Vladimir Gašparović

Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

BACKGROUND The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Continuous Renal Replacement Therapy (CRRT) or Intermittent Hemodialysis (IHD)—What Is the Procedure of Choice in Critically Ill Patients?

Although at present there is no prospective randomized study which could show significantly better survival of patients on continuous procedures, the majority of intensivists advocate this technique of renal function replacement due to generally accepted opinion that it has less effect on circulation of already hemodynamically unstable patients. In our prospective randomized study with 104 patients, we also did not observe any difference in 28 days survival, in total survival, as well as in circulatory instability between two treatment modalities. Even in subgroup of 80 patients with sepsis and septic shock there were no difference in survival. Sepsis was the underlying disorder in 52 and septic shock in 28 patients out of 104 patients analyzed in this study Our prospective randomized study did not show a statistically significant difference between the two methods of renal replacement therapy. Survival rates were not affected and neither was the occurrence of hemodynamic instability. We believe that both methods are complementary; IHD for faster elimination of electrolytes and waste products elimination, CRRT for regulation of higher calories requirements and for hemodynamically unstable patients. The expectations that one method is superior to the other in the term of better survival have not been corroborated by the current data available in the literature. The choice of the method should be individualized. ARF, which is an integral part of MOF, is a problem frequently encountered in critically ill patient treated in the ICU, but outcome of these patients depends closely on the control of basic event. Evaluation of each of the supportive procedures is therefore hindered by the fact that the underlying disease has the crucial effect on survival and the type of supportive procedure less so.

A prospective observational study of the relationship of critical illness associated hyperglycaemia in medical ICU patients and subsequent development of type 2 diabetes

IntroductionCritical illness is commonly complicated by hyperglycaemia caused by mediators of stress and inflammation. Severity of disease is the main risk factor for development of hyperglycaemia, but not all severely ill develop hyperglycemia and some do even in mild disease. We hypothesised that acute disease only exposes a latent disturbance of glucose metabolism which puts those patients at higher risk for developing diabetes.MethodsMedical patients with no history of impaired glucose metabolism or other endocrine disorder admitted to an intensive care unit between July 1998 and June 2004 were considered for inclusion. Glucose was measured at least two times a day, and patients were divided into the hyperglycaemia group (glucose ≥7.8 mmol/l) and normoglycaemia group. An oral glucose tolerance test was performed within six weeks after discharge to disclose patients with unknown diabetes or pre-diabetes who were excluded. Patients treated with corticosteroids and those terminally ill were also excluded from the follow-up which lasted for a minimum of five years with annual oral glucose tolerance tests.ResultsA five-year follow-up was completed for 398 patients in the normoglycaemia group, of which 14 (3.5%) developed type 2 diabetes. In the hyperglycaemia group 193 patients finished follow-up and 33 (17.1%) developed type 2 diabetes. The relative risk for type 2 diabetes during five years after the acute illness was 5.6 (95% confidence interval (CI) 3.1 to 10.2).ConclusionsPatients with hyperglycaemia during acute illness who are not diagnosed with diabetes before or during the hospitalization should be considered a population at increased risk for developing diabetes. They should, therefore, be followed-up, in order to be timely diagnosed and treated.

Hyperglycemia in sepsis is a risk factor for development of type II diabetes

BACKGROUND Hyperglycemia is frequent in sepsis, even in patients without diabetes or impaired glucose metabolism. It is a consequence of inflammatory response and stress, so its occurrence is related to severity of illness. However, not all severely ill develop hyperglycemia and some do even in mild disease. We hypothesized the existence of latent disturbance of glucose metabolism that contributes to development of hyperglycemia and that those patients might have increased risk for diabetes. METHODS Patients admitted with sepsis and no history of impaired glucose metabolism were included and divided in the hyperglycemia group (glucose >or=7.8 mmol/L) and normoglycemia group. Severity of sepsis was assessed. Surviving patients without diabetes at discharge were followed-up for 5 years to investigate risk for development of diabetes. RESULTS Hyperglycemia was related to severity of sepsis. Follow-up was finished for 55 patients with hyperglycemia, of which 8 (15.7%) developed diabetes, and 118 patients with normoglycemia, of which 5 (4.2%) developed diabetes (P = .002). Relative risk for developing type 2 diabetes was 4.29 (95% CI, 1.35-13.64). CONCLUSION Patients with hyperglycemia in sepsis who are not diagnosed with diabetes before or during the hospitalization should be considered a population at increased risk for developing diabetes.

Free serum DNA is an early predictor of severity in acute pancreatitis

OBJECTIVES Cell-free DNA has been investigated as a diagnostic marker in many diseases, including acute conditions. Our hypothesis was that in acute pancreatitis free serum DNA correlates with the extent of pancreatic necrosis and that it may be an early marker of severity. DESIGN AND METHODS Free DNA was measured in sera from 30 patients with acute pancreatitis at admission, on the first, fourth and seventh day following admission. RESULTS On the first day following admission patients who would develop severe pancreatitis had significantly higher serum DNA levels than those with mild disease (median 0.271 ng/microL vs. 0.059 ng/microL respectively; P<0.001). This parameter showed very good characteristics as a potential severity predictor (area under ROC curve 0.97). Free serum DNA was in correlation with the extent of pancreatic necrosis. CONCLUSIONS Free serum DNA correlates with the extent of pancreatic necrosis and is a potential early marker of severe acute pancreatitis.

