Paulo Marcelino

Routine Transthoracic Echocardiography in a General Intensive Care Unit: an 18 Month Survey in 704 Patients

The authors analyzed 704 transthoracic echocardiographic (TTE) examinations, performed routinely to all admitted patients to a general 16-bed Intensive Care Unit (ICU) during an 18-month period. Data acquisition and prevalence of abnormalities of cardiac structures and function were assessed, as well as the new, previously unknown severe diagnoses. A TTE was performed within the first 24 h of admission on 704 consecutive patients, with a mean age of 61.5+/-17.5 years, ICU stay of 10.6+/-17.1 days, APACHE II 22.6+/-8.9, and SAPS II 52.7+/-20.4. In four patients, TTE could not be performed. Left ventricular (LV) dimensions were quantified in 689 (97.8%) patients, and LV function in 670 (95.2%) patients. Cardiac output (CO) was determined in 610 (86.7%), and mitral E/A in 399 (85.9% of patients in sinus rhythm). Echocardiographic abnormalities were detected in 234 (33%) patients, the most common being left atrial (LA) enlargement (n=163), and LV dysfunction (n=132). Patients with these alterations were older (66+/-16.5 vs 58.1+/-17.4, p<0.001), presented a higher APACHE II score (24.4+/-8.7 vs 21.1+/-8.9, p<0.001), and had a higher mortality rate (40.1% vs 25.4%, p<0.001). Severe, previously unknown echocardiographic diagnoses were detected in 53 (7.5%) patients; the most frequent condition was severe LV dysfunction. Through a multivariate logistic regression analysis, it was determined that mortality was affected by tricuspid regurgitation (p=0.016, CI 1.007-1.016) and ICU stay (p<0.001, CI 1-1.019). We conclude that TTE can detect most cardiac structures in a general ICU. One-third of the patients studied presented cardiac structural or functional alterations and 7.5% severe previously unknown diagnoses.

High incidence of thrombotic complications early after liver transplantation for familial amyloidotic polyneuropathy

Early thrombotic complications are critical causes of in‐hospital morbidity after orthotopic liver transplantation (OLT), potentially culminating in graft loss. The aim of this study was to retrospectively analyse these complications, trying to identify associated independent risk factors. This retrospective analysis included 223 OLTs performed on 213 patients, in a 30‐month period. Eighty‐six OLTs were performed on familial amyloidotic polyneuropathy (FAP) patients. Preoperative details (primary diagnosis and Child‐Turcotte‐Pugh classification, when applicable), surgical features (including type of arterial reconstruction), postoperative variables and outcome were analysed. The observation period ended 30 days post‐OLT, until discharge or in‐hospital death. Early thrombotic complications were diagnosed in 16 cases (7.2%), affecting mainly FAP patients (n = 12). Hepatic artery thrombosis (HAT) was the most frequent early thrombotic event (n = 12): incidence in FAP patients 11.6% (n = 10) versus incidence in non FAP patients 1.5% (n = 2), P = 0.001. By logistic regression analysis, FAP turned out to be an independent risk factor for early thrombotic complications, and specifically for HAT. The type of arterial reconstruction and other analysed surgical and medical factors did not influence early HAT occurrence. In conclusion, FAP was identified in this study as an independent risk factor for early HAT, a new datum not yet described in the literature.

Domino versus deceased donor liver transplantation: Association with early graft function and perioperative bleeding

