The concept of bacterial translocation and gut-origin sepsis as causes of systemic infectious complications and multiple organ deficiency syndrome in surgical and critically ill patients has been a recurring issue over the last decades attracting the scientific interest. Although gastrointestinal dysfunction seemingly arises frequently in intensive care unit patients, it is usually underdiagnosed or underestimated, because the pathophysiology involved is incompletely understood and its exact clinical relevance still remains controversial with an unknown yet probably adverse impact on the patients’ outcome. The purpose of this review is to define gut-origin sepsis and related terms, to describe the mechanisms leading to gut-derived complications, and to illustrate the therapeutic options to prevent or limit these untoward processes.
Gut failure; bacterial translocation; selective gut decontamination; immunonutrition
Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods.
Sepsis due to bloodstream infections (BSI) from July 2006 until March 2013 was recorded in a multicenter study in 46 departments. Patients were divided into sepsis admitted in the emergencies and hospitalized in the general ward (GW) and sepsis developing after admission in the Intensive Care Unit (ICU). The primary endpoints were the changes of epidemiology and the factors related with BSIs by multidrug-resistant (MDR) pathogens; the secondary endpoint was the impact of de-escalation on antimicrobial therapy.
754 patients were studied; 378 from 2006–2009 and 376 from 2010–2013. Major differences were recorded between periods in the GW. They involved increase of: sepsis severity; the incidence of underlying diseases; the incidence of polymicrobial infections; the emergence of Klebsiella pneumoniae as a pathogen; and mortality. Factors independently related with BSI by MDR pathogens were chronic hemofiltration, intake of antibiotics the last three months and residence into long-term care facilities. De-escalation in BSIs by fully susceptible Gram-negatives did not affect final outcome. Similar epidemiological differences were not found in the ICU; MDR Gram-negatives predominated in both periods.
The epidemiology of sepsis in Greece differs in the GW and in the ICU. De-escalation in the GW is a safe strategy.
Bloodstream infections; Sepsis; De-escalation; Resistance
Many experimental and clinical studies have confirmed a continuous cross-talk between both sympathetic and parasympathetic branches of autonomic nervous system and inflammatory response, in different clinical scenarios. In cardiovascular diseases, inflammation has been proven to play a pivotal role in disease progression, pathogenesis and resolution. A few clinical studies have assessed the possible inter-relation between neuro-autonomic output, estimated with heart rate variability analysis, which is the variability of R-R in the electrocardiogram, and different inflammatory biomarkers, in patients suffering from stable or unstable coronary artery disease (CAD) and heart failure. Moreover, different indices derived from heart rate signals' processing, have been proven to correlate strongly with severity of heart disease and predict final outcome. In this review article we will summarize major findings from different investigators, evaluating neuro-immunological interactions through heart rate variability analysis, in different groups of cardiovascular patients. We suggest that markers originating from variability analysis of heart rate signals seem to be related to inflammatory biomarkers. However, a lot of open questions remain to be addressed, regarding the existence of a true association between heart rate variability and autonomic nervous system output or its adoption for risk stratification and therapeutic monitoring at the bedside. Finally, potential therapeutic implications will be discussed, leading to autonomic balance restoration in relation with inflammatory control.
heart rate variability; inflammation; autonomic nervous system; coronary artery disease; cardiovascular disease; mortality
Procalcitonin (PCT) has emerged as a valuable marker of sepsis. The potential role of PCT in diagnosis and therapy monitoring of intravascular catheter-related bloodstream infections (CRBSI) in intensive care unit (ICU) is still unclear and was evaluated.
Forty-six patients were included in the study, provided they were free of infection upon admission and presented the first episode of suspected CRBSI during their ICU stay. Patients who had developed any other infection were excluded. PCT was measured daily during the ICU hospitalization. Primary endpoint was proven CRBSI. Therapy monitoring as according to infection control was also evaluated.
Among the 46 patients, 26 were diagnosed with CRBSI. Median PCT on the day of infection suspicion (D0) was 7.70 and 0.10 ng/ml for patients with and without proven CRBSI, respectively (p < 0.001). The area under the curve (AUC) for PCT was 0.990 (95% CI; 0.972 – 1.000), whereas a cut-off value of 0.70 ng/ml provided sensitivity and specificity of 92.3 and 100% respectively. In contrast, the AUC for white blood cells (WBC) was 0.539 (95% CI; 0.369 – 0.709), and for C-reactive protein (CRP), 0.603 (95% CI; 0.438 – 0.768). PCT was the best predictor of proven infection. Moreover, an increase >0.20 ng/ml of PCT between the D0 and any of the 4 preceding days was associated with a positive predictive value exceeding 96%. PCT concentrations from the D2 to D6 after suspected infection tended to decrease in controlled patients, whereas remained stable in non-controlled subjects. A PCT concentration exceeding 1.5 ng/ml during D3 was associated with lack of responsiveness to therapy (p = 0.028).
