Luuk Wieske

Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients

Objectives:Correct classification of the source of infection is important in observational and interventional studies of sepsis. Centers for Disease Control and Prevention criteria are most commonly used for this purpose, but the robustness of these definitions in critically ill patients is not known. We hypothesized that in a mixed ICU population, the performance of these criteria would be generally reduced and would vary among diagnostic subgroups. Design:Prospective cohort. Setting:Data were collected as part of a cohort of 1,214 critically ill patients admitted to two hospitals in The Netherlands between January 2011 and June 2011. Patients:Eight observers assessed a random sample of 168 of 554 patients who had experienced at least one infectious episode in the ICU. Each patient was assessed by two randomly selected observers who independently scored the source of infection (by affected organ system or site), the plausibility of infection (rated as none, possible, probable, or definite), and the most likely causative pathogen. Assessments were based on a post hoc review of all available clinical, radiological, and microbiological evidence. The observed diagnostic agreement for source of infection was classified as partial (i.e., matching on organ system or site) or complete (i.e., matching on specific diagnostic terms), for plausibility as partial (2-point scale) or complete (4-point scale), and for causative pathogens as an approximate or exact pathogen match. Interobserver agreement was expressed as a concordant percentage and as a kappa statistic. Interventions:None. Measurements and Main Results:A total of 206 infectious episodes were observed. Agreement regarding the source of infection was 89% (183/206) and 69% (142/206) for a partial and complete diagnostic match, respectively. This resulted in a kappa of 0.85 (95% CI, 0.79–0.90). Agreement varied from 63% to 91% within major diagnostic categories and from 35% to 97% within specific diagnostic subgroups, with the lowest concordance observed in cases of ventilator-associated pneumonia. In the 142 episodes for which a complete match on source of infection was obtained, the interobserver agreement for plausibility of infection was 83% and 65% on a 2- and 4-point scale, respectively. For causative pathogen, agreement was 78% and 70% for an approximate and exact pathogen match, respectively. Conclusions:Interobserver agreement for classifying sources of infection using Centers for Disease Control and Prevention criteria was excellent overall. However, full concordance on all aspects of the diagnosis between independent observers was rare for some types of infection, in particular for ventilator-associated pneumonia.

The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest.

INTRODUCTION Treatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25-0.5 °C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome. METHODS This retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 °C was dichotomized in a high (≥ 0.5 °C/h) or normal rate (<0.5 °C/h). Fever was defined as >38 °C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months. RESULTS From 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01-4.57), p<0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64-3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88-7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31-1.30), p = 0.22. CONCLUSIONS This study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome.

Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

BACKGROUND Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. METHODS This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. FINDINGS The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1·86 [95% CI 1·21-2·86]; p=0·0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0·64 [0·40-1·04]; p=0·061), 16 (23%) of 71 people with a Mars3 endotype (HR 0·71 [0·41-1·22]; p=0·19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1·13 [0·63-2·04]; p=0·69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0·33 (0·09-0·58; p=0·008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. INTERPRETATION This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. FUNDING Center for Translational Molecular Medicine, Netherlands.

Second opinions and tertiary referrals in neurology

Background and objectiveThe number of neurological second opinions (SO) and tertiary referrals (TR) is increasing. The main purpose of this study was to assess whether a day-care admission made a meaningful contribution to standard neurological outpatient care, for a wide range of second opinions and tertiary referrals.MethodsAll new patients attending an academic neurological day-care clinic in a 6-month period were investigated. Before admission, all previous medical correspondence and ancillary investigations were reviewed. On the day of admission, extensive time was available for clinical evaluation and additional ancillary investigations and an attempt was made to come to a final diagnosis. Demographic characteristics, duration of symptoms, patient satisfaction, new diagnoses and treatment consequences were studied.Results300 patients (183 SO and 117 TR) were evaluated. In total 103 patients (35 %) received a new diagnosis (26 % SO vs. 48 % TR, p < 0.001) and 69 (67 %) of these had therapeutic implications. A new treatment advice was given to a total of 149 patients (50 %), which was similar in both groups (48 % vs. 53 %). Second opinions were considered medically less relevant than tertiary referrals (39 % vs. 64 %, p < 0.001). The number of new diagnoses differed largely between various diagnosis categories. Especially somatoform disorders and radicular syndromes were often newly diagnosed.ConclusionA high number of second opinion and tertiary referral patients benefits from a day-care admission in a neurological outpatient clinic. Careful selection for referral of patients who will benefit from daycare admission may even enlarge the diagnostic and therapeutic yield.