This study sought to evaluate the potential impact of domino liver transplantation (DLT) on initial graft function and early postoperative outcome in patients with cirrhosis in a Portuguese liver transplantation center. A retrospective comparative analysis was performed between 77 domino recipients (from familial amyloidotic polyneuropathy donors) and 91 deceased donor recipients, all submitted to primary elective whole liver transplantation, using the piggyback technique, in a 42‐month period. Outcome parameters included graft dysfunction (defined as either primary nonfunction or initial poor function, according to the Ploeg‐Maring criteria) and Clavien II‐IV complications in the first postoperative week. Domino and deceased donor recipients had similar preoperative severity indices (Child‐Pugh classification and Model for End‐Stage Liver Disease score) and immediate postoperative severity scores (APACHE II [Acute Physiology and Chronic Health Evaluation II] and SAPS II [Simplified Acute Physiology Score II]). In DLT, donors were younger, cold ischemia time was shorter, and intraoperative transfusion requirements of packed red blood cells and fresh‐frozen plasma were significantly lower. Graft dysfunction incidence was 3.4‐fold lower in DLT: 5.2% (only 4 cases of initial poor function) versus 18.0% (1 primary nonfunction and 15 cases of initial poor function), P = 0.010. Postoperative bleeding was the most frequent early Clavien II‐IV complication (n = 29, 17.3%), with an incidence 2.2‐fold lower in domino recipients. A statistically significant difference was not found in the other analyzed Clavien II‐IV complications, intensive care unit stay, mechanical ventilation time, intensive care unit mortality, and 1‐year survival rate. In conclusion, in this study the younger donors and shorter ischemic time associated with DLT may provide a protective role in regards to graft dysfunction and perioperative bleeding, which are 2 important determinants of early morbidity after liver transplantation. Liver Transpl, 2011.

Three-dimensional co-culture of human hepatocytes and mesenchymal stem cells: improved functionality in long-term bioreactor cultures

The development of human cell models that can efficiently restore hepatic functionality and cope with the reproducibility and scalability required for preclinical development poses a significant effort in tissue engineering and biotechnology. Primary cultures of human hepatocytes (HHs), the preferred model for in vitro toxicity testing, dedifferentiate and have short‐term viability in two‐dimensional (2D) cultures. In this study, hepatocytes isolated from human liver tissue were co‐cultured with human bone marrow mesenchymal stem cells (BM‐MSCs) as spheroids in automated, computer‐controlled, stirred‐tank bioreactors with perfusion operation mode. A dual‐step inoculation strategy was used, resulting in an inner core of parenchymal liver tissue with an outer layer of stromal cells. Hepatocyte polarization and morphology as well as the mesenchymal phenotype of BM‐MSCs were maintained throughout the culture period and the crosstalk between the two cell types was depicted. The viability, compact morphology and phenotypic stability of hepatocytes were enhanced in co‐cultures in comparison to monocultures. Gene expression of phase I and II enzymes was higher and CYP3A4 and CYP1A2 activity was inducible until week 2 of culture, being applicable for repeated‐dose toxicity testing. Moreover, the excretory activity was maintained in co‐cultures and the biosynthetic hepatocellular functions (albumin and urea secretion) were not affected by the presence of BM‐MSCs. This strategy might be extended to other hepatic cell sources and the characterization performed brings knowledge on the interplay between the two cell types, which may be relevant for therapeutic applications. Copyright

The End-Organ Impairment in Liver Cirrhosis: Appointments for Critical Care

Liver cirrhosis (LC) can lead to a clinical state of liver failure, which can exacerbate through the course of the disease. New therapies aimed to control the diverse etiologies are now more effective, although the disease may result in advanced stages of liver failure, where liver transplantation (LT) remains the most effective treatment. The extended lifespan of these patients and the extended possibilities of liver support devices make their admission to an intensive care unit (ICU) more probable. In this paper the LC is approached from the point of view of the pathophysiological alterations present in LC patients previous to ICU admission, particularly cardiovascular, but also renal, coagulopathic, and encephalopathic. Infections and available liver detoxifications devices also deserve mentioning. We intend to contribute towards ICU physician readiness to the care for this particular type of patients, possibly in dedicated ICUs.