We suggest that PCT could be a helpful diagnostic and prognostic marker of CRBSI in critically ill patients. Both absolute values and variations should be considered.
Sepsis is associated with systemic inflammatory responses and induction of coagulation system. Neutrophil extracellular traps (NETs) constitute an antimicrobial mechanism, recently implicated in thrombosis via platelet entrapment and aggregation.
In this study, we demonstrate for the first time the localization of thrombogenic tissue factor (TF) in NETs released by neutrophils derived from patients with gram-negative sepsis and normal neutrophils treated with either serum from septic patients or inflammatory mediators involved in the pathogenesis of sepsis. Localization of TF in acidified autophagosomes was observed during this process, as indicated by positive LC3B and LysoTracker staining. Moreover, phosphatidylinositol 3-kinase inhibition with 3-MA or inhibition of endosomal acidification with bafilomycin A1 hindered the release of TF-bearing NETs. TF present in NETs induced thrombin generation in culture supernatants, which further resulted in protease activated receptor-1 signaling.
This study demonstrates the involvement of autophagic machinery in the extracellular delivery of TF in NETs and the subsequent activation of coagulation cascade, providing evidence for the implication of this process in coagulopathy and inflammatory response in sepsis.
Crush asphyxia is different from positional asphyxia, as respiratory compromise in the latter is caused by splinting of the chest and/or diaphragm, thus preventing normal chest expansion. There are only a few cases or small case series of crush asphyxia in the literature, reporting usually poor outcomes.
We present the case of a 44-year-old Caucasian man who developed traumatic asphyxia with severe thoracic injury and mild brain edema after being crushed under heavy auto vehicle mechanical parts. He remained unconscious for an unknown time. The treatment included oropharyngeal intubation and mechanical ventilation, bilateral chest tube thoracostomies, treatment of brain edema and other supportive measures. Our patient’s outcome was good. Traumatic asphyxia is generally under-reported and most authors apply supportive measures, while the final outcome seems to be dependent on the length of time of the chest compression and on the associated injuries.
Treatment for traumatic asphyxia is mainly supportive with special attention to the re-establishment of adequate oxygenation and perfusion; treatment of the concomitant injuries might also affect the final outcome.
Even though temperature is a continuous quantitative variable, its measurement has been considered a snapshot of a process, indicating whether a patient is febrile or afebrile. Recently, other diagnostic techniques have been proposed for the association between different properties of the temperature curve with severity of illness in the Intensive Care Unit (ICU), based on complexity analysis of continuously monitored body temperature. In this study, we tried to assess temperature complexity in patients with systemic inflammation during a suspected ICU-acquired infection, by using wavelets transformation and multiscale entropy of temperature signals, in a cohort of mixed critically ill patients.
Twenty-two patients were enrolled in the study. In five, systemic inflammatory response syndrome (SIRS, group 1) developed, 10 had sepsis (group 2), and seven had septic shock (group 3). All temperature curves were studied during the first 24 hours of an inflammatory state. A wavelet transformation was applied, decomposing the signal in different frequency components (scales) that have been found to reflect neurogenic and metabolic inputs on temperature oscillations. Wavelet energy and entropy per different scales associated with complexity in specific frequency bands and multiscale entropy of the whole signal were calculated. Moreover, a clustering technique and a linear discriminant analysis (LDA) were applied for permitting pattern recognition in data sets and assessing diagnostic accuracy of different wavelet features among the three classes of patients.
Statistically significant differences were found in wavelet entropy between patients with SIRS and groups 2 and 3, and in specific ultradian bands between SIRS and group 3, with decreased entropy in sepsis. Cluster analysis using wavelet features in specific bands revealed concrete clusters closely related with the groups in focus. LDA after wrapper-based feature selection was able to classify with an accuracy of more than 80% SIRS from the two sepsis groups, based on multiparametric patterns of entropy values in the very low frequencies and indicating reduced metabolic inputs on local thermoregulation, probably associated with extensive vasodilatation.
