Antithrombin III in patients with severe sepsis: a pharmacokinetic study

Objectives: To evaluate the safety, pharmacokinetics, and the practicability of two different antithrombin III (AT III) high-dose regimens in patients with severe sepsis.¶Design: Prospective, open, randomized, 2 parallel groups, multinational clinical trial.¶Setting: Eleven academic medical center intensive care units (ICU) in Austria, Belgium, Denmark, Germany, Norway and Sweden.¶Patients: Thirty-three patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III.¶Interventions: Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days, resulting in a total dose for both dosage regimens of 30,000 IU AT III.¶Measurements: All patients were evaluated for safety and all but one for pharmacokinetics.¶Results and conclusions: The administration of AT III was safe and well tolerated. The overall 28-day all-cause mortality was 30 % (43 % intermittent bolus infusions; 21 % continuous infusion). The mean probability of dying according to the SAPS II was 48 %. The difference in mortality between both groups was within the range of chance. AT III plasma levels were elevated from low baseline levels to above 120 % soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days. Functional and immunologic levels of AT III corresponded very well. With an overall median volume of distribution of 4.5 l (range: 2.4–6.5 l), AT III only moderately extended beyond plasma. The overall median elimination half-life was 18.6 h (range: 5.1–37.4). Overall, median response was 1.75 % per IU/kg (range: 1.14–2.8).¶The variability of elimination parameters was quite noteworthy (CV = 41–59 %), whereas distribution-related parameters showed a moderate variability (CV = 24 %). In spite of this variability, both high-dose IV regimens reliably provided AT III levels above 120 % for all but one patient. An increased mortality was observed for patients with a distribution volume exceeding 4.5 l (or a response < 1.7 % per IU/kg). AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon. The continuous infusion regimen was slightly preferred by the investigators with regard to practicability.     

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

Introduction

Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic–pituitary–adrenal axis.

Materials and method

This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-α and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death.

Results

On admission, DHEAS was extremely low in septic shock (1.2 ± 0.8 mol/l) in comparison with multiple trauma patients (2.4 ± 0.5 μmol/l; P < 0.05) and control patients (4.2 ± 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 ± 0.3 μmol/l) than did survivors (1.7 ± 1.1 μmol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points.

Conclusion

We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.     

Whole-Genome Mapping as a Novel High-Resolution Typing Tool for Legionella pneumophila

Legionella is the causative agent for Legionnaires'' disease (LD) and is responsible for several large outbreaks in the world. More than 90% of LD cases are caused by Legionella pneumophila, and studies on the origin and transmission routes of this pathogen rely on adequate molecular characterization of isolates. Current typing of L. pneumophila mainly depends on sequence-based typing (SBT). However, studies have shown that in some outbreak situations, SBT does not have sufficient discriminatory power to distinguish between related and nonrelated L. pneumophila isolates. In this study, we used a novel high-resolution typing technique, called whole-genome mapping (WGM), to differentiate between epidemiologically related and nonrelated L. pneumophila isolates. Assessment of the method by various validation experiments showed highly reproducible results, and WGM was able to confirm two well-documented Dutch L. pneumophila outbreaks. Comparison of whole-genome maps of the two outbreaks together with WGMs of epidemiologically nonrelated L. pneumophila isolates showed major differences between the maps, and WGM yielded a higher discriminatory power than SBT. In conclusion, WGM can be a valuable alternative to perform outbreak investigations of L. pneumophila in real time since the turnaround time from culture to comparison of the L. pneumophila maps is less than 24 h.     

Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003

BACKGROUND: In a meta-analysis published in October 2001, we reported that new and old classes of antihypertensive drugs had similar long-term efficacy and safety. Furthermore, we observed that in clinical trials in hypertensive or high-risk patients gradients in systolic pressure accounted for most differences in outcome. OBJECTIVE: To test whether our previous conclusions would hold, we updated our quantitative overview with new information from 14 clinical trials presented before 1 March 2003. METHODS: To compare new and old antihypertensive drugs, we computed pooled odds ratios from stratified 2 x 2 contingency tables. If Zelen's test of heterogeneity was significant, we used a random effects model. In a meta-regression analysis, we correlated odds ratios with corresponding between-group differences in systolic pressure. We then contrasted observed odds ratios with those predicted from gradients in systolic pressure. MAIN OUTCOMES: Differences in achieved systolic blood pressure and incidence of total and cardiovascular mortality, cardiovascular events, stroke, myocardial infarction and heart failure. NEW VERSUS OLD DRUGS: In 15 trials, 120 574 hypertensive patients were randomized to old drugs (diuretics or beta-blockers) or new agents [calcium-channel blockers, alpha-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin type-1 receptor (AR1) blockers]. Old and new drugs provided similar protection against total and cardiovascular mortality and fatal plus non-fatal myocardial infarction. Calcium-channel blockers, including (-8%, P = 0.07) or excluding verapamil (-10%, P = 0.02), as well as AR1 blockers (-24%, P = 0.0002) resulted in better stroke prevention than did the old drugs, whereas the opposite trend was observed for ACE inhibitors (+10%, P = 0.03). The risk of heart failure was higher (P < 0.0001) on calcium-channel blockers (+33%) and alpha-blockers (+102%) than on conventional therapy involving diuretics. META-REGRESSION: Between-group differences in achieved systolic pressure ranged from 0.1 to 3.2 mmHg in seven actively controlled trials (73 237 patients), and from 2.1 to 22.1 mmHg in seven studies comparing varying intensities of blood pressure lowering (11 128 patients). For these 14 new trials, we predicted outcome from achieved systolic blood pressure using our previously published meta-regression models based on 30 trials with 149 407 patients. In general, predicted and observed odds ratios were similar. Larger reductions in systolic pressure (weighted mean 1.8 mmHg) in two trials accounted for the advantage of AR1 blockers over conventional therapy in the prevention of stroke. Only for cardiovascular mortality in very old patients (P = 0.02) and for cardiovascular events and myocardial infarction in old Australians (P < 0.05), the observed odds ratios deviated from our predictions based on the gradients in systolic blood pressure. INTERPRETATION: The hypothesis that new antihypertensive drugs, such as calcium-channel blockers, alpha-blockers, ACE inhibitors or AR1 blockers might influence cardiovascular prognosis over and beyond their antihypertensive effects remains unproven. The finding that blood pressure differences largely accounted for cardiovascular outcome emphasizes the desirability of tight blood pressure control. However, the level to which blood pressure must be lowered to achieve maximal benefit remains currently unknown.     

Does the declining prevalence of Helicobacter pylori unmask patients with idiopathic peptic ulcer disease? Trends over an 8 year period

OBJECTIVES: Recent studies have suggested that the prevalence of Helicobacter pylori infection in patients with ulcer disease who were not using non-steroidal anti-inflammatory drugs (NSAIDs) has been overestimated. The decreasing prevalence of H. pylori could lead to a relative increase in the number of patients with this idiopathic peptic ulcer disease (IPUD). This study aimed to investigate the prevalence of IPUD and any possible trends. DESIGN AND METHODS: The reports of all upper gastro-intestinal endoscopies performed in a Dutch regional hospital over the period 1991 to 1998 were reviewed. If a gastric and/or duodenal ulcer had been diagnosed, data concerning possible H. pylori infection (culture, histology, rapid in-house urease test) were retrieved. If H. pylori tests were negative, hospital files were examined for possible use of NSAIDs or other rare causes of ulcer disease. When these were not found, stored biopsy specimens were tested for H. heilmanii by using the polymerase chain reaction technique. RESULTS: Ulcer disease was diagnosed in 405 patients who had undergone endoscopy (159 with gastric ulcer, 235 with duodenal ulcer, and 11 with both gastric and duodenal ulcer). H. pylori infection was found in 349 of these patients (86.2%). Thirty-three of the 56 H. pylori negative patients used NSAIDs and three patients had Crohn's disease, leaving 20 patients with IPUD (4.9%, 12 gastric ulcer and eight duodenal ulcer). Time trends over the study period showed a decrease of H. pylori associated peptic ulcer disease (P <0.002) and an increase of NSAID associated peptic ulcer disease (P <0.0005). The prevalence of IPUD remained stable (P=0.978). CONCLUSIONS: The prevalence of patients with H. pylori negative ulcer disease significantly decreased in our study population due to an increase in the number of patients with NSAID associated peptic ulcer disease. IPUD was rare and its prevalence did not increase over a period of 8 years.     

Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food‐borne bacterial pathogens

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron‐deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron‐ and infection‐induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin‐2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron‐deficient diet after infection. Next, mice on the iron‐deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host–pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.