Fibrilación ventricular con parada cardiorrespiratoria durante la administración de dexmedetomidina / Ventricular fibrillation and cardiorespiratory arrest during dexmedetomidine administration

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5-year mortality in cardiac surgery patients with low cardiac output syndrome treated with levosimendan: prognostic evaluation of nt-probnp and c-reactive protein.

AIM: To determine the clinical risk factors predictive of the 5--year mortality in patients with low cardiac output syndrome (LCOS) after cardiac surgery. In addition, to assess the influence of inflammation and myocardial dysfunction severity, as measured by C--reactive protein (CRP) and N--terminal pro--brain natriuretic peptide (NT--proBNP) concentrations, on outcome. METHODS: We studied 30 patients who underwent cardiac surgery and developed postoperative LCOS requiring inotropic support for longer than 48 hours after intensive care unit (ICU) admission. All patients received a 24--hour infusion of levosimendan after study enrolment. We measured the following at baseline, 24 h, 48 h and 7 days: clinical data, serum NT--proBNP and serum CRP levels. Patients were followed--up at 5 years for death by any cause. A risk--adjusted Cox proportional hazards regression model was used for statistical analysis. Hazard ratios and their 95% confidence intervals (CI) are presented. RESULTS: The 5--year mortality was 36.6% (n = 11). The predictors of 5--year mortality were the presence of dilated cardiomyopathy (HR = 36.909; 95% CI: 1.901-716.747; P = 0.017), a higher central venous pressure (CVP) at 48 hours (HR = 2.686; 95% CI: 1.383-5.214; P = 0.004), and lower CRP levels on day 7 (HR = 0.963; 95% CI: 0.933-0.994; P = 0.021). NT--proBNP levels showed a trend to higher initial levels in survivors without statistical significance, but were not associated with 5--year mortality. CONCLUSIONS: The presence of dilated cardiomyopathy, elevated CVP at 48 h and reduced CRP levels on day 7 predicted 5--year mortality in patients who developed postoperative LCOS after cardiac surgery. NT--proBNP levels in the first postoperative week were not predictors of long--term outcomes.

Ausencia de vena yugular interna derecha, hallazgo ecográfico / Absence of a right internal yugular vein, an ultrasound finding

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Predictors of long-term mortality in patients with cirrhosis undergoing cardiac surgery.

AIM: Little is known regarding the long-term outcome in cirrhotic patients undergoing cardiac surgery. The objective of this study was to identify preoperative and postoperative mortality risk factors and to determine the best predictors of long-term outcome. METHODS: Fifty-eight consecutive cirrhotic patients requiring cardiac surgery between January 2004 and January 2009 were prospectively studied at our institution. Seven patients (12%) died. A complete follow-up was performed in the whole survival group until November 2012 (mean 46±28 months). Variables usually measured on admission and during the first 24 h of the postoperative period were evaluated together with cardiac surgery scores (Parsonnet, EuroSCORE), liver scores (Child-Turcotte-Pugh, Model for End-Stage Liver Disease, United Kingdom End-Stage Liver Disease score), and ICU scores (Acute Physiology and Chronic Health Evaluation II and III, Simplified Acute Physiology Score II and III, Sequential Organ Failure Assessment). RESULTS: Twelve patients (23.5%) died during follow-up; six were Child class A and six class B. Comparing survivors vs. non-survivors using univariate analysis, variables associated with better long-term outcome were lower arterial lactate 24 h after admission (1.7±0.4 vs. 2.1±0.7 mmol·L(-1), P=0.03) and higher urine output in the first 24 h (2029±512 vs. 1575±627 mL, P=0.03). The receiver operating characteristic curve showed that the Simplified Acute Physiology Score III score had the best predictive value for long-term outcome (AUC: 77.4±0.76%; sensitivity: 83.3%; specificity: 64.9%, P=0.005). Multivariate analysis identified Simplified Acute Physiology Score III score (P=0.02) and urine output in the first 24 h (P=0.02) as independent factors associated with long-term outcome. Long-term survival was 82.4% for Child A, 47.6% for Child B and 33.3% for Child C (P=0.001). CONCLUSION: Long-term survival in cirrhotic patients requiring cardiac surgery is a more valuable prognostic measure than short-term survival. Urine output in the first 24 h may be a valuable predictor of long-term outcome in these patients. The Simplified Acute Physiology Score III is also useful.