We suggest that complexity analysis of temperature signals can assess inherent thermoregulatory dynamics during systemic inflammation and has increased discriminating value in patients with infectious versus noninfectious conditions, probably associated with severity of illness.
Separation from mechanical ventilation is a difficult task, whereas conventional predictive indices have not been proven accurate enough, so far. A few studies have explored changes of breathing pattern variability for weaning outcome prediction, with conflicting results. In this study, we tried to assess respiratory complexity during weaning trials, using different non-linear methods derived from theory of complex systems, in a cohort of surgical critically ill patients.
Thirty two patients were enrolled in the study. There were 22 who passed and 10 who failed a weaning trial. Tidal volume and mean inspiratory flow were analyzed for 10 minutes during two phases: 1. pressure support (PS) ventilation (15-20 cm H2O) and 2. weaning trials with PS: 5 cm H2O. Sample entropy (SampEn), detrended fluctuation analysis (DFA) exponent, fractal dimension (FD) and largest lyapunov exponents (LLE) of the two respiratory parameters were computed in all patients and during the two phases of PS. Weaning failure patients exhibited significantly decreased respiratory pattern complexity, reflected in reduced sample entropy and lyapunov exponents and increased DFA exponents of respiratory flow time series, compared to weaning success subjects (p < 0.001). In addition, their changes were opposite between the two phases of the weaning trials. A new model including rapid shallow breathing index (RSBI), its product with airway occlusion pressure at 0.1 sec (P0.1), SampEn and LLE predicted better weaning outcome compared with RSBI, P0.1 and RSBI* P0.1 (conventional model, R2 = 0.874 vs 0.643, p < 0.001). Areas under the curve were 0.916 vs 0.831, respectively (p < 0.05).
We suggest that complexity analysis of respiratory signals can assess inherent breathing pattern dynamics and has increased prognostic impact upon weaning outcome in surgical patients.
Liberation from the ventilator is a difficult task, whereas early echocardiographic indices of weaning readiness are still lacking. The aim of this study was to test whether tricuspid annular plane systolic excursion (TAPSE) and right ventricular (RV) systolic (Sm) and diastolic (Em & Am) tissue Doppler imaging (TDI) velocities are related with duration of weaning in mechanically ventilated patients with acute respiratory failure due to acute pulmonary edema (APE).
Detailed quantification of left and right ventricular systolic and diastolic function was performed at admission to the Intensive Care Unit by Doppler echocardiography, in a cohort of 32 mechanically ventilated patients with APE. TAPSE and RV TDI velocities were compared between patients with and without prolonged weaning (≥ or < 7 days from the first weaning trial respectively), whereas their association with duration of ventilation and left ventricular (LV) echo-derived indices was tested with multivariate linear and logistic regression analysis.
Patients with prolonged weaning (n = 12) had decreased TAPSE (14.59 ± 1.56 vs 19.13 ± 2.59 mm), Sm (8.68 ± 0.94 vs 11.62 ± 1.77 cm/sec) and Em/Am ratio (0.98 ± 0.80 vs 2.62 ± 0.67, p <0.001 for all comparisons) and increased Ε/e' (11.31 ± 1.02 vs 8.98 ± 1.70, p <0.001) compared with subjects without prolonged weaning (n = 20). Logistic regression analysis revealed that TAPSE (R2 = 0.53, beta slope = 0.76, p < 0.001), Sm (R2 = 0.52, beta = 0.75, p < 0.001) and Em/Am (R2 = 0.57, beta = 0.32, p < 0.001) can predict length of weaning ≥ 7 days. The above measures were also proven to correlate significantly with Ε/e' (r = -0.83 for TAPSE, r = -0.87 for Sm and r = -0.79 for Em/Am, p < 0.001 for all comparisons).
We suggest that in mechanically ventilated patients with APE, low TAPSE and RV TDI velocities upon admission are associated with delayed liberation from mechanical ventilation, probably due to more severe LV heart failure.
A nation-wide surveillance study was conducted in Greece in order to provide a representative depiction of pneumococcal carriage in the pre-vaccination era and to evaluate potential risk factors for carriage of resistant strains in healthy preschool children attending daycare centers.
A study group was organized with the responsibility to collect nasopharyngeal samples from children. Questionnaires provided demographic data, data on antibiotic consumption, family and household data, and medical history data. Pneumococcal isolates were tested for their susceptibility to various antimicrobial agents and resistant strains were serotyped.
