Krisztina Madách

4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study

IntroductionActivation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.MethodsWe enrolled 208 Caucasian patients with severe sepsis due to pneumonia admitted to an intensive care unit (ICU). Patients were followed up until ICU discharge or death. Clinical data were collected prospectively and the PAI-1 4G/5G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. Patients were stratified according to the occurrence of multiple organ dysfunction syndrome, septic shock or death.ResultsWe found that carriers of the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome (odds ratio [OR] 95% confidence interval [CI] = 1.335 - 5.604; p = 0.006) and a 2.57-fold higher risk for septic shock (OR 95%CI = 1.180 - 5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture also supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome (adjusted odds ratio [aOR] = 2.957; 95%CI = 1.306 -6.698; p = 0.009) and septic shock (aOR = 2.603; 95%CI = 1.137 - 5.959; p = 0.024). However, genotype and allele analyses have not shown any significant difference regarding mortality in models non-adjusted or adjusted for acute physiology and chronic health evaluation (APACHE) II. Patients bearing the 4G allele had higher disseminated intravascular coagulation (DIC) score at admission (p = 0.007) than 5G/5G carriers. Moreover, in 4G allele carriers the length of ICU stay of non-survivors was longer (p = 0.091), fewer ventilation-free days (p = 0.008) and days without septic shock (p = 0.095) were observed during the first 28 days.ConclusionsIn Caucasian patients with severe sepsis due to pneumonia carriers of the 4G allele of PAI-1 polymorphism have higher risk for multiple organ dysfunction syndrome and septic shock and in agreement they showed more fulminant disease progression based on continuous clinical variables.

Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies

Heat shock proteins (Hsps) are ubiquitous and phylogenetically conserved molecules. They are usually considered to be intracellular proteins with molecular chaperone and cytoprotective functions. However, Hsp70 (HSPA1A) is present in the peripheral circulation of healthy nonpregnant and pregnant individuals. In normal pregnancy, circulating Hsp70 levels are decreased, and show a positive correlation with gestational age and an inverse correlation with maternal age. The capacity of extracellular Hsp70 to elicit innate and adaptive proinflammatory (Th1-type) immune responses might be harmful in pregnancy and may lead to the maternal immune rejection of the fetus. Decreased circulating Hsp70 level, consequently, may promote the maintenance of immunological tolerance to the fetus. Indeed, elevated circulating Hsp70 concentrations are associated with an increased risk of several pregnancy complications. Elevated Hsp70 levels in healthy pregnant women at term might also have an effect on the onset of labor. In preeclampsia, serum Hsp70 levels are increased, and reflect systemic inflammation, oxidative stress and hepatocellular injury. Furthermore, serum Hsp70 levels are significantly higher in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) than in severely preeclamptic patients without HELLP syndrome. In HELLP syndrome, elevated serum Hsp70 level indicates tissue damage (hemolysis and hepatocellular injury) and disease severity. Increased circulating Hsp70 level may not only be a marker of these conditions, but might also play a role in their pathogenesis. Extracellular Hsp70 derived from stressed and damaged, necrotic cells can elicit a proinflammatory (Th1) immune response, which might be involved in the development of the maternal systemic inflammatory response and resultant endothelial damage in preeclampsia and HELLP syndrome. Circulating Hsp70 level is also elevated in preterm delivery high-risk patients, particularly in treatment-resistant cases, and may be a useful marker for evaluating the curative effects of treatment for preterm delivery. In addition, increased circulating Hsp70 levels observed in asthmatic pregnant patients might play a connecting role in the pathomechanism of asthmatic inflammation and obstetrical/perinatal complications. Nevertheless, a prospective study should be undertaken to determine whether elevated serum Hsp70 level precedes the development of any pregnancy complication, and thus can help to predict adverse maternal or perinatal pregnancy outcome. Moreover, the role of circulating Hsp70 in normal and pathological pregnancies is not fully known, and further studies are warranted to address this important issue.

Elevated serum 70 kDa heat shock protein level reflects tissue damage and disease severity in the syndrome of hemolysis, elevated liver enzymes, and low platelet count.