Tratamiento de úlceras severas de pie diabético con factor de crecimiento epidérmico recombinante (Heberprot-P). Análisis retrospectivo de los resultados obtenidos en Argentina / Tratamento de úlceras severas de pé diabético com fator de crescimento epidérmico recombinante (Heberprot-P). Análise retrospectiva dos resultados obtidos na Argentina / Treatment of severe diabetic foot ulcers with recombinant human epidermal growth factor (Heberprot-P®. Retrospective analysis of the results obtained in Argentina

Antecedentes: Los tratamientos actualmente disponibles para aquellos pacientes que presentan úlceras severas por pie diabético incluyen distintas medidas terapéuticas, tanto médicas como quirúrgicas. Sin embargo, la tasa de amputación en los pacientes con úlceras severas continúa siendo elevada. La administración local de factor de crecimiento epidérmico humano para promover la granulación y la cicatrización de úlceras crónicas severas por pie diabético es una nueva alternativa que se ha comenzado a utilizar en la práctica médica enciertos países. El factor de crecimiento epidérmico humano recombinante es una alternativa de tratamiento actualmente disponible en Argentina.Objetivo: El objetivo del presente trabajo es evaluar los resultados del tratamiento de las úlceras severas de pie diabético (Wagner 3-4) con factor de crecimiento epidérmico (Heberprot-P) utilizado en la práctica médica habitual. Métodos: Se incluyeron en el presente análisis retrospectivo 124 pacientes (67% hombres y 33% mujeres) con diagnóstico de Pie Diabético (42% Wagner 3 y 57% Wagner 4) que fueron tratados con una dosis de 75 μg del factor de crecimiento epidérmico, Heberprot-P®, administrado por peri e intralesionalmente desde Marzo de 2009 a Diciembre de 2011. Los pacientes fueron atendidos en forma ambulatoria en los servicios de nutrición y cirugía vascular de hospitales públicos y privados de la Argentina. Resultados: El 91% de los pacientes presentó respuesta de granulación parcial. La tasa de respuesta de granulación total obtenida fue del 70.3%, con una tasa de cierre total de la úlcera en el 69.2% de los pacientes. El tiempo medio de cicatrización fue de 13 semanas. El porcentaje de pacientes amputados y con recurrencia de la lesión luego de 6 meses de seguimiento fue del 10.4% y 4.2% respectivamente. El tratamiento fue bien tolerado. Se presentaron eventos adversos (EAs) en el 29% de los pacientes. Los más frecuentes fueron escalofríos, infección local ...

Antecedentes: Os tratamentos atualmente disponíveis para pacientes que apresentam úlceras severas devido a pé diabético incluem diferentes medidas terapêuticas, tanto médicasquanto cirúrgicas. Entretanto, a taxa de amputação nos pacientes com úlceras severas continua sendo elevada. A administração local de fator de crescimento epidérmico humano para promover a granulação e a cicatrização de úlceras crônicas severas por pé diabético é uma nova alternativa que começou a ser utilizada na prática médica em alguns países. O fator de crescimento epidérmico humano recombinante é uma alternativa de tratamento atualmente disponível na Argentina. Objetivo: O objetivo do presente trabalho é avaliar os resultados do tratamento das úlcerasseveras de pé diabético (Wagner 3-4) com fator de crescimento epidérmico (Heberprot-P®) utilizado na prática médica habitual. Métodos: Incluiram-se na presente análise retrospectiva 124 pacientes (67% homens e 33% mulheres) com diagnóstico de Pé Diabético (42% Wagner 3 e 57% Wagner 4) que foram tratados com uma dose de 75 μg do fator de crescimento epidérmico, Heberprot-P®, administrado por peri e intralesionalmente de março de 2009 a dezembro de 2011. Ospacientes foram atendidos de forma ambulatória nos serviços de nutrição e cirurgia vascular dos hospitais públicos e privados da Argentina. Resultados: 91% dos pacientes apresentou resposta de granulação parcial. A taxa deresposta de granulação total obtida foi de 70.3%, com uma taxa de fechamento total da úlcera em 69.2% dos pacientes. O tempo médio de cicatrização foi de 13 semanas. A porcentagem de pacientes amputados e com recorrência da lesão depois de 6 meses de seguimento foide 10.4% e 4.2% respectivamente. O tratamento foi bem tolerado. Apresentaram-se eventos adversos (EAs) em 29% dos pacientes. Os mais frequentes foram calafrios, infecção local, dorno local de aplicação, febre e hipotensão arterial, de intensidade leve-moderados...