New long circulating magnetoliposomes as contrast agents for detection of ischemia-reperfusion injuries by MRI

UNLABELLED New long circulating magnetoliposomes coated with polyethylene glycol (PEG), and loaded with PEG-coated 10nm superparamagnetic iron oxide nanoparticles (SPION), were developed. The magnetoliposomes relaxivities r1, r2 measured in a magnetic field of 7 T showed a minor effect on T1, but a major effect on T2. These nanosystems were used as a negative contrast agent for MRI in a nonclinical study to visualize, in a rat model of liver ischemia, ischemia-reperfusion injuries. Magnetic resonance micro-images (MRM) at 7 T were obtained for rat liver with and without magnetoliposomes administration and analyzed in comparison with liver biomarkers and histological results. These new long circulating magnetoliposomes enhanced the detection of lesions indicating their potential use as efficient MRI negative contrast agent for the detection of liver ischemia-reperfusion injuries. FROM THE CLINICAL EDITOR This paper describes the generation of PEGylated magnetoliposomes and demonstrates their feasibility as negative contrast agents in a liver ischemia-reperfusion rat model.

Transthyretin Proteins Regulate Angiogenesis by Conferring Different Molecular Identities to Endothelial Cells

Background: The biological effects of transthyretin proteins on vasculature remain unknown. Results: V30M transthyretin tetramer modulates endothelial global gene expression, down-regulating pro-angiogenic genes, inducing apoptosis and inhibiting migration. Conclusion: Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells. Significance: This work has critical implications in the prevention of early hepatic artery thrombosis in familial amyloidotic polyneuropathy patients after liver transplantation. Familial amyloidotic polyneuropathy (FAP) has a high prevalence in Portugal, and the most common form of hereditary amyloidosis is caused by an amyloidogenic variant of transthyretin (TTR) with a substitution of methionine for valine at position 30 (V30M). Until now, the available efficient therapy is liver transplantation, when performed in an early phase of the onset of the disease symptoms. However, transplanted FAP patients have a significantly higher incidence of early hepatic artery thrombosis compared with non-FAP transplanted patients. Because FAP was described as an independent risk factor for early hepatic artery thrombosis, more studies to understand the underlying mechanisms involved in this outcome are of the utmost importance. Knowing that the liver is the major site for TTR production, we investigated the biological effects of TTR proteins in the vasculature and on angiogenesis. In this study, we identified genes differentially expressed in endothelial cells exposed to the WT or V30M tetramer. We found that endothelial cells may acquire different molecular identities when exposed to these proteins, and consequently TTR could regulate angiogenesis. Moreover, we show that V30M decreases endothelial survival by inducing apoptosis, and it inhibits migration. These findings provide new knowledge that may have critical implications in the prevention of early hepatic artery thrombosis in FAP patients after liver transplantation.

Echocardiography: a fundamental part of the intensive care curriculum.

The purpose of this letter is to emphasize some of the particular attributes of echocardiography, based on our experience over 20 years in its application in critically ill patients. In our opinion echocardiography is under-used, and its benefits can only truly be recognized if it is routinely applied as a diagnostic tool. In fact, it is a highly dynamic technique that permits direct visualization and assessment of all of the cardiac structures, as well as of the pulmonary artery and haemodynamic status. More than any other diagnostic tool, echocardiography allows detection of valvular disease; evaluation of systolic and diastolic function, and pericardial disease; and demonstration of intracardiac shunts and quantification thereof. Furthermore, one can calculate flows and pressures at various levels, study systole and diastole, and ultimately determine whether the data obtained are accurate, based on the dynamics of cardiac structures. Haemodynamic evaluation provides information in a just a few minutes, making it possible to initiate interventions immediately, at the level of volume repletion, cardiac contractility or peripheral resistance. Besides the primary cardiac entities (e.g. myocardial infarction, valvular disease and thrombi, etc.) that may benefit from echocardiographic evaluation, other cardiac abnormalities may also be revealed under stressful conditions. Among these, diastolic dysfunction deserves particular attention because it is quite common in those beyond middle age, and may assume great importance in a critically ill patient with sepsis, pneumonia or chronic respiratory disease. If undetected, it may determine the difference between life and death. Our group identified a highly significant correlation between the isovolumetric relaxation time (an important phase of diastole) and time of weaning from mechanical ventilation [1]. Other situations that are frequently encountered involve myocardium stunning, which may occur in diverse critical illnesses, as we mentioned before. Less common but no less important are right/left intracardiac shunts, which are often unsuspected and responsible for unexplained clinical deterioration in patients subjected to positive pressure ventilation. When a mechanically ventilated patient becomes more hypoxaemic despite efforts to improve ventilation, shunt-induced hypoxemia caused by a patent foramen ovale should be suspected, among other causes such as pulmonary embolism [2]. Only echocardiography can identify such specific abnormalities in mechanically ventilated patients, when weaning is difficult or refractory hypoxaemia is not explained by pulmonary disease alone. The main issue is that, globally, further knowledge and practice of echocardiography are required if we are to recognize its potential within the framework of general intensive care. Thus, our message is that we must first study patients using echo-cardiography, including clinical data, and then act accordingly. The contribution of echocardiography to the diagnosis and prompt treatment of many commonly overlooked situations may ultimately be associated with a decrease in morbidity and mortality. For this reason, we must promote training in echocardiography, as well as its routine use as an essential examination [3,4]. In our opinion, based on 20 years experience in echocardiography, the enormous advantages offered by this noninvasive technique renders it an indispensable tool in general intensive care units; consequently, training of physicians from specialities other than cardiology is required. Bluntly, it must become part of the intensivists curriculum.

