Alexandra Heininger

Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study

Introduction Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. Methods In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. Results 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Conclusion Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups. ClinicalTrials.gov NCT00464204

Human cytomegalovirus infections in nonimmunosuppressed critically ill patients.

ObjectiveTo assess the occurrence of active human cytomegalovirus (HCMV) infection and HCMV disease and to evaluate potential risk factors in immunocompetent intensive care patients after major surgery or trauma. DesignA prospective clinical study. SettingAn anesthesiological intensive care unit (ICU) in a university hospital. PatientsFifty-six anti-HCMV immunoglobulin G (IgG) seropositive patients without manifest immunodeficiency whose simplified acute physiology score (SAPS II) value rose to ≥41 points during their ICU stay. InterventionsOnce a week, the patients were examined for active HCMV infection by polymerase chain reaction and by viral cultures from blood and lower respiratory tract secretions. Three times a week, detailed clinical examination for signs of HCMV disease was carried out. Measurements and Main Results Twenty of the 56 ICU patients (35.6%) who met the study criteria of a SAPS II score >40 points and anti-HCMV IgG seropositivity developed an active HCMV infection as diagnosed by the detection of HCMV DNA in leukocytes, plasma, or respiratory tract secretions. In seven patients, the virus was isolated in the respiratory tract secretions. Severe HCMV disease appeared in two patients with pneumonia or encephalitis respectively. In patients with active HCMV infection, the mortality tended to be higher (55%) than in those without (36%); the duration of intensive care treatment of the survivors was significantly longer in the patients with active HCMV infection (median 30 vs. 23 days;p = .0375). Univariate testing for factors associated with active HCMV infection showed the importance of sepsis at admission (p = .011) and prolonged pretreatment on the ward or in an external ICU (p = .002); the relevance of underlying malignant disease was borderline (p = .059). Multiple regression analysis identified only sepsis to be independently associated with active HCMV infection (p = .02; odds ratio, 4.62). ConclusionsEven in a group of ICU patients without manifest immunodeficit who were anti-HCMV IgG seropositive and had reached a SAPS II score of ≥41 points, active HCMV infection occurred frequently (35.6%). Septic patients were affected twice as often as the total study population. In 2 of the 20 cases, active HCMV infection progressed to severe HCMV disease. Proper diagnosis demands special clinical attention combined with extended virological examinations. Further studies in a larger patient group should evaluate the influence of HCMV on ICU mortality.

Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis.

IntroductionSepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis.MethodsIn a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis.ResultsSix out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects.ConclusionsThese data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.

Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration.

Background: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements. Methods: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC. Results: Peak levels in plasma amounted to 39.5 ± 10.5 mg/l (mean ± SD) and trough levels were 2.4 ± 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 ± 0.77 h. The sieving coefficient of meropenem was 0.91 ± 0.10 and the recovery in hemofiltrate amounted to 30.9 ± 11.5% of the dose. Conclusions: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.

Treatment of Meningitis Due to Methicillin-Resistant Staphylococcus epidermidis with Linezolid

ABSTRACT Methicillin-resistant Staphylococcus epidermidis (MRSE) can cause nosocomial meningitis in the presence of prosthetic devices. Vancomycin is the treatment of choice, but its penetration into the cerebrospinal fluid is poor, especially in cases without severe meningeal inflammation. We successfully used linezolid to treat a case of posttraumatic MRSE meningitis with a low-level inflammatory response. Therapeutic effectiveness was documented microbiologically and by the simultaneous measurement of linezolid levels in serum and cerebrospinal fluid.

DNase Pretreatment of Master Mix Reagents Improves the Validity of Universal 16S rRNA Gene PCR Results

ABSTRACT DNase I pretreatment of 16S rRNA gene PCR reagents was tested. The DNase I requirement for the elimination of false-positive results varied between 0.1 and 70 IU per master mix depending on the applied Taq polymerase. PCR sensitivity was mostly maintained when 0.1 IU of DNase I was used.