OBJECTIVE We have recently demonstrated that serum 70 kDa heat shock protein (Hsp70) levels are increased in the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). The aim of the present study was to investigate in an independent, larger cohort of patients whether serum Hsp70 levels are related to laboratory markers of HELLP syndrome. STUDY DESIGN The study population included 14 patients with HELLP syndrome. Serum Hsp70 levels were measured by enzyme-linked immunosorbent assay. The relationship between serum Hsp70 levels and laboratory markers of hemolysis, hepatocellular damage, renal insufficiency, inflammation or disseminated intravascular coagulation (DIC), as well as platelet count was investigated by calculating correlation coefficients, standardized regression coefficients and by principal component analysis. RESULTS Serum Hsp70 levels showed a very strong correlation to the markers of hemolysis (plasma free hemoglobin level, serum lactate dehydrogenase activity, and total bilirubin level) and of hepatocellular injury (serum aminotransferase activities), supported also by principal component analysis. Furthermore, circulating Hsp70 concentration reflected the severity of HELLP syndrome as expressed by the significant inverse correlation to the lowest platelet count. By contrast, there was no relationship between serum Hsp70 levels and markers of inflammation, coagulation, fibrinolysis or renal insufficiency. CONCLUSION Elevated serum 70 kDa heat shock protein level seems to reflect tissue damage (hemolysis and hepatocellular injury) and disease severity in patients with HELLP syndrome. However, further investigations are needed to determine the clinical relevance of these findings.

Analysis of the 8.1 ancestral MHC haplotype in severe, pneumonia-related sepsis

The most frequent Caucasian MHC haplotype, AH8.1 - associated with numerous immunopathological differences and certain autoimmune diseases - was recently linked to the delayed onset of bacterial colonization in cystic fibrosis. Based on this observation, we hypothesized that the carriers of AH8.1 have lower risk for a worse outcome in sepsis. AH8.1 carrier state was determined in 207 Caucasian patients with severe, pneumonia-related sepsis. Our data showed that in patients without chronic obstructive pulmonary disease (COPD), septic shock - a serious consequence of the bacterial infection - occurred significantly less frequently (OR=0.3383; 95% CI=0.1141-0.995; p=0.043) in carriers of AH8.1, than in non-carriers. According to the multivariate logistic regression analysis, this haplotype had an independent protective role against septic shock in all patients (OR=0.315; 95% CI=0.100-0.992; p=0.048), particularly in COPD-free patients (OR=0.117; 95% CI=0.025-0.554; p=0.007). These results indicate that AH8.1 may confer protection against the progression of bacterial infection, and this could explain, at least partially, its high frequency in the Caucasian population.

Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies ☆

BACKGROUND The secondary forms of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (secondary TMA) emerge as complications of coexisting diseases. OBJECTIVES We hypothesized that secondary TMA could be characterized by the presence of relative ADAMTS13 deficiency and complement activation, and this relationship may have a prognostic value for outcome. PATIENTS AND METHODS Fifty-three patients with thrombotic microangiopathy (TMA) and coexisting disease (such as malignancies, sepsis, heart surgery with extracorporeal circulation, solid organ transplantation, systemic autoimmune disorders), 41 patient controls, and 34 healthy controls were enrolled in our case-control study with 30days follow-up. Complement profile (from serum) and activation products, von Willebrand factor (VWF, from EDTA plasma), and ADAMTS13 activity were determined. RESULTS ADAMTS13 activity was reduced, while VWF level was elevated in secondary TMA patients. The activity of the classical, lectin and alternative pathways, as well as the levels of C3, C4, and Factor H were significantly lower in secondary TMA patients, and were accompanied by high activation product levels (C3a and sC5b-9). Factor H concentration correlated to relative ADAMTS13 deficiency (i.e. VWF/ADAMTS13 ratio (r=-0.368, p=0.019)). 28/53 patients (53%) died during the follow-up period. Increased sC5b-9, C3a, and C reactive protein levels were all associated with a poor patient outcome. CONCLUSIONS Our results indicate that the secondary TMA syndrome and its poor outcome is characterized by relative ADAMTS13 deficiency, inflammation, and complement activation with consumption via the classical and alternative pathways. It is yet to be determined whether complement inhibition could be a possible therapeutic option for patients with secondary TMA.

Mucosal Immunity and the Intestinal Microbiome in the Development of Critical Illness

The intestinal community, including the commensal microbial flora as well as the host tissues, represents a functional whole in vivo. Under physiological circumstances, this symbiosis brings great benefit for the host; however, critical illness induces profound disturbances in the intestinal ecosystem affecting both procaryotic and eucaryotic members. Today, 25 years after the gut was first described as a motor of multiple organ dysfunction syndrome, the role of the injured splanchnic compartment in the pathomechanism and development of critical illness is still in the first line of research. Multiple mechanisms have been identified by which the stressed gut may affect host homeostasis, and how external intervention might help to rebalance physiology. This paper provides a brief overview of the present of this field.

