fibrillation that can lead to sudden cardiac death, although affected individuals may have a normal ECG. Mutations in the cardiac sodium channel gene SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent Na+ channel (Na(v)1.5), are identified in 15-30% of patients with Brugada syndrome. Most SCN5A mutations lead to a 'loss-of-function' phenotype, reducing the Na+ current during the early phases of the action potential. Several nongenetic factors have been mentioned in the literature as possible inductors of the ECG pattern resembling Brugada syndrome. As such, a Brugada-type ECG may appear in some patients during febrile states and in those who are under the influence of cocaine and pharmaceutical drugs that have a sodium channel-blocking effect. It has been also reported that chest pain and ST elevation Brugada pattern occur during febrile states. We present a case of revelation of Brugada pattern in a 61-year-old Italian man complaining of pain in the left hipocondrium during a febrile state. Also this report confirms that Brugada pattern should be considered as one of differential diagnoses when we examine the patients during a febrile state.

A comprehensive cardiopulmonary simulation model for the analysis of hypercapnic respiratory failure.

We developed a new comprehensive cardiopulmonary model that takes into account the mutual interactions between the cardiovascular and the respiratory systems along with their short-term regulatory mechanisms. The model includes the heart, systemic and pulmonary circulations, lung mechanics, gas exchange and transport equations, and cardio-ventilatory control. Results show good agreement with published patient data in case of normoxic and hyperoxic hypercapnia simulations. In particular, simulations predict a moderate increase in mean systemic arterial pressure and heart rate, with almost no change in cardiac output, paralleled by a relevant increase in minute ventilation, tidal volume and respiratory rate. The model can represent a valid tool for clinical practice and medical research, providing an alternative way to experience-based clinical decisions.