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.

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.

[Urgent laparoscopic adrenalectomy in acute crisis caused by pheochromocytoma]. / 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.

Impact of molecular mimicry on the clinical course and outcome of sepsis syndrome.

We investigated the impact of molecular mimicry between pathogenic microbes and their antigenic surrounding on the clinical course and outcome of pneumonia induced sepsis. Using mathematical prediction, we estimated the mimicry tendency of the identified pathogenic flora of patients with the human proteome as well as intestinal microbes. Since gut bacteria become invasive and hostile in critical illness, mimicry between these organisms and the infectious flora is expected to be rather hyperinflammatory type, in contrast to the expectedly tolerogenic self versus pathogen cross-reactions. Differential effects of these two kinds of cross-reactions were studied. The predicted similarity of the identified pathogenic flora and intestinal microbes was higher in non-survivor patients compared to survivors (P=0.019). Higher values of "pathogen versus intestinal flora/pathogen versus human proteome" mimicry ratios (inflammatory quotients) were associated with mortality at a higher extent of significance (P<0.01), and correlated with admission APACHE II disease severity scores (R=0.311; P=0.017). We also found a correlation between the previously reported sepsis mortality rates by causative agent and the corresponding inflammatory quotients of these pathogens (R=0.738; P<0.05). Gram negative species showed higher similarity to intestinal bacteria and reached higher inflammatory quotients compared to Gram positives (P=0.01 and P<0.01, respectively). The disadvantageous effect of "pathogen versus intestinal flora" mimicry - presumably due to the extension of inflammation from the infectious focus to the already injured gut - is in accordance with the gut-lymph hypothesis, assessing that the destruction of the intestinal symbiosis culminates in the formation of damageous gut origin lymph. Our results raise the idea that molecular mimicry between pathogenic microbes and their antigenic surrounding might be a contributing factor behind the clinically and experimentally observed differences in microbiologically distinct forms of sepsis syndrome.

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.

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.

INTRODUCTION: Activation 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: In 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.

Mathematical analysis of clinical data reveals a homunculus of bacterial mimotopes protecting from autoimmunity via oral tolerance in human.

Oral tolerance (OT) means systemic immunological unresponsiveness to harmless antigens present in the gastrointestinal tract. We presumed that tolerance to these antigens may also protect self-proteins that show immunological similarity to the intestinal normal flora. To investigate the existence and in vivo relevance of such a tolerogenic molecular mimicry, we focused our attention to Autoimmune Polyendocrine Syndrome type 1 (APS1) and Hemolysis, Elevated Liver Enzymes, Low Platelet count (HELLP) syndrome. APS1 is a human form of Autoimmune Regulator (AIRE) dysfunction with severely impaired central immunotolerance to a specific set of autoantigens, allowing investigation of tolerogenic mimicry by itself, without a disturbing background. HELLP syndrome is a mediocre manifestation of thrombotic microangiopathy, complicating pregnancy, with platelet-fibrin deposits in small blood vessels and transient development of autoantibodies. Impaired microcirculation in the liver is well described, while intestinal ischemia is possible but has not yet been studied. As the harmless nature of an antigen is essential for OT, ischemia-induced bacterial microinvasion represses this process. In case that oral tolerance to a bacterial homunculus is an existing way of self-protection and has an in vivo relevance when central tolerance is intact, significant intestinal ischemia--if present--is expected to promote autoimmunity in HELLP syndrome. We used an experimentally validated, highly reliable mathematical algorithm to predict the extent of immunological similarity between a certain autoantigen and intestinal bacteria. We found a strong negative correlation between the similarity of autoantigens to intestinal bacteria and the production of specific autoantibodies in APS1 (R=-0.70, P=0.002), while a positive correlation was observed in patients with predominantly the severe/moderately severe form of HELLP syndrome according to Mississippi classification (R=0.94, P=0.005). Autoantigen length inversely correlated with the production of autoantibodies in APS1 (R=-0.68, P=0.004). As a longer chain with more epitopes associates with an increased possibility of mimicry to any proteome, molecular mimicry in general--regarding at least major tissue-specific autoantigens--seems to be rather protective. Our calculations support the hypothesis that OT to an intestinal "bacterial homunculus" is an in vivo relevant mechanism of self-protection in humans, furthermore, HELLP syndrome presumably associates with significant intestinal ischemia and leak, resulting in transient autoimmunity via loss of OT.

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.

[Transfusion problems in surgery and anesthesiology. The causes, consequences, prevention and treatment of perioperative anemia]. / A sebészet és az aneszteziológia transzfúziológiai problémái. A perioperatív anaemia okai, következményei, megelózése és kezelése.

INTRODUCTION: The classical indication for blood transfusion is the correction of oxygen delivery failure, and the elimination of tissue ischaemia. Such indications in the surgical and anesthesiological practice are the acute haemorrhagic states (trauma, acute gastrointestinal bleeding, intraoperative hemorrhage), as well as diseases associated with chronic blood loss (occult bleeding caused by malignancies, and ulcerating processes etc.). The traditional surgical and anesthesiological viewpoint has adopted a remarkably liberal approach to the indication of blood transfusion, and a whole range of its subtle, medium-long term adverse effects has been taken into account only recently. The purpose of this review was to analyze the causes and pathophysiological consequences of perioperative anemia and blood loss, as well as to reconsider the proper indications of blood transfusion in the view of immunological sequela. The most recent data on the transfusion related immuno-depression and immunomodulation are summarized. The authors wish to provide clues for the definition of "transfusion trigger", in addition, methods available for the clinical practice to reduce blood demand and to restore oxygen transport capacity during surgical and anesthesiological interventions are revisited. Based on the review of the literature and the personal experience of the authors the practical recommendations concerning the administration of blood and blood products should be summarized as follows: 1. Blood transfusion is rarely indicated if the hemoglobin level is above 10 g/dl, and in fact always necessary if it is less than 6 g/dl, especially, if the anemia developed acutely. 2. The "transfusion trigger" is subject to continued debate, and whether a particular patient with intermediary (6-10 g/dl) Hb levels should be transfused or not must be assessed in the perspective of the potential complications initiated by the inadequate oxygenation. 3. If major co-morbidity (e.g. emphysema, ischaemic heart disease) is present, 10 g/dl Hb, in case of respirator dependency 12 g/dl Hb levels justify the administration of transfusion. If feasible, the beneficial effects of allogenous blood sparing methodologies should be utilized. CONCLUSIONS: Although the National Blood Supply Service is excellently organized in Hungary, the current clinical practice is not satisfactory. The use of up-to-date methods at the average surgical departments is suboptimal, and due to the lack of knowledge concerning the recent advances in immunology the clinicians are far too liberal in the indication of blood transfusion. The objective is to establish a modern surgical and anesthesiological transfusion practice based on the solid understanding of immunological facts, and to modernize the continued education, as well as to improve the financing of costly blood saving methodologies.