Joerg C. Schefold

Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients

IntroductionNeuron specific enolase (NSE) has been proven effective in predicting neurological outcome after cardiac arrest with a current cut off recommendation of 33 μg/l. However, most of the corresponding studies were conducted before the introduction of mild therapeutic hypothermia (MTH). Therefore we conducted a study investigating the association between NSE and neurological outcome in patients treated with MTHMethodsIn this prospective observational cohort study the data of patients after cardiac arrest receiving MTH (n = 97) were consecutively collected and compared with a retrospective non-hypothermia (NH) group (n = 133). Serum NSE was measured 72 hours after admission to ICU. Neurological outcome was classified according to the Pittsburgh cerebral performance category (CPC 1 to 5) at ICU discharge.ResultsNSE serum levels were significantly lower under MTH compared to NH in univariate analysis. However, in a linear regression model NSE was affected significantly by time to return of spontaneous circulation (ROSC) and ventricular fibrillation rhythm but not by MTH. The model for neurological outcome identified NSE, NSE*MTH (interaction) as well as time to ROSC as significant predictors. Receiver Operating Characteristic (ROC) analysis revealed a higher cutoff value for unfavourable outcome (CPC 3 to 5) with a specificity of 100% in the hypothermia group (78.9 μg/l) compared to the NH group (26.9 μg/l).ConclusionsRecommended cutoff levels for NSE 72 hours after ROSC do not reliably predict poor neurological outcome in cardiac arrest patients treated with MTH. Prospective multicentre trials are required to re-evaluate NSE cutoff values for the prediction of neurological outcome in patients treated with MTH.

Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms.

BACKGROUND Tryptophan (Trp) is catabolized by indoleamine 2,3-dioxygenase (IDO). Changes in Trp metabolism and IDO activity in chronic kidney disease (CKD) have not been widely studied, and the impact of haemodialysis is uncertain. Here we investigate Trp catabolism, IDO activity and the role of inflammation in moderate to very severe CKD and haemodialysis. METHODS Eighty individuals were included in a prospective blinded endpoint analysis. Using tandem mass spectrometry, serum levels of Trp, kynurenine (Kyn), kynurenic-acid (Kyna), quinolinic-acid (Quin), 5-hydroxytryptophan (OH-Trp), serotonin (5-HT), estimated IDO activity and inflammatory markers were assessed in 40 CKD patients (age 57 +/- 14 years, 21 male, creatinine 4.5 +/- 2.7, n = 17 receiving haemodialysis), and in 40 healthy controls (age 34 +/- 9 years, 26 male). RESULTS Trp levels were unchanged in CKD (P = 0.78 versus controls). Serum levels of Kyn, Kyna and Quin increased with CKD severity (stages 4, 5 versus controls all P < or = 0.01). IDO activity was significantly induced in CKD and correlated with disease severity (stages 3-5 versus controls, all P < or = 0.01) and inflammatory markers [high-sensitivity C-reactive protein (hsCRP), soluble TNF-receptor-1 (sTNFR-I); both P < or = 0.03]. IDO products (Kyn, Kyna, Quin) correlated also with hsCRP and sTNFR-I (all P < or = 0.04). Haemodialysis did not influence IDO activity (P = 0.26) and incompletely removed Kyn, Kyna, Quin, OH-Trp and 5-HT by 22, 26, 50, 44 and 34%, respectively. In multiple regression, IDO activity correlated with hsCRP and sTNFR-I (both P < or = 0.03) independent of serum creatinine, age and body weight. CONCLUSIONS IDO activity and serum levels of tryptophan catabolites of the kynurenine pathway increase with CKD severity. In CKD, induction of IDO may primarily be a consequence of chronic inflammation.