Between February and May 2004, from a total population of 2536 healthy children, a yield of 746 pneumococci was isolated (carriage rate 29.41%). Resistance rates differed among geographic regions. Recent antibiotic use in the last month was strongly associated with the isolation of resistant pneumococci to a single or multiple antibiotics. Serotypes 19F, 14, 9V, 23F and 6B formed 70.6% of the total number of resistant strains serotyped.
Recent antibiotic use is a significant risk factor for the colonization of otherwise healthy children's nasopharynx by resistant strains of S pneumoniae. The heptavalent pneumococcal conjugate vaccine could provide coverage for a significant proportion of resistant strains in the Greek community. A combined strategy of vaccination and prudent antibiotic use could provide a means for combating pneumococcal resistance.
Acute respiratory distress syndrome (ARDS) is characterized by the presence of fibrin-rich inflammatory exudates in the intra-alveolar spaces and the extensive migration of neutrophils into alveoli of the lungs. Tissue factor (TF)-dependent procoagulant properties of bronchoalveaolar lavage fluid (BALF) obtained from ARDS patients favor fibrin deposition, and are likely the result of cross-talk between inflammatory mediators and hemostatic mechanisms. However, the regulation of these interactions remains elusive. Prompted by previous findings suggesting that neutrophils, under certain inflammatory conditions, can express functional TF, we investigated the contribution of intra-alveolar neutrophils to the procoagulant properties of BALF from patients with ARDS. Our results confirm that the procoagulant properties of BALF from ARDS patients are the result of TF induction, and further indicate that BALF neutrophils are a main source of TF in intra-alveolar fluid. We also found that BALF neutrophils in these patients express significantly higher levels of TF than peripheral blood neutrophils. These results suggest that the alveolar microenvironment contributes to TF induction in ARDS. Additional experiments indicated that the ability of BALF to induce TF expression in neutrophils from healthy donors can be abolished by inhibiting C5a or TNF-α signaling, suggesting a primary role for these inflammatory mediators in the up-regulation of TF in alveolar neutrophils in ARDS. This cross-talk between inflammatory mediators and the induction of TF expression in intra-alveolar neutrophils may be a potential target for novel therapeutic strategies to limit ARDS-associated disturbances of coagulation.
Recent evidence has underscored the role of hypoxia and angiogenesis in the pathogenesis of idiopathic fibrotic lung disease. Inhibitor of growth family member 4 (ING4) has recently attracted much attention as a tumor suppressor gene, due to its ability to inhibit cancer cell proliferation, migration and angiogenesis. The aim of our study was to investigate the role of ING4 in the pathogenesis of pulmonary fibrosis both in the bleomycin (BLM)-model and in two different types of human pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP).
Experimental model of pulmonary fibrosis was induced by a single tail vein injection of bleomycin in 6- to 8-wk-old C57BL/6mice. Tissue microarrays coupled with qRT-PCR and immunohistochemistry were applied in whole lung samples and paraffin-embedded tissue sections of 30 patients with IPF, 20 with COP and 20 control subjects.
A gradual decline of ING4 expression in both mRNA and protein levels was reported in the BLM-model. ING4 was also found down-regulated in IPF patients compared to COP and control subjects. Immunolocalization analyses revealed increased expression in areas of normal epithelium and in alveolar epithelium surrounding Masson bodies, in COP lung, whereas showed no expression within areas of active fibrosis within IPF and COP lung. In addition, ING4 expression levels were negatively correlated with pulmonary function parameters in IPF patients.
Our data suggest a potential role for ING4 in lung fibrogenesis. ING4 down-regulation may facilitate aberrant vascular remodelling and fibroblast proliferation and migration leading to progressive disease.
Respiratory motion artifact in intubated and mechanically ventilated patients often reduces the quality of helical computed tomography pulmonary angiography (CTPA). Apneic oxygenation is a well established intra-operative technique that allows adequate oxygenation for short periods (up to 10 min) in sedated and paralyzed patients. We describe the use of the apneic oxygenation for elimination of respiratory motion artefact in an intubated patient undergoing CTPA.
Respiratory failure may develop during the later stages of pregnancy and is usually associated with tocolysis or other co-existing conditions such as pneumonia, sepsis, pre-eclampsia or amniotic fluid embolism syndrome.