Background: Treatments currently available for patients with severe diabetic foot ulcers include different therapeutic alternatives as well as surgery measures. However, amputationrate in these patients is still high. Local administration of recombinant human epidermal growth factor (Heberprot-P®) to promote granulation and healing of severe chronic ulcers in diabetic foot is the new alternative that has been recently applied in some countries. Thisproduct is currently available in Argentina. Objective: The purpose of the present work is to evaluate the results of the local treatment of severe diabetic foot ulcers (Wagner 3-4) with recombinant human epidermal growth factor (Heberprot-P®) used in daily medical practice. Methods: From March 2009 to December 2011, 124 patients (67% men and 33% women) diagnosed with diabetic foot ulcer (42% Wagner 3 and 57% Wagner 4) who had receivedperi and intralesional administration of 75 μg of Heberprot-P®, were included in this retrospective analysis. These patients were outpatients seen at the nutrition, diabetes and vascular departments of argentine public and private hospitals. Results: Granulation response was shown in 91% of patients. The complete granulation response rate obtained was 70.3%, with a complete ulcer closure in 69.2% of the patients.Mean wound healing time was 13 weeks. After 6 month follow up, there were 10.4% amputations and 4.2% recurrence. The treatment was well tolerated. Adverse events (AEs)were reported in 29% of patients. The most frequent were shiver, local infection, pain in the application site, fever and arterial hypotension, all with mild to moderate intensity. Threeserious AEs (SAEs) were reported: two of them were patients with lower limb infections and the third a case of anaphylactic reaction, all with complete recovery. No deaths were reported. ...

Is short-term amiodarone use post cardiac surgery a cause of acute respiratory failure?

AIM: It was believed that amiodarone-related adverse respiratory effects were found only when receiving amiodarone on a long-term basis, but several reports seem to contradict this hypothesis. The aim of this study was to evaluate, in an intensive care unit (ICU), the possibility of acute respiratory toxicity induced by short-term amiodarone administration following cardiac surgery. METHODS: We conducted a prospective clinical trial of 111 consecutive patients admitted to our ICU after cardiac surgery (basically, coronary artery bypass graft and/or valve surgery) and who received short-term prophylactic amiodarone treatment if they were considered at high risk of developing atrial fibrillation. We administered 900 mg/day intravenously for the first 2 days and 600 mg/day on the following days of the ICU stay. The oxygenation index (PaO2/FiO2 ratio) was evaluated at admission, and then 24 and 48 h postsurgery. RESULTS: One-hundred and two patients were included in the study (9 were excluded for bradycardia), and 25 received amiodarone treatment. The Parsonnet and APACHE II scores differed slightly between the treated and nontreated groups. There were no significant differences between the treated and nontreated groups with respect to left atrial pressure, the number of packed red cells transfused or the oxygenation index at admission and 24 and 48 h postsurgery. CONCLUSION: The short-term administration of amiodarone under the conditions of the present study does not seem to affect respiratory function.

Selective prophylaxis of atrial fibrillation with amiodarone after cardiac surgery.

