Sascha Tafelski

Impact of adherence to standard operating procedures for pneumonia on outcome of intensive care unit patients.

Background:Pneumonia accounts for almost half of intensive care unit (ICU) infections and nearly 60% of deaths from nosocomial infections. It increases hospital stay by 7–9 days, crude mortality by 70% and attributable mortality by 30%. Objective:Our purpose was to assess the impact of standard operating procedures adapted to the local resistance rates in the initial empirical treatment for pneumonia on duration of first pneumonia episode, duration of mechanical ventilation, and length of ICU stay. Design:Prospective observational cohort study with retrospective expert audit. Setting:Five anesthesiologically managed ICUs at University hospital (one cardio-surgical, one neurosurgical, two interdisciplinary, and one intermediate care). Patients:Of 524 consecutive patients with ≥36 hr ICU treatment 131 patients with pneumonia on ICU were identified. Their first pneumonia episode was evaluated daily for adherence to standard operating procedures. Pneumonia was diagnosed according to the American Thoracic Society guidelines. Patients with >70% compliance were assigned to high adherence group (HAG), patients with ≤70% to low adherence group (LAG). Measurements and Results:HAG consisted of 45 (49 first episode) patients, LAG of 86 (82 first episode) patients, respectively. Mean duration of treatment of the first pneumonia episode was 10.11 ± 7.95 days in the LAG and 6.22 ± 3.27 days in the HAG (p = 0.001). Duration of mechanical ventilation was 317.59 ± 336.18 hrs in the LAG and 178.07 ± 191.33 hrs in the HAG (p = 0.017). Length of ICU stay was 20.24 ± 16.59 days in the LAG and 12.04 ± 10.42 days in the HAG (p = 0.001). Limitations:Barriers in compliance need further evaluation. Conclusion:Adherence to standard operating procedure is associated with a shorter duration of treatment of first pneumonia episode, a shorter duration of mechanical ventilation, and a shorter ICU stay.

Long-term effect of computer-assisted decision support for antibiotic treatment in critically ill patients: a prospective ‘before/after’ cohort study

Objectives Antibiotic resistance has risen dramatically over the past years. For individual patients, adequate initial antibiotic therapy is essential for clinical outcome. Computer-assisted decision support systems (CDSSs) are advocated to support implementation of rational anti-infective treatment strategies based on guidelines. The aim of this study was to evaluate long-term effects after implementation of a CDSS. Design This prospective ‘before/after’ cohort study was conducted over four observation periods within 5 years. One preinterventional period (pre) was compared with three postinterventional periods: directly after intensive implementation efforts (post1), 2 years (post2) and 3 years (post3) after implementation. Setting Five anaesthesiological-managed intensive care units (ICU) (one cardiosurgical, one neurosurgical, two interdisciplinary and one intermediate care) at a university hospital. Participants Adult patients with an ICU stay of >48 h were included in the analysis. 1316 patients were included in the analysis for a total of 12 965 ICU days. Intervention Implementation of a CDSS. Outcome measures The primary end point was percentage of days with guideline adherence during ICU treatment. Secondary end points were antibiotic-free days and all-cause mortality compared for patients with low versus high guideline adherence. Main results Adherence to guidelines increased from 61% prior to implementation to 92% in post1, decreased in post2 to 76% and remained significantly higher compared with baseline in post3, with 71% (p=0.178). Additionally, antibiotic-free days increased over study periods. At all time periods, mortality for patients with low guideline adherence was higher with 12.3% versus 8% (p=0.014) and an adjusted OR of 1.56 (95% CI 1.05 to 2.31). Conclusions Implementation of computerised regional adapted guidelines for antibiotic therapy is paralleled with improved adherence. Even without further measures, adherence stayed high for a longer period and was paralleled by reduced antibiotic exposure. Improved guideline adherence was associated with reduced ICU mortality. Trial registration number ISRCTN54598675.

Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients

Objective To determine whether the Arg753Gln polymorphism of the toll-like receptor 2 (TLR2) gene and the Asp299Gly polymorphism of the TLR4 gene in critically ill patients affect their clinical outcomes. Methods Medical and surgical patients in three intensive care units (ICU) were enrolled in this prospective study. TLR2 and TLR4 gene polymorphisms were determined using restriction fragment length polymorphism analysis. Results A total of 145 patients were included in this study: 28 patients carried heterozygous mutations (10 in the TLR2 gene, 19 in the TLR4 gene, and one combined) and 117 patients were wild type. Severe sepsis was observed in 33% of wild types (n = 38), 60% of the TLR2 group (n = 6), and 63% of the TLR4 group (n = 12); the difference was significant between the TLR4 and wild type groups. Both TLR groups demonstrated a shorter time-to-onset of severe sepsis or septic shock. Only the TLR4 group demonstrated significant progression towards septic shock compared with the wild type group. Length of ICU stay was significantly prolonged in the TLR4 group compared with the wild type group, but not in the TLR2 group. Conclusions Two common SNPs of the TLR2 and TLR4 genes – Arg753Gln and Asp299Gly – were associated with a shorter time-to-onset of severe sepsis or septic shock in patients admitted to the ICU.

