The Prognostic Value of a Liver Function Test Using Indocyanine Green (ICG) Clearance in Patients with Multiple Organ Dysfunction Syndrome (MODS).

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is common in intensive care units (ICUs) and is associated with high mortality. Although there have been multiple investigations into a multitude of organ dysfunctions, little is known about the role of liver dysfunction. In addition, clinical and laboratory findings of liver dysfunction may occur with a significant delay. Therefore, the aim of this study was to investigate whether a liver function test, based on indocyanine green (ICG)-clearance, contains prognostic information for patients in the early phase of MODS. METHODS: The data of this analysis were based on the MODIFY study, which included 70 critically ill patients of a tertiary medical ICU in the early phase of MODS (≤24 h after diagnosis by an APACHE II score ≥ 20 and a sinus rhythm ≥ 90 beats per minute, with the following subgroups: cardiogenic (cMODS) and septic MODS (sMODS)) over a period of 18 months. ICG clearance was characterized by plasma disappearance rate = PDR (%/min); it was measured non-invasively by using the LiMON system (PULSION Medical Systems, Feldkirchen, Germany). The PDR was determined on the day of study inclusion (baseline) and after 96 h. The primary endpoint of this analysis was 28-day mortality. RESULTS: ICG clearance was measured in 44 patients of the MODIFY trial cohort, of which 9 patients had cMODS (20%) and 35 patients had sMODS (80%). Mean age: 59.7 ± 16.5 years; 31 patients were men; mean APACHE II score: 33.6 ± 6.3; 28-day mortality was 47.7%. Liver function was reduced in the total cohort as measured by a PDR of 13.4 ± 6.3%/min At baseline, there were no relevant differences between survivors and non-survivors regarding ICG clearance (PDR: 14.6 ± 6.1%/min vs. 12.1 ± 6.5%/min; p = 0.21). However, survivors showed better liver function than non-survivors after 96 h (PDR: 21.9 ± 6.3%/min vs. 9.2 ± 6.3%/min, p < 0.05). Consistent with these findings, survivors but not non-survivors show a significant improvement in the PDR (7.3 ± 6.3%/min vs. -2.9 ± 2.6%/min; p < 0.01) within 96 h. In accordance, receiver-operating characteristic curves (ROCs) at 96 h but not at baseline show a link between the PDR and 28-day mortality (PDR at 96 h: AUC: 0.87, 95% CI: 0.76-0.98; p < 0.01. CONCLUSIONS: In our study, we found that ICG clearance at baseline did not provide prognostic information in patients in the early stages of MODS despite being reduced in the total cohort. However, improvement of ICG clearance 96 h after ICU admission is associated with reduced 28-day mortality.

Treatment of patients with multiple organ dysfunction syndrome (MODS) with an electromagnetic field coupled to biorhythmically defined impulse configuration: the MicrocircMODS study.

BACKGROUND: To potentially improve impaired vasomotion of patients with multiple organ dysfunction syndrome (MODS), we tested whether an electromagnetic field of low flux density coupled with a biorhythmically defined impulse configuration (Physical Vascular Therapy BEMER®, PVT), in addition to standard care, is safe and feasible and might improve disturbed microcirculatory blood flow and thereby improve global haemodynamics. METHODS: In a prospective, monocentric, one-arm pilot study, 10 MODS patients (APACHE II score 20-35) were included. Patients were treated, in addition to standard care, for 4 days with PVT (3 treatment periods of 8 min each day; day 1: field intensity 10.5 µT; day 2:14 µT, day 3:17.5 µT; day 4:21.0 µT). Primary endpoint was the effect of PVT on sublingual microcirculatory perfusion, documented by microvascular flow index (MFI). Patient safety, adverse events, and outcomes were documented. RESULTS: An increase in MFI by approximately 25% paralleled 4-day PVT, with the increase starting immediately after the first PVT and lasting over the total 4-day treatment period. Concerning global haemodynamics (secondary endpoints), halving vasopressor use within 24 h, and haemodynamic stabilisation paralleled 4-day PVT with an increase in cardiac index, stroke volume index, and cardiac power index by 30%-50%. No adverse events (AEs) or serious adverse events (SAEs) were classified as causally related to the medical product (PVT) or study. Three patients died within 28 days and one patient between 28 and 180 days. CONCLUSION: PVT treatment was feasible and safe and could be performed without obstruction of standard patient care. An increase in microcirculatory blood flow, a rapid reduction in vasopressor use, and an improvement in global haemodynamics paralleled PVT treatment. Findings of this pilot study allowed forming a concept for a randomized trial for further proof.