Change in transferrin sialylation is a potential prognostic marker for severity of acute pancreatitis.

OBJECTIVES Early prediction of severe acute pancreatitis is one of the problems in clinical practice. Since many diseases are associated with alteration in glycosylation, in this work we studied sialylation of transferrin and serum proteins in acute pancreatitis. DESIGN AND METHODS Sialylation was analyzed during first eight days of hospitalization of 30 patients and compared to 28 healthy controls. Transferrin sialylation was measured using enzyme linked lectin assay, while sialic acid on proteins was measured using resorcinol method. RESULTS Both analyzed parameters changed during studied period. The change in transferrin sialylation between Day1 and Day2 of hospitalization was shown to be an early prognostic marker of acute pancreatitis, with better sensitivity (88.9%) and specificity (90.5%) than other markers tested. CONCLUSIONS Sialylation of transferrin and total serum proteins reflects the intensity of inflammatory response during acute pancreatitis and could be used as prognostic parameter for disease severity.

Hematologic malignancies in the medical intensive care unit – Outcomes and prognostic factors

Abstract Objectives To analyze clinical characteristics, treatment, outcomes of critically ill patients with hematologic malignancies (HM) admitted to the medical intensive care unit (ICU) and to identify predictors of adverse outcome. Methods We analyzed prospectively 170 patients. Data included: demographic characteristics, hematologic diagnosis, reasons for ICU admission, transplant status, the presence of neutropenia, acute physiology and chronic health evaluation-II and sequential organ failure assessment scores, and level of organ support. Predictors of ICU mortality were evaluated using univariate and multivariate analysis. Results In total, 73% of patients had high-grade malignancy, 47.6% received intensive chemotherapy before admission, and 30% underwent hematologic stem cell transplantation procedure. In total, 116 (68.2%) of patients were mechanically ventilated; 88 (51.8%) required invasive mechanical ventilation (MV). Non-invasive ventilation started in 28 (16.5%) patients and was successful in 11 (6.5%). The ICU mortality rate was 53.5%, and the mortality of MV patients was 75.9%. Need for vasopressors at admission and MV were identified as independent predictors of fatal outcome. Conclusion The ICU mortality of critically ill patients with HM is high, particularly in the group of MV. Need for vasopressors at admission and MV were independent predictors of ICU mortality. Majority of patients required invasive MV due to severe respiratory failure and non-invasive MV was sufficient only in small number of cases with favorable outcome.

Prior statin therapy is associated with milder course and better outcome in acute pancreatitis – A cohort study

BACKGROUND Statin treatment was shown to be associated with improved outcomes in several inflammatory conditions. We wanted to evaluate the effects of statin therapy on the course and outcome of acute pancreatitis (AP). METHODS A prospective cohort study included patients with acute pancreatitis divided into two groups according to statin use prior to hospitalization. Age, sex, etiology of AP, Ransons score, APACHE II score and maximal CRP were recorded. Outcome measures were hospital length of stay and mortality. Matching of patients for matched analyses was done using individual matching and propensity score matching using variables a priori associated with course and outcome of acute pancreatitis. RESULTS Inclusion criteria were met for 1062 patients of whom 92 were taking statins. Statin users were older and had higher body mass indexes. Severe disease was more common in the no-statin group than in statin group (20.6% vs. 8.7% respectively). All severity markers were also higher in the no-statin group. All cause mortality was not different, while cardiovascular mortality was higher in the statin group in the cohort analysis. After matching by either method, the severity of disease was greater for the patients without statins treatment. Pancreatitis related mortality was higher in the no-statin group after matching. Among patients who developed severe AP, statin users showed lower Ransons and APACHE II scores and lower maximal CRP. CONCLUSIONS Prior statin treatment significantly reduces morbidity and mortality in acute pancreatitis. Further studies are needed to evaluate possible therapeutic use of statins in acute pancreatitis.

Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2

Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56+ NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

Aetiology and outcome of acute renal failure secondary to war related trauma and infectious disease in Croatia

Summary: The aim of our study was to explore the aetiology and the outcome of acute renal failure (ARF) during the war in Croatia. of the 2132 patients admitted to our hospital between April 1990 and November 1992 due to war related trauma, 11 (0.5%) developed ARF. We believe that the development of ARF in these patients was secondary to an overwhelming septic process. Most of our patients suffered from multiple organ failure. of the 11 patients suffering from ARF due to war related trauma only four recovered (63.6% had died). We attribute the lethal outcome to the progression of the septic process. Patients who developed ARF due to infectious diseases unrelated to trauma had a different prognosis. Acute renal failure caused by the Hantan virus ran a benign course, in both its oliguric and non‐oliguric form. Patients who developed ARF as a complication of leptospirosis also had a good prognosis. Although ARF is usually of a multifactorial genesis, our study aimed to emphasize the importance of disseminated septic processes as a cause of ARF.