Non invasive evaluation of central venous pressure using echocardiography in the intensive care – Specific features of patients with right ventricular enlargement and chronic exacerbated pulmonary disease

OBJECTIVES To determine the possibility of non-invasive estimation of central venous pressure (CVP) through inferior vena cava (IVC) analysis, using transthoracic echocardiography (TTE). DESIGN A prospective 3-year study. SETTING A 16-bed medical/surgical Intensive Care Unit (ICU). METHODS Patients admitted to the ICU were enrolled. CVP measurement and TTE (determining cardiac chambers dimension and left ventricular shortening fraction) with IVC analysis (maximum dimension and IVC index) were performed simultaneously. Parametric and non-parametric statistical analysis was performed to establish correlations between variables. RESULTS 560 patients were admitted to the study, including 477 in whom IVC was analysed, aging 62.2 +/- 17.3 years, a mean ICU stay 11.9 +/- 18.7 days, a APA- CHE II score 23.9 +/- 8.9 and a SAPS II score 55.7 +/- 20.4. Through linear regression analysis CVP was influenced by IVC index (p=0.001), IVC maximum dimension (p=0.013) and presence of mechanical ventilation (p=0.002). A statistically significant correlation was found between the following parameters: an IVC index < 25% and a CVP > 13 mmHg; an IVC index and a CVP 26%-50%; an IVC index > 51% and CVP < 7 mmHg; an IVC maximum dimension > 20mm and a CVP > 13 mmHg; an IVC maximum dimension < 10 mmHg and CVP < 7 mmHg. Patients with right ventricle enlargement presented a lack of agreement between IVC maximum dimension and CVP > 7 mmHg was observed, and in patients with chronic respiratory failure (who presented a high prevalence of right ventricular enlargement) a lack of agreement between IVC index > 50% and CVP < 7 mmHg was also observed. CONCLUSIONS IVC analysis is a possible way to non-invasively estimate CVP in a medical /surgical ICU. However, patients with right ventricular enlargement and admitted with chronic respiratory failure present a lack of agreement between IVC parameters and low values of CVP. IVC dimension is a marker of chronic disease and IVC index correlated better with CVP.

The Evolving Concepts of Haemodynamic Support: From Pulmonary Artery Catheter to Echocardiography and Theragnostics

Echocardiography is a non-invasive tool, aimed towards the anatomical and functional characterization of the heart. In Intensive Care it is considered nowadays as a necessary tool for patient evaluation. However, the information obtained using echocardiography is not the same as provided by other means, namely the invasive ones. In recent years there has been a significant evolution in the general concepts of haemodynamic support for the critically ill patient. In this new environment, echocardiography has gained particular relevance. In this text the new positioning of echocardiography in the light of the new concepts for hemodynamic support is described, as well as, the need for a specific formative program directed towards Intensive Care physicians. A new generation of biomarkers can also add relevant information and start a new era in haemodynamic support. They may help to further characterize the disease process, identifying patients at risk, as well as, characterize specific organ failure as well as monitoring therapy.