Emergence of increasing linezolid-resistance in enterococci in a post-outbreak situation with vancomycin-resistant Enterococcus faecium

During 2004 and at the start of 2005 a university hospital in Southwest Germany was affected by an extensive outbreak of vancomycin-resistant Enterococcus faecium (VRE). Although the outbreak was contained, linezolid-resistant enterococci emerged during and after the outbreak as the usage of linezolid became more common. Linezolid resistance was no longer limited to VRE. Nosocomial spread of linezolid-resistant but vancomycin-susceptible E. faecium was detected and these strains also emerged in patients without prior drug exposure. Linezolid should therefore be used with caution and the susceptibility of isolates monitored over time. Isolation precautions and screening of contacts should be considered to avoid spread of resistant isolates.

Disseminated fatal human cytomegalovirus disease after severe trauma.

Objective: Disseminated human cytomegalovirus (HCMV) disease is considered to be uncommon in critically ill but otherwise not immunosuppressed patients. We describe the case of a trauma victim who developed fatal HCMV disease that initially presented as pseudomembranous colitis and resulted in sudden cardiac death. Design: Case report of fatal HCMV disease in a previously healthy patient after multiple trauma. Setting: Surgical intensive care unit (ICU). Patient: A 63‐yr‐old male patient with multiple injuries. Interventions and Measurements: Under ICU treatment, symptoms of HCMV reactivation presenting as pseudomembranous colitis appeared 32 days after trauma. Detailed laboratory examinations for HCMV infection were performed, including complement fixation titer, immunoglobulin G and M, polymerase chain reaction, and virus isolation. Results: The intravital detection of HCMV DNA in serum, leukocytes, and a colonic biopsy specimen indicated HCMV reactivation. Postmortem examination findings, including positive viral cultures, showed severe disseminated HCMV disease with involvement of the colon and myocardium. Conclusions: The lack of specific clinical symptoms of HCMV disease and the delay until viral culture results are available make an exact and timely diagnosis of HCMV disease difficult. Its prevalence in critically ill but otherwise not immunosuppressed patients is currently unknown and possibly underestimated. Because severe illness or trauma can cause immunodysfunction and, thus, may contribute to an increased rate of HCMV disease, detailed studies are warranted to evaluate the real risk in the ICU setting.

Detection of pneumonia associated pathogens using a prototype multiplexed pneumonia test in hospitalized patients with severe pneumonia.

Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods – particularly in patients with prior antibiotic treatment – and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time. Trial Registration Deutsches Register Klinischer Studien (DRKS) DRKS00005684

Validation criteria for nucleic acid amplification techniques for bacterial infections.

Abstract Nucleic acid techniques (NATs), such as species-specific and universal polymerase chain reactions (PCRs), are finding ever wider use in the diagnosis of bacterial infection. However, although universal PCR assays, in particular, approach a type of modern Petri dish, they have a number of limitations which restrict their applicability. The sensitivity of universal PCR is lower than that of many species-specific PCRs, and the contamination of samples and PCR reagents with irrelevant DNA from various sources remains a problem. Thus, NATs in general and universal PCR assays in particular require careful validation to be of value for the diagnosis of infection. Validation includes sampling, DNA extraction/isolation, template amplification and visualisation of the results. Furthermore, it implies the establishment of measures of asepsis, the inclusion of positive and negative controls, techniques to optimise the release of DNA from bacterial cells, adequate repetition of the amplification reaction, and routine testing of reagent negative and inhibition controls. Finally, it entails the comparison of results obtained by NATs with those obtained by conventional microbiological methods and matching with clinical evidence of infection. Validation of NATs in clinical diagnosis remains an ongoing challenge. Because of these limitations, NATs can only serve as adjunct tools for the diagnosis of infection in selected cases; they cannot replace conventional culturing techniques. Clin Chem Lab Med 2008;46:909–18.