AIM: Atrial fibrillation (AF) is common after cardiac surgery, but prophylaxis for patients especially prone to developing this arrhythmia has not been studied to date. We investigated amiodarone as prophylaxis for AF in selected patients after open-heart surgery. METHODS: In the first stage we studied a group of 204 consecutive cardiac surgery patients and devised a formula from some of the known risk factors of AF for each sex to serve as a predictor model. In this first group we were able to quantify the probability of developing this arrhythmia. In the second stage we applied this formula to a group of 231 consecutive cardiac surgery patients and then selectively treated the high-risk patients for AF: 25 men (16.1%) and 29 women (53.7%). In the first 24 h of treatment with amiodarone, 22 patients (10 men and 12 women) were excluded from the study due to sinus bradycardia. Therapy consisted of amiodarone 900 mg intravenously every 24 h for the first 2 postoperative days, followed by 600 mg intravenously every 24 h until discharge from the Intensive Care Unit. RESULTS: Expected AF in males fell from 34.4% (52/151) in the observation group to 11% (17/155) in the treated group, and in females from 50.9% in the observation group (27/53) to 9.3% (5/54) in the treated group (P<0.001). CONCLUSIONS: Patient-selective prophylaxis of AF with amiodarone can be a highly effective measure.

Bacterial inclusion bodies are cytotoxic in vivo in absence of functional chaperones DnaK or GroEL.

Cytotoxicity of cytoplasmic bacterial inclusion bodies has been explored in vivo in cells producing a model, misfolding-prone beta-galactosidase fusion protein. The formation of such aggregates does not result in detectable toxicity on Escherichia coli producing cells. However, a deficiency in the main chaperones DnaK or GroEL but not in other components of the heat shock system such as the chaperone ClpA or the protease Lon, promotes a dramatic inhibition of cell growth. The role of DnaK and GroEL in minimizing toxicity of in vivo protein aggregation is discussed in the context of the conformational stress and the protein quality control system.

Localization of chaperones DnaK and GroEL in bacterial inclusion bodies.

By immunostaining and transmission electron microscopy, chaperones DnaK and GroEL have been identified at the solvent-exposed surface of bacterial inclusion bodies and entrapped within these aggregates, respectively. Functional implications of this distinct localization are discussed in the context of Escherichia coli protein quality control.

Folding of a misfolding-prone beta-galactosidase in absence of DnaK.

In absence of chaperone DnaK, bacterially produced misfolding-prone proteins aggregate into large inclusion bodies, but still a significant part of these polypeptides remains in the soluble cell fraction. The functional analysis of the model beta-galactosidase fusion protein VP1LAC produced in DnaK(-) cells has revealed that the soluble version exhibits important folding defects and that it is less stable and less active than when produced in wild-type DnaK(+) cells. In addition, we have observed that the induction of gene expression at the very late exponential phase enhances twofold the stability of VP1LAC, a fact that in DnaK(-) background results in a dramatic increase of its specific activity up to phenotypically detectable levels. These results indicate that the chaperone DnaK is critical for the folding of misfolding-prone proteins and also that the soluble form reached in its absence by a fraction of polypeptides is not necessarily supportive of biological activity. In the case of E. coli beta-galactosidase, the catalytic activity requires assembling into tetramers and the fine organization of the activating interfaces holding the active sites, what might not be properly reached in absence of DnaK.

A mathematical approach to molecular organization and proteolytic disintegration of bacterial inclusion bodies.

The in vivo proteolytic digestion of bacterial inclusion bodies (IBs) and the kinetic analysis of the resulting protein fragments is an interesting approach to investigate the molecular organization of these unconventional protein aggregates. In this work, we describe a set of mathematical instruments useful for such analysis and interpretation of observed data. These methods combine numerical estimation of digestion rate and approximation of its high-order derivatives, modelling of fragmentation events from a mixture of Poisson processes associated with differentiated protein species, differential equations techniques in order to estimate the mixture parameters, an iterative predictor-corrector algorithm for describing the flow diagram along the cascade process, as well as least squares procedures with minimum variance estimates. The models are formulated and compared with data, and successively refined to better match experimental observations. By applying such procedures as well as newer improved algorithms of formerly developed equations, it has been possible to model, for two kinds of bacterially produced aggregation prone recombinant proteins, their cascade digestion process that has revealed intriguing features of the IB-forming polypeptides.