We present the case of a 34-year-old healthy woman with a twin pregnancy at 31 weeks and 6 days who experienced acute respiratory failure, a few hours after administration of tocolysis (ritodrine), due to preterm premature rupture of the membranes. Her chest discomfort was significantly ameliorated after the ritodrine infusion was stopped and a Cesarean section was performed 48 hours later under spinal anesthesia; however, 2 hours after surgery she developed severe hypoxemia, hypotension, fever and mild coagulopathy. The patient was intubated and transferred to the intensive care unit where she made a quick and uneventful recovery within 3 days. As there was no evidence for drug- or infection-related thromboembolic or myocardial causes of respiratory failure, we conclude that our patient experienced a rare type of non-fatal amniotic fluid embolism.
In spite of the lack of solid scientific support for our diagnosis, we conclude that our patient suffered an uncommon type of amniotic fluid embolism syndrome and we believe that this report highlights the need for extreme vigilance and a high index of suspicion for such a diagnosis in any pregnant individual.
We describe a case of Saccharomyces boulardii fugaemia in a critically ill patient with septic shock treated with a probiotic agent containing this yeast. We attributed this fugaemia to gut translocation. Our use of caspofugin yielded excellent results.
Amiodarone is a widely used antiarrythmic drug, which may produce secondary effects on the thyroid. In 14–18% of amiodarone-treated patients, there is overt thyroid dysfunction, usually in the form of amiodarone-induced thyrotoxicosis, which can be difficult to manage with standard medical treatment.
Presented is the case of a 65-year-old man, under chronic treatment of atrial fibrillation with amiodarone, who was admitted to the Intensive Care Unit with acute cardio-respiratory failure and fever. He was recently hospitalized with respiratory distress, attributed to amiodarone-induced pulmonary fibrosis. Clinical and laboratory investigation revealed thyrotoxicosis due to amiodarone treatment. He was begun on thionamide, prednisone and beta-blockers. After a short term improvement of his clinical status the patient underwent percutaneous tracheotomy due to weaning failure from mechanical ventilation, which led to the development of recurrent thyrotoxicosis, unresponsive to medical treatment. Finally, the patient developed multiple organ failure and died, seven days later.
We suggest that percutaneous tracheotomy could precipitate a thyrotoxic crisis, particularly in non-euthyroid patients suffering from concurrent severe illness and should be performed only in parallel with emergency thyroid surgery, when indicated.
The use of biomarkers in medicine lies in their ability to detect disease and support diagnostic and therapeutic decisions. New research and novel understanding of the molecular basis of the disease reveals an abundance of exciting new biomarkers who present a promise for use in the everyday clinical practice. The past fifteen years have seen the emergence of numerous clinical applications of several new molecules as biologic markers in the research field relevant to acute respiratory distress syndrome (translational research). The scope of this review is to summarize the current state of knowledge about serum biomarkers in acute lung injury and acute respiratory distress syndrome and their potential value as prognostic tools and present some of the future perspectives and challenges.
Serum biomarkers; acute respiratory distress syndrome; acute lung injury; cytokines; KL-6; surfactant proteins; adhesion molecules.
The predictive role of many cytokines has not been well defined in Acute Respiratory Distress Syndrome (ARDS).
We measured prospectively IL-4, IL-6, IL-6 receptor, IL-8, and IL-10, in the serum and bronchoalveolar lavage fluid (BALF) in 59 patients who were admitted to ICU in order to identify predictive factors for the course and outcome of ARDS. The patients were divided into three groups: those fulfilling the criteria for ARDS (n = 20, group A), those at risk for ARDS and developed ARDS within 48 hours (n = 12, group B), and those at risk for ARDS but never developed ARDS (n = 27, group C).
An excellent negative predictive value for ARDS development was found for IL-6 in BALF and serum (100% and 95%, respectively). IL-8 in BALF and IL-8 and IL-10 serum levels were higher in non-survivors in all studied groups, and were associated with a high negative predictive value. A significant correlation was found between IL-8 and APACHE score (r = 0.60, p < 0.0001). Similarly, IL-6 and IL-6r were highly correlated with PaO2/FiO2 (r = -0.27, p < 0.05 and r = -0.55, p < 0.0001, respectively).
BALF and serum levels of the studied cytokines on admission may provide valuable information for ARDS development in patients at risk, and outcome in patients either in ARDS or in at risk for ARDS.
ARDS; cytokines; bronchoalveolar lavage; outcome