Computer-assisted Decision Support for Changing Practice in Severe Sepsis and Septic Shock

Computer-assisted decision support systems (CDSS) are designed to improve infection management. The aim of this prospective, clinical pre- and post-intervention study was to investigate the influence of CDSS on infection management of severe sepsis and septic shock in intensive care units (ICUs). Data were collected for a total of 180 days during two study periods in 2006 and 2007. Of the 186 patients with severe sepsis or septic shock, 62 were stratified into a low adherence to infection management standards group (LAG) and 124 were stratified into a high adherence group (HAG). ICU mortality was significantly increased in LAG versus HAG patients (Kaplan–Meier analysis). Following CDSS implementation, adherence to standards increased significantly by 35%, paralleled with improved diagnostics, more antibiotic-free days and a shortened time until antibiotics were administered. In conclusion, adherence to infection standards is beneficial for patients with severe sepsis or septic shock and CDSS is a useful tool to aid adherence.

Randomized controlled clinical trial evaluating multiplex polymerase chain reaction for pathogen identification and therapy adaptation in critical care patients with pulmonary or abdominal sepsis

Objective To determine whether a multiplex polymerase chain reaction (PCR)-based test could reduce the time required for initial pathogen identification in patients in an intensive care unit (ICU) setting. Methods This double-blind, parallel-group randomized controlled trial** enrolled adults with suspected pulmonary or abdominal sepsis caused by an unknown pathogen. Both the intervention and control groups underwent the standard blood culture (BC) testing, but additional pathogen identification, based on the results of a LightCycler® SeptiFast PCR test, were provided in the intervention group. Results The study enrolled 37 patients in the control group and 41 in the intervention group. Baseline clinical and demographic characteristics were similar in both groups. The PCR-based test identified a pathogen in 10 out of 41 (24.4%) patients in the intervention group, with a mean duration from sampling to providing the information to the ICU of 15.9 h. In the control group, BC results were available after a significantly longer period (38.1 h). Conclusion The LightCycler® SeptiFast PCR test demonstrated a significant reduction in the time required for initial pathogen identification, compared with standard BC.

Membrane-bound glucocorticoid receptors on distinct nociceptive neurons as potential targets for pain control through rapid non-genomic effects

Glucocorticoids were long believed to primarily function through cytosolic glucocorticoid receptor (GR) activation and subsequent classical genomic pathways. Recently, however, evidence has emerged that suggests the presence of rapid non-genomic GR-dependent signaling pathways within the brain, though their existence in spinal and peripheral nociceptive neurons remains elusive. In this paper, we aim to systemically identify GR within the spinal cord and periphery, to verify their putative membrane location and to characterize possible G protein coupling and pain modulating properties. Double immunofluorescence confocal microscopy revealed that GR predominantly localized in peripheral peptidergic and non-peptidergic nociceptive C- and Aδ-neurons and existed only marginally in myelinated mechanoreceptive and proprioreceptive neurons. Within the spinal cord, GR predominantly localized in incoming presynaptic nociceptive neurons, in pre- and postsynaptic structures of the dorsal horn, as well as in microglia. GR saturation binding revealed that these receptors are linked to the cell membrane of sensory neurons and, upon activation, they trigger membrane targeted [35S]GTPγS binding, indicating G protein coupling to a putative receptor. Importantly, subcutaneous dexamethasone immediately and dose-dependently attenuated acute nociceptive behavior elicited in an animal model of formalin-induced pain hypersensitivity compared to naive rats. Overall, this study provides firm evidence for a novel neuronal mechanism of GR agonists that is rapid, non-genomic, dependent on membrane binding and G protein coupling, and acutely modulates nociceptive behavior, thus unraveling a yet unconsidered mechanism of pain relief.