The impact of dnaKJ overexpression on recombinant protein solubility results from antagonistic effects on the control of protein quality.

We have produced increasing levels of DnaK and its co-chaperone DnaJ along with the model VP1LAC misfolding-prone protein, to explore the role of DnaK on the management of Escherichia coli inclusion bodies. While relative solubility of VP1LAC is progressively enhanced, the heat-shock response is down-regulated as revealed by decreasing levels of GroEL. This is accompanied by an increasing yield of VP1LAC and a non-regular evolution of its insoluble fraction, at moderate levels of DnaK resulting in more abundant inclusion bodies. Also, the impact of chaperone co-expression is much more pronounced in wild type cells than in a DnaK- mutant, probably due to the different background of heat shock proteins in these cells. The involvement of DnaK in the supervision of misfolding proteins is then pictured as a dynamic balance between its immediate holding and folding activities, and the side-effect downregulation of the heat shock response though the limitation of other chaperone and proteases activities.

Protein aggregation in recombinant bacteria: biological role of inclusion bodies.

Protein aggregation is an ordinary consequence of thermal stress. In recombinant bacteria, the over-expression of plasmid-encoded genes triggers transcription of heat-shock genes and other stress responses and often results in the aggregation of the encoded protein as inclusion bodies. The formation of these deposits represents a major obstacle for the production of biologically active polypeptides and restricts the spectrum of protein products being available for the industrial-biomedical market. Inclusion body formation was formerly considered to occur passively by the irretrievable deposition of partially-folded intermediates. Increasing evidence, however, indicates that protein aggregation in bacteria occurs as a reversible process deeply integrated in the cell mechanisms for coping with thermal stress, and that inclusion bodies are structurally dynamic structures. Inclusion body formation might actually be supported by the cellular machinery that when operated under specific stress conditions, transiently stores misfolded polypeptides until they could be further processed: either refolded or proteolysed. A better understanding of protein aggregation in cell physiology could allow not only inclusion body formation to be minimized more efficiently for a higher soluble yield, but also to comprehend in detail the intricacy of cell mechanisms committed to handling the misfolding danger.

Role of molecular chaperones in inclusion body formation.

Protein misfolding and aggregation are linked to several degenerative diseases and are responsible for the formation of bacterial inclusion bodies. Roles of molecular chaperones in promoting protein deposition have been speculated but not proven in vivo. We have investigated the involvement of individual chaperones in inclusion body formation by producing the misfolding-prone but partially soluble VP1LAC protein in chaperone null bacterial strains. Unexpectedly, the absence of a functional GroEL significantly reduced aggregation and favoured the incidence of the soluble protein form, from 4 to 35% of the total VP1LAC protein. On the other hand, no regular inclusion bodies were then formed but more abundant small aggregates up to 0.05 microm(3). Contrarily, in a DnaK(-) background, the amount of inclusion body protein was 2.5-fold higher than in the wild-type strain and the average volume of the inclusion bodies increased from 0.25 to 0.38 microm(3). Also in the absence of DnaK, the minor fraction of soluble protein appears as highly proteolytically stable, suggesting an inverse connection between proteolysis and aggregation managed by this chaperone. In summary, GroEL and DnaK appear as major antagonist controllers of inclusion body formation by promoting and preventing, respectively, the aggregation of misfolded polypeptides. GroEL might have, in addition, a key role in driving the protein transit from the soluble to the insoluble cell fraction and also in the opposite direction. Although chaperones ClpB, ClpA, IbpA and IbpB also participate in these processes, the impact of the respective null mutations on bacterial inclusion body formation is much more moderate.