Mild therapeutic hypothermia shortens intensive care unit stay of survivors after out-of-hospital cardiac arrest compared to historical controls

IntroductionPersistent coma is a common finding after cardiac arrest and has profound ethical and economic implications. Evidence suggests that therapeutic hypothermia improves neurological outcome in these patients. In this analysis, we investigate whether therapeutic hypothermia influences the length of intensive care unit (ICU) stay and ventilator time in patients surviving out-of-hospital cardiac arrest.MethodsA prospective observational study with historical controls was conducted at our medical ICU. Fifty-two consecutive patients (median age 62.6 years, 43 males, 34 ventricular fibrillation) submitted to therapeutic hypothermia after out-of-hospital cardiac arrest were included. They were compared with a historical cohort (n = 74, median age 63.8 years, 53 males, 43 ventricular fibrillation) treated in the era prior to hypothermia treatment. All patients received the same standard of care. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. Univariate analyses and multiple regression models were used.ResultsIn survivors, therapeutic hypothermia and baseline disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] score) were both found to significantly influence ICU stay and ventilator time (all P < 0.01). ICU stay was shorter in survivors receiving therapeutic hypothermia (median 14 days [interquartile range (IQR) 8 to 26] versus 21 days [IQR 15 to 30] in the control group; P = 0.017). ICU length of stay and time on ventilator were prolonged in patients with CPC 3 or 4 compared with patients with CPC 1 or 2 (P = 0.003 and P = 0.034, respectively). Kaplan-Meier analysis showed improved probability for 1-year survival in the hypothermia group compared with the controls (log-rank test P = 0.013).ConclusionTherapeutic hypothermia was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest. Moreover, profound improvements in both neurological outcome and 1-year survival were observed.

Intensive care unit—acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock

Sepsis presents a major health care problem and remains one of the leading causes of death within the intensive care unit (ICU). Therapeutic approaches against severe sepsis and septic shock focus on early identification. Adequate source control, administration of antibiotics, preload optimization by fluid resuscitation and further hemodynamic stabilisation using vasopressors whenever appropriate are considered pivotal within the early—golden—hours of sepsis. However, organ dysfunction develops frequently in and represents a significant comorbidity of sepsis. A considerable amount of patients with sepsis will show signs of severe muscle wasting and/or ICU-acquired weakness (ICUAW), which describes a frequently observed complication in critically ill patients and refers to clinically weak ICU patients in whom there is no plausible aetiology other than critical illness. Some authors consider ICUAW as neuromuscular organ failure, caused by dysfunction of the motor unit, which consists of peripheral nerve, neuromuscular junction and skeletal muscle fibre. Electrophysiologic and/or biopsy studies facilitate further subclassification of ICUAW as critical illness myopathy, critical illness polyneuropathy or critical illness myoneuropathy, their combination. ICUAW may protract weaning from mechanical ventilation and impede rehabilitation measures, resulting in increased morbidity and mortality. This review provides an insight on the available literature on sepsis-mediated muscle wasting, ICUAW and their potential pathomechanisms.

Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis

IntroductionPatients with sepsis often demonstrate severely impaired immune responses. The hallmark of this state of immunoparalysis is monocytic deactivation characterized by decreased human leukocyte antigen (HLA)-DR expression and reduced production of proinflammatory cytokines. Recently, diminished numbers of dendritic cells (DCs) were reported in patients with sepsis. However, little is known about DC phenotype and function in human sepsis. We therefore compared phenotypic and functional changes in monocyte and DC subsets in patients with sepsis and immunoparalysis.MethodsIn a prospective observational analysis, 16 consecutive patients with severe sepsis and septic shock (age 59.2 ± 9.7 years, 13 male, Sequential Organ Failure Assessment score 6.1 ± 2.7) and immunoparalysis (monocytic HLA-DR expression < 5,000 antibodies/cell) and 16 healthy volunteers were included. Peripheral blood DC counts, HLA-DR expression and ex vivo cytokine production were evaluated in comparison with monocyte subsets over time.ResultsAt baseline, a profound reduction in the numbers of myeloid DCs (MDCs), plasmacytoid DCs (PDCs), and CD14dimCD16positive monocytes was observed in sepsis whereas CD14brightCD16negative and CD14brightCD16positive monocyte numbers were increased. HLA-DR expression was reduced on all monocyte and DC subsets. Production of proinflammatory cytokines and intracellular cytokine staining in response to lipopolysaccharide and lipoteichoic acid was impaired in monocyte subsets and MDCs, whereas IL-10 secretion was increased. IFNα response by stimulated PDCs was significantly decreased compared with controls. At day 28, HLA-DR expression and cytokine production of DC and monocyte subsets remained lower in septic patients compared with controls.ConclusionsIn sepsis, long-lasting functional deactivation is common to all circulating monocyte and DC subsets. In addition to decreased peripheral blood DC counts, functional impairment of antigen-presenting cells may contribute to an impaired antimicrobial defense in sepsis.

Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period

PURPOSE To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. METHODS Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48 h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. RESULTS The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). DISCUSSION Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

INFERIOR VENA CAVA DIAMETER CORRELATES WITH INVASIVE HEMODYNAMIC MEASURES IN MECHANICALLY VENTILATED INTENSIVE CARE UNIT PATIENTS WITH SEPSIS

Early optimization of fluid status is of central importance in the treatment of critically ill patients. This study aims to investigate whether inferior vena cava (IVC) diameters correlate with invasively assessed hemodynamic parameters and whether this approach may thus contribute to an early, non-invasive evaluation of fluid status. Thirty mechanically ventilated patients with severe sepsis or septic shock (age 60 +/- 15 years; APACHE-II score 31 +/- 8; 18 male) were included. IVC diameters were measured throughout the respiratory cycle using transabdominal ultrasonography. Consecutively, volume-based hemodynamic parameters were determined using the single-pass thermal transpulmonary dilution technique. This was a prospective study in a tertiary care academic center with a 24-bed medical intensive care unit (ICU) and a 14-bed anesthesiological ICU. We found a statistically significant correlation of both inspiratory and expiratory IVC diameter with central venous pressure (p = 0.004 and p = 0.001, respectively), extravascular lung water index (p = 0.001, p < 0.001, respectively), intrathoracic blood volume index (p = 0.026, p = 0.05, respectively), the intrathoracic thermal volume (both p < 0.001), and the PaO(2)/FiO(2) oxygenation index (p = 0.007 and p = 0.008, respectively). In this study, IVC diameters were found to correlate with central venous pressure, extravascular lung water index, intrathoracic blood volume index, the intrathoracic thermal volume, and the PaO(2)/FiO(2) oxygenation index. Therefore, sonographic determination of IVC diameter seems useful in the early assessment of fluid status in mechanically ventilated septic patients. At this point in time, however, IVC sonography should be used only in addition to other measures for the assessment of volume status in mechanically ventilated septic patients.

The Glasgow coma score is a predictor of good outcome in cardiac arrest patients treated with therapeutic hypothermia

BACKGROUND With the recent introduction of therapeutic hypothermia the application of sedation becomes necessary in cardiac arrest patients. We therefore analysed the usefulness of the Glasgow coma score (GCS) for outcome prediction in survivors of cardiac arrest treated with therapeutic hypothermia. PATIENTS AND METHODS In a prospective observational study we identified 72 comatose patients admitted to our intensive care unit after cardiac arrest. All patients were treated with therapeutic hypothermia. After sedation stop the Glasgow coma scale (GCS) was recorded until day 4. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. RESULTS Forty-four of 72 patients (61%) were discharged with a favourable neurological outcome (CPC 1+2). GCS was significantly higher in patients with good outcome compared to patients with unfavourable outcome at every point in time after sedation stop (p<0.001). The value for prediction of good outcome with the highest accuracy was a GCS>4 at the first day after sedation stop (sensitivity 61%, PPV 90% and AUC 0.808) and GCS>6 in the following days (sensitivity 84%, PPV 92.5% and AUC 0.921 at day 4). In particular a score of >3 on the motor component of the GCS predicted good outcome with a specificity of 100% (sensitivity 43%) at the first day. CONCLUSIONS Our results indicate that monitoring of the GCS is a simple and reliable method for clinical outcome assessment in patients treated with therapeutic hypothermia. Thus, GCS monitoring remains a powerful tool to predict outcome of patients treated with therapeutic hypothermia.