Observational clinical study on the effects of different dosing regimens on vancomycin target levels in critically ill patients: Continuous versus intermittent application

Different dosing regimens for vancomycin are in clinical use: intermittent infusion and continuous administration. The intention of using these different dosing regimens is to reduce toxicity, to achieve target levels faster and to avoid treatment failure. The aim of this phase IV study was to compare safety and effectiveness in both administration regimens. The study was conducted in 2010 and 2011 in three postoperative intensive care units (ICUs) in a tertiary care university hospital in Berlin, Germany. Adult patients with vancomycin therapy and therapeutic drug monitoring were included. Out of 675 patients screened, 125 received vancomycin therapy, 39% with intermittent and 61% with continuous administration. Patients with continuous administration achieved target serum levels significantly earlier (median day 3 versus 4, p=0.022) and showed fewer sub-therapeutic serum levels (41% versus 11%, p<0.001). ICU mortality rate, duration of ICU stay and duration of ventilation did not differ between groups. Acute renal failure during the ICU stay occurred in 35% of patients with intermittent infusion versus 26% of patients with continuous application (p=0.324). In conclusion, continuous administration of vancomycin allowed more rapid achievement of targeted drug levels with fewer sub-therapeutic vancomycin levels observed. This might indicate that patients with more severe infections or higher variability in renal function could benefit from this form of administration.

Adherence to Standard Operating Procedures is Crucial for Intensive Care Unit Survival of Elderly Patients

Elderly patients account for 42–52% of intensive care unit (ICU) admissions and for almost 60% of all ICU days in the USA and up to 50% receive inappropriate antibiotic treatment. The aim of this study was to evaluate whether adherence to Standard Operating Procedures (SOPs) reduced ICU mortality in an elderly population. The study included consecutive patients (n = 228) aged ≤ 60 years with an ICU stay of > 72 h. SOPs were based on evidence-based medicine guidelines for diagnosis and treatment of infections, and on local resistance rates. According to preset indicators of quality management standards and assessment of different degrees of adherence, an implementation rate > 70% was considered adherent (high adherence group [HAG]) and ≤ 70% was considered non-adherent (low adherence group [LAG]). Patients in the HAG (n = 137) had significantly reduced mortality compared with LAG patients (n = 91): 5.8% versus 19.8%, respectively. It was concluded that adherence to SOPs based on evidence-based medicine that consider local resistance rates for antibiotic treatment in elderly ICU patients is associated with a lower mortality rate.

Acute mechanical sensitization of peripheral nociceptors by aldosterone through non-genomic activation of membrane bound mineralocorticoid receptors in naive rats

Recently, there is increasing interest in the role of peripheral mineralocorticoid receptors (MR) to modulate pain, but their localization in neurons and glia of the periphery and their distinct involvement in pain control remains elusive. In naive Wistar rats our double immunofluorescence confocal microscopy of the spinal cord, dorsal root ganglia, sciatic nerve and innervated skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)- and trkA-immunoreactive (IR) nociceptive neurons and only marginally with myelinated trkB-IR mechanoreceptive and trkC-IR proprioreceptive neurons underscoring a pivotal role for MR in the modulation of pain. MR could not be detected in Schwann cells, satellite cells, and astrocytes and only scarcely in spinal microglia cells excluding a relevant functional role of glia-derived MR at least in naïve rats. Intrathecal (i.t.) and intraplantar (i.pl.) application of increasing doses of the MR selective agonist aldosterone acutely increased nociceptive behavior which was reversible by a MR selective antagonist and most likely due to non-genomic effects. This was further substantiated by the first identification of membrane bound MR specific binding sites in sensory neurons of dorsal root ganglia and spinal cord. Therefore, a crucial role of MR on nociceptive neurons but not on glia cells and their impact on nociceptive behavior most likely due to immediate non-genomic effects has to be considered under normal but more so under pathological conditions in future studies.

Obesity in critically ill patients is associated with increased need of mechanical ventilation but not with mortality

Worldwide incidence of obesity is increasing and impaired outcome in postoperative patients has been described. Antibiotic prescribing is complicated by different pharmacology in this population. This study evaluates mortality and morbidity of obese postoperative patients and explores possible relation to antibiotic therapy. Therefore, data obtained in a prospective study in 2009-2010 were analysed. Postoperative patients on 5 ICUs were included with >48h of ICU treatment and documented body-mass-index (BMI). Altogether 451 non-obese patients (BMI<30kg/m(2)) were compared with 130 obese patients including propensity score matching. There was significant heterogeneity of baseline characteristics. ICU-mortality was 7.5% in non-obese and 7.7% in obese patients (p>0.999), but 65.4% of obese patients required mechanical ventilation compared with only 53.2% of non-obese patients (p=0.016). These findings were validated in multivariate regression analyses (adjusted OR for ICU-mortality for obese patients 0.53, 95%-CI 0.188-1.321, p=0.197; adjusted OR for mechanical ventilation 1.841, 95%-CI 1.113-3.076, p=0.018). Results were confirmed by propensity score matching. Therapeutic drug monitoring for vancomycin (TDM) showed that underdosing and overdosing occurred more often in obese patients and sufficient TDM levels were less often achieved. In conclusion, obesity is associated with increased morbidity but ICU mortality is equal compared with a non-obese population. Pharmacological differences might explain observed differences in antibiotic therapy and in obese patients TDM might be especially of importance.