Association of subendocardial viability ratio and mortality in the elderly population: results from the CARdiovascular disease, Living and Ageing in Halle study.

OBJECTIVES: The subendocardial viability ratio (SEVR) reflects the balance of myocardial oxygen supply and demand. Low SEVR indicates a reduced subendocardial perfusion and has been shown to predict mortality in patients with kidney disease and diabetes. The aim of this study is to investigate the association of SEVR and mortality in the elderly population. METHODS: We analysed data from the CARdiovascular disease, Living and Ageing in Halle (CARLA) study. SEVR was estimated noninvasively by radial artery tonometry and brachial blood pressure measurement. The study population was divided into a low (SEVR ≤130%) and normal (SEVR >130%) SEVR group. Cox-regression was used for survival analysis. RESULTS: In total, 1414 participants (635 women, 779 men) aged from 50 to 87 years (mean age 67.3 years) were included in the analysis. The all-cause mortality was 22.7% during a median follow-up of 10.5 years. The unadjusted association of SEVR with all-cause mortality decreased from 3.52 (1.31-9.46) [hazard ratio (95% confidence interval) for low SEVR ≤ 130% versus normal SEVR > 130%] among those younger than 60 years to 0.86 (0.50-1.48) among those older than 80 years and from 1.81 (0.22-14.70) to 0.75 (0.30-1.91) for cardiovascular mortality. Sex-specific unadjusted analyses demonstrated an association of SEVR with all-cause and cardiovascular mortality in men [2.32 (1.61-3.34) and 2.24 (1.18-4.24)], but not in women [1.53 (0.87-2.72) and 1.14 (0.34-3.82)]. CONCLUSION: Our data suggests that SEVR is an age dependent predictor for all-cause mortality, predominantly in men younger than 60 years.

[Relationship between cardiac output, heart rate and microcirculation in patients with multiorgan dysfunction syndrome]. / Zusammenhang zwischen Herzzeitvolumen, Herzfrequenz und Mikrozirkulation bei Patienten mit Multiorgandysfunktionssyndrom.

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is one of the main causes of death in intensive care units. There is evidence that microcirculation in sepsis and coronary shock is regulated separately from hemodynamics. This study investigates the relationship between heart rate (HR), cardiac output (CO) and microcirculation in patients with MODS. METHODS: This is a partial analysis of the "MODIFY study" (Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome [MODS] by Ivabradine). During the period 05/2010-09/2011, the microcirculation of 46 patients with septic and coronary MODS was measured using the sidestream dark field technique on the day of inclusion and 96 h later. Patients were randomized into a control and ivabradine treatment group. RESULTS: Overall, there is a relevant improvement in microcirculation over time small perfused vessels, SPV [%] on day 0, d0:56.5 ± 34.2/d4:73.2 ± 22.1 (p = 0.03); perfused vessel density, PVDsmall [1/mm2] d0:7.5 ± 5.0/d4:9.8 ± 3.4 (p = 0.04); proportion of perfused vessels, PPVsmall [%] d0:51.6 ± 31.6/d4:66.7 ± 21.8 (p = 0.04); microcirculatory flow index, MFI d0:1.7 ± 1.0/d4:2.2 ± 0.7 (p = 0.05). Administration of ivabradine shows no effect. In patients with coronary MODS, there is a relevant correlation between microcirculatory parameters and cardiac output (SPV [%]: r = 0.98, p = 0.004). Patients with coronary MODS show better microcirculation values at high heart rates (> 100 bpm), while patients with septic MODS show an opposite relationship. CONCLUSION: The results indicate that in critically ill patients, depending on the genesis of the MODS, there are different relationships between HF or CO values, on the one hand, and the parameters of the microcirculation, on the other.

Transbronchial cryobiopsy in unexplained, severe ARDS: a single center retrospective case series.