Management of Invasive Candidiasis and Candidemia in critically ill adults – Expert opinion of the European Society of Anaesthesia (ESA) Intensive Care scientific subcommittee

OBJECTIVE The global burden of invasive fungal disease is increasing. Candida albicans remains the leading cause of fungal bloodstream infections, although non-albicans candidal infections are emerging. Areas of controversy regarding diagnosis and management are hampering our ability to respond effectively to this evolving threat. The purpose of this narrative review is to address current controversies and provide recommendations to supplement guidelines. DIAGNOSIS OF INVASIVE CANDIDIASIS Diagnosis of invasive candidiasis requires a combination of diagnostic tests and patient risk factors. Beta-D glucan and Candida albicans germ tube antibody are both used as biomarkers as adjuncts to diagnosis, although direct culture remains the gold standard. Scoring systems are available to help distinguish between colonization and invasive disease. TREATMENT OF INVASIVE CANDIDIASIS Echinocandins are recommended as first-line therapy in candidaemia, with de-escalation to fluconazole when clinical stability is achieved. Empirical therapy is highly recommended in high-risk patients, but a more targeted pre-emptive approach is now being favoured. The evidence for prophylactic therapy remains weak. SUMMARY Mortality attributable to invasive candidiasis may be as high as 70%. Prompt diagnosis and treatment, in conjunction with source control, are the key to improving outcomes.

Experiences of the Department of Anesthesiology and Intensive Therapy of Semmelweis University during the 2009 pandemic H1N1 (pH1N1) influenza outbreak

Abstract Introduction: The 2009 pandemic 2009 H1N1 (pH1N1) influenza A virus shows a markedly different disease pattern than seasonal strains, causing critical illness in relatively young, female, pregnant individuals as well as in comorbid patients. Materials and methods: The Department of Anesthesiology and Intensive Therapy of Semmelweis University served as a regional influenza center for the adult critically ill during the winter of pH1N1 outbreak. We analyzed data collected from 26 suspected pH1N1 critically ill patients treated in our unit during this period. Results: Sixteen cases were confirmed as pH1N1 infection with RT-PCR, while the other 10 patients with influenza like illness showed tendency to a different age and comorbidity, as well as outcome characteristics, suggesting a different pathogenesis. Confirmed pH1N1 patients showed a mean age of 50.5 years (median: 44; range: 20–85), with female predominancy (69%). Comorbidity was present in 69% of cases (chronic heart conditions, chronic pulm...

Antibiotic therapy in the critically ill - expert opinion of the Intensive Care Medicine Scientific Subcommittee of the European Society of Anaesthesiology

Antimicrobial treatment is the cornerstone of infection treatment, and the selection of appropriate antibiotic treatment for critically ill patients is challenging. Clinicians working with critically ill patients usually feel a greater obligation towards their patient than towards maintenance of the delicate ecological balance of prevalent microbiological threats and their resistance patterns. Although antibiotic overtreatment is a frequent phenomenon, patient outcomes need not be compromised when antibiotic treatment is driven by informed decision-making.At the 2016 Euro Anaesthesia Conference (London, UK), the European Society of Anaesthesia Intensive Care Scientific Subcommittee convened an expert panel on antibiotic therapy. This article summarises the main conclusions of the panel, namely the principles of antibiotic therapy that all physicians working with critically ill patients must know.Antimicrobial treatment is the cornerstone of infection treatment, and the selection of appropriate antibiotic treatment for critically ill patients is challenging. Clinicians working with critically ill patients usually feel a greater obligation towards their patient than towards maintenance of the delicate ecological balance of prevalent microbiological threats and their resistance patterns. Although antibiotic overtreatment is a frequent phenomenon, patient outcomes need not be compromised when antibiotic treatment is driven by informed decision-making. At the 2016 Euro Anaesthesia Conference (London, UK), the European Society of Anaesthesia Intensive Care Scientific Subcommittee convened an expert panel on antibiotic therapy. This article summarises the main conclusions of the panel, namely the principles of antibiotic therapy that all physicians working with critically ill patients must know.

Phaeochromocytomás krízisben végzett acut laparoscopos adrenalectomia

CASE REPORT Authors present the case of a 30-year-old female patient, who was admitted to the ICU because of hypertensive crisis accompanied by chest complains, cardiac decompensation, progrediating short of breath and unconsciousness. Despite the quick examinations and the prompt treatment multi-organ failure developed 3 days after admission. Investigations revealed the underlying cause, which was a left-sided suprarenal neoplasm. Hence, multidisciplinary decision was made to carry out a laparoscopic adrenalectomy urgently. The histology examination of the removed neoplasm was pheochromocytoma. In the postoperative period the condition of the patient gradually improved, her symptoms and complains settled, and finally she was discharged in a healthy condition. DISCUSSION The diagnosis of a pheochromocytoma is a difficult task, the symptoms and complains caused by it can simulate many other illnesses. The acute crisis caused by pheochromocytoma usually can be treated conservatively, but in more severe cases with impending multi-organ failure an urgent operative treatment can be unavoidable. Though the operative risk is relatively high, the correct intra- and postoperative treatment with a quick laparoscopic procedure can be effective.