A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a.

In sepsis, endotoxin, interleukin 6 (IL-6), and complement-activation product 5a (C5a) trigger inflammatory cascades resulting in monocytic deactivation. When this occurs, the outcome is often uncontrolled infection, multiple organ dysfunction, and death. We tested here whether simultaneous reduction of systemic endotoxin, IL-6, and C5a levels could be achieved via selective extracorporeal immunoadsorption (IA) and whether this would restore monocytic responsiveness and improve organ function. Therefore, 33 patients with severe sepsis or septic shock were enrolled in a prospective, 1:2case-control matched, blinded endpoint evaluation trial. In addition to best supportive care, 11 of these patients (mean age, 57.8 ± 2.2 years; Acute Physiology and Chronic Health Evaluation II score, 23.7 ± 1.6) received simultaneous endotoxin IA, IL-6 IA, and C5a IA on 5 consecutive days for 7.5 h each. Our observational end points were the course of monocytic immunity (monocytic HLA-DR expression) and other indices of inflammation and disease severity. In patients receiving IA, the mean circulating level of IL-6 was reduced from 361.7 ± 116.0 to 38.2 ± 15.2 pg/mL (P = 0.02), and of C5a from 297.6 ± 43.1 to 79.2 ± 14.5 ng/mL (P < 0.001). Two indices of endotoxemia were reduced also. Treated patients had lower C-reactive protein and Acute Physiology and Chronic Health Evaluation II scores at day 7 (P = 0.004 and P = 0.0001, respectively). Monocytic HLA-DR improved in the treated patients but not in controls (P < 0.0001). Under treatment, HLA-DR was found to recover in all patients with immunoparalysis (4,993.6 ± 1,162 to 15,295.3 ± 2,197 molecules per cell; P = 0.002). Here, we demonstrate that simultaneously reducing circulating endotoxin, IL-6, and C5a levels by selective IA reverses monocytic deactivation and improves organ system functions. This novel strategy might open a new therapeutic avenue for an interventional extracorporeal treatment of patients with sepsis.

Mild therapeutic hypothermia after cardiac arrest and the risk of bleeding in patients with acute myocardial infarction

BACKGROUND The aim of the study was to report the impact of our hypothermia protocol on survival and neurological outcome. Furthermore, we were interested in the risk of bleeding complications in patients with acute myocardial infarction (AMI) being treated with percutaneous coronary revascularisation (PCI) and therapeutic hypothermia. METHODS AND RESULTS In a prospective observational study we identified 31 comatose patients (25 male, age 65+/-13 years) admitted to our intensive care unit with out-of-hospital cardiac arrest due to AMI who were treated with hypothermia. They were compared to 31 historical age- and gender-matched controls (25 male, age 65+/-12 years) admitted after out-of-hospital cardiac arrest due to AMI in the era prior to hypothermia treatment. Peak creatinine kinase-MB was 118 U/L (94-248) in the hypothermia group and 131 U/L (98-257) in controls (p=0.51). In the hypothermia group, 19 patients were discharged with a favourable neurological outcome, whereas in controls, such outcome was observed in only six patients (p=0.002). In both groups, haemoglobin values and platelet counts declined during the first 48 h (all p<0.001). No differences regarding bleeding complications (p=1.0), transfusion requirements (p=1.0), and the number of transfusions (p=0.9) were observed between the groups. CONCLUSIONS A major improvement in neurological outcome was observed in patients treated with hypothermia. Our results indicate that the combination of reperfusion strategies and the application of hypothermia do not carry an excessive risk of bleeding complications. Patients with AMI and out-of-hospital cardiac arrest should receive the optimal therapy for both conditions, that is, either thrombolysis or PCI and therapeutic hypothermia.