Is Critical Illness Neuromyopathy and Duration of Mechanical Ventilation Decreased by Strict Glucose Control

Strict glycemic control (SGC) is reported to have a beneficial effect on critical illness polyneuropathy/myopathy (CINM) and the duration of mechanical ventilation. The methodology used to diagnose CINM differs substantially in studies on this topic. This may influence the reported treatment effect. We reviewed literature on the effect of SGC on CINM and duration of ventilation by conducting a OVID Medline systematic electronic search of literature describing effects of SGC on occurrence of CINM and the effect of SGC on the duration of mechanical ventilation. A beneficial effect of SGC on CINM, diagnosed by needle myography, was reported in three studies. One of these studies showed that the incidence of weakness or failure to wean did not decrease by SGC, as the number of electrophysiological studies (EMG) ordered for these problems remained the same. Another study reported no improvement of muscle strength due to SGC. SGC reduced the duration of mechanical ventilation in three studies while six other studies did not report this beneficial effect. SGC seems to have a beneficial effect on CINM, but the reported risk reduction is likely to be an overestimation of the treatment effect due to the diagnostic methods used. Duration of mechanical ventilation may not be a reliable surrogate marker for CINM and a beneficial effect of SGC on this parameter has not been proven. We propose to use the recently developed diagnostic criteria for ICU-acquired weakness and critical illness neuromyopathy in future studies.

Early prediction of intensive care unit-acquired weakness using easily available parameters: a prospective observational study.

Introduction An early diagnosis of Intensive Care Unit–acquired weakness (ICU–AW) using muscle strength assessment is not possible in most critically ill patients. We hypothesized that development of ICU–AW can be predicted reliably two days after ICU admission, using patient characteristics, early available clinical parameters, laboratory results and use of medication as parameters. Methods Newly admitted ICU patients mechanically ventilated ≥2 days were included in this prospective observational cohort study. Manual muscle strength was measured according to the Medical Research Council (MRC) scale, when patients were awake and attentive. ICU–AW was defined as an average MRC score <4. A prediction model was developed by selecting predictors from an a–priori defined set of candidate predictors, based on known risk factors. Discriminative performance of the prediction model was evaluated, validated internally and compared to the APACHE IV and SOFA score. Results Of 212 included patients, 103 developed ICU–AW. Highest lactate levels, treatment with any aminoglycoside in the first two days after admission and age were selected as predictors. The area under the receiver operating characteristic curve of the prediction model was 0.71 after internal validation. The new prediction model improved discrimination compared to the APACHE IV and the SOFA score. Conclusion The new early prediction model for ICU–AW using a set of 3 easily available parameters has fair discriminative performance. This model needs external validation.

Muscle and nerve inflammation in intensive care unit-acquired weakness: a systematic translational review

BACKGROUND Intensive care unit-acquired weakness (ICU-AW) is an important complication of critical illness. The main risk factors, sepsis and the systemic inflammatory response syndrome, suggest an inflammatory pathogenesis. In this systematic translational review we summarize current knowledge on inflammation in muscle and nerve tissue in animal models of ICU-AW and in critically ill patients with ICU-AW. METHODS We conducted a systematic search in the databases of MEDLINE, EMBASE and Web of Science using predefined search and selection criteria. From the included studies we extracted data on study characteristics and on inflammation in muscle and nerve tissue. RESULTS The literature search yielded 349 unique articles, of which 12 animal studies and 20 human studies fulfilled the in- and exclusion criteria. All studies had important shortcomings in methodological quality. In the animal studies, inflammation of muscle tissue was found, represented by cellular infiltration and increased local levels of various inflammatory mediators. In human studies, high levels of various inflammatory mediators were found in muscle and nerve tissue of ICU-AW patients. CONCLUSION This systematic translational review suggests a role for local inflammation in ICU-AW, but the available evidence is limited and studies have severe methodological limitations.

Examination of cardiovascular and peripheral autonomic function in the ICU: a pilot study

Critical illness may affect the autonomic nervous system. Decreased cardiovascular autonomic function measured by heart rate variability (HRV) has been reported in critically ill patients but limited information exists about other autonomic functions. The cold face test (CFT) and skin wrinkle test (SWT) have never been investigated in critically ill patients. Feasibility and safety of the CFT and SWT were investigated in critically ill patients. Exclusion criteria: polyneuropathy, autonomic neuropathy, admission after stroke, spinal cord injury or cardiac arrest. For the CFT, a cold pack was applied to the forehead to measure the maximal increase in RR interval. The simulated SWT was used and wrinkling was assessed on a five-point scale. HRV was investigated using power spectral analysis of continuous 5-min ECG recordings. Twelve critically ill patients were included (mean age 54). No adverse effects for the CFT and SWT were noted. The CFT could be performed in 10 patients and showed an abnormal response in 9. The SWT could be performed in 11 patients; results were abnormal in 6. HRV analysis showed decreased HRV in all patients. CFT and HRV responses were correlated with each other, no correlation was found between SWT and CFT or HRV results. The CFT and SWT are feasible and safe in critically ill patients. Cardiovascular dysfunction may be more prevalent in critical illness than peripheral sympathetic dysfunction. Influence of confounders and further validation of these tests needs to be investigated.