BACKGROUND: Acute respiratory distress syndrome (ARDS) deptics an acute form of lung infjury with often severe respiratory impairment that requires invasive mechanical ventilation. Since ARDS can be caused by several distinct etiologies, correct characterization is desired and frequently challenging. Surgical lung biopsy was previously reported to be of additive value. We describe our institutional experience using transbronchial cryobiopsy (TBCB) for further characterization of severe and unexplained ARDS cases. CASE PRESENTATION: We retrospectively collected data of TBCB in patients with unexplained ARDS, whether with or without ECMO-support. Between 2019 and 2020 TBCB was performed in eight patients. Decision for the intervention was decided in multidisciplinary discussion. Five patients were treated with ECMO. The median duration of invasive ventilation before TBCB was 24 days. TBCB was performed in one segment, that was prophylactically occluded by Watanabe spigot or swab after the procedure. Histology results and their contribution to further therapeutic decisions were analyzed. Histology revealed five diffuses alveolar damage, one acute fibrinoid organizing pneumonia, one cryptogenic organizing pneumonia and one lung cancer. All results contributed to the decision of further management. While no pneumothorax or severe endobronchial bleeding occurred, two delayed hematothoraces needed surgical treatment. No patients died due to TBCB. CONCLUSION: TBCB is feasible in ARDS even during ECMO treatment. Histologic results can play a significant role in therapeutic and ethic discussion to guide the patients' care. Side effects should be considered and monitored.

Association of arterial stiffness and heart failure with preserved ejection fraction in the elderly population - results from the CARLA study.

Arterial stiffness has been suspected as a cause of left ventricular diastolic dysfunction and may thereby contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, this association is derived from a small number of studies and application of outdated criteria to diagnose HFpEF. This study aimed to investigate the association of arterial stiffness measured by the augmentation index (AIx) and criteria for diagnosing HFpEF according to the recommended HFA-PEFF score. Our analysis based on data from the first follow-up of the CARdiovascular Disease, Living and Ageing in Halle study. The current analysis included participants with available information about comorbidities and risk factors for HFpEF, parameters for calculation of the HFA-PEFF and noninvasive AIx estimated by applanation tonometry. The association of AIx and HFA-PEFF was investigated through descriptive and inductive statistics. A total of 767 participants were included in the analysis. AIx was associated with E/e', left ventricular wall thickness (LVWT), relative wall thickness, left ventricular mass index (LVMI) and NT-proBNP but not with e' or left atrial volume index. However, after adjustment for confounders, only LVMI and LVWT remained associated with AIx. Males with a high AIx had a 3.2-fold higher likelihood of HFpEF than those with a low AIx. In contrast, that association was not present in females. In summary, AIx is associated with the morphological domain of the HFA-PEFF score represented by LVMI and LVWT. Higher values of AIx are associated with a higher likelihood for HFpEF in elderly males but not in females.

The relationship of skin autofluorescence with diastolic function and HFA-PEFF score in a general population of older people.

BACKGROUND AND AIMS: Advanced glycation end-products accumulation in tissue as measured by Skin autofluorescence (SAF) is related to diastolic function in specific patient populations. This analysis aims at investigating this relationship in a general population of older persons. METHODS AND RESULTS: Based on data from the CARLA cohort at first follow-up, 245 subjects were analyzed and stratified according to cardiovascular risk factors (CVRF). We used linear regression to investigate the association between diastolic function evaluated by echocardiography, HFA-PEFF score, and SAF. Univariable regression analysis showed an association of SAF with septal-E/e' (standardised beta = 1.11, 95% CI = 0.51-1.71) and A (3.42, 95% CI = 0.72-6.12), the former persisting after adjustment for age, sex and CVRF (0.67, 95% CI = 0.05-1.28). Septal-E/e' remained related to SAF only in the high cardiovascular risk stratum (1.16, 95% CI = 0.26-2.06). SAF was related to HFA-PEFF score (0.27, 95% CI = 0.10-0.43) but not after correcting for age and sex (0.16, 95% CI = 0.00-0.32) and CVRF and glomerular filtration rate (0.12, 95% CI = -0.07 - 0.27). SAF was related to the HFA-PEFF score only for participants with high cardiovascular risk (0.23, 95% CI = 0.02-0.45). CONCLUSION: In a general community-dwelling older population, SAF is related to diastolic function as measured by septal-E/e'. Further research is necessary to assess if SAF is a potential screening tool for diastolic dysfunction in