Neurofilaments as a plasma biomarker for ICU-acquired weakness: an observational pilot study

IntroductionEarly diagnosis of intensive care unit – acquired weakness (ICU-AW) using the current reference standard, that is, assessment of muscle strength, is often hampered due to impaired consciousness. Biological markers could solve this problem but have been scarcely investigated. We hypothesized that plasma levels of neurofilaments are elevated in ICU-AW and can diagnose ICU-AW before muscle strength assessment is possible.MethodsFor this prospective observational cohort study, neurofilament levels were measured using ELISA (NfHSMI35 antibody) in daily plasma samples (index test). When patients were awake and attentive, ICU-AW was diagnosed using the Medical Research Council scale (reference standard). Differences and discriminative power (using the area under the receiver operating characteristic curve; AUC) of highest and cumulative (calculated using the area under the neurofilament curve) neurofilament levels were investigated in relation to the moment of muscle strength assessment for each patient.ResultsBoth the index test and reference standard were available for 77 ICU patients. A total of 18 patients (23%) fulfilled the clinical criteria for ICU-AW. Peak neurofilament levels were higher in patients with ICU-AW and had good discriminative power (AUC: 0.85; 95% CI: 0.72 to 0.97). However, neurofilament levels did not peak before muscle strength assessment was possible. Highest or cumulative neurofilament levels measured before muscle strength assessment could not diagnose ICU-AW (AUC 0.59; 95% CI 0.37 to 0.80 and AUC 0.57; 95% CI 0.32 to 0.81, respectively).ConclusionsPlasma neurofilament levels are raised in ICU-AW and may serve as a biological marker for ICU-AW. However, our study suggests that an early diagnosis of ICU-AW, before muscle strength assessment, is not possible using neurofilament levels in plasma.

Is gentamicin affecting the neuromuscular system of critically ill patients

Dear Editor, Intensive care unit-acquired weakness (ICU-AW) is a common and important neuromuscular complication of critical illness [1]. No recognized treatment for ICU-AW is available [1], increasing the need for prevention whenever possible. Currently advocated preventive measures are aimed at controlling risk factors, like avoiding hyperglycemia and minimizing use of corticosteroids [1]. Aminoglycosides may be another modifiable risk factor, although findings differ across studies [1]. In a previous study, we identified early aminoglycoside treatment as a predictor of ICU-AW [2]. In that study, we did not assess the association between aminoglycoside serum levels, which is a more reliable indicator of actual exposure, and ICU-AW or correct for the influence of possible confounders. Therefore, we conducted this post hoc analysis to investigate if there is an exposure-dependent association, independent of possible confounders, between cumulative gentamicin serum exposure in the first 2 days after ICU admission and ICU-AW. Study methodology is described in the electronic supplementary material. A cohort of 212 critically patients, 103 diagnosed with ICU-AW, were included. Clinical characteristics are described elsewhere [2]. Gentamicin was administered in 51/103 (50 %) of the patients with ICU-AW compared to 30/109 (28 %; p \ 0.01) patients without ICU-AW within the first 2 days after ICU admission. Distributions of cumulative gentamicin dosage and the area under the concentration–time curve until 48 h after administration (AUC0–48h) levels for all patients and for patients treated with gentamicin are shown in Fig. E1 in the electronic supplementary material. Table 1 displays the univariable and multivariable analyses. Treatment with gentamicin was independently associated with ICUAW. Both cumulative gentamicin dosage and AUC0–48h levels had a positive and exposure-dependent association with ICU-AW. No other antibiotics were associated with ICU-AW, except for vancomycin (Table E1 in the electronic supplementary material). When both cumulative serum gentamicin and vancomycin exposure were included in the model, the odds ratio for developing ICU-AW for every 100 mg/L increase in AUC0–48h was 1.36 (95 % CI 1.06–1.77; p = 0.02) for gentamicin and 1.11 (95 % CI 1.01–1.24; p = 0.04) for vancomycin. Results were similar when missing data was imputed (Table E2 in the electronic supplementary material). Important limitations of our analysis are that no causal relation can be deduced from this observational study, with the inherent risk of residual confounding. Also, electrophysiological studies and muscle biopsies were not used to differentiate between the disorders causing ICU-AW. The underlying mechanisms by which gentamicin may cause or contribute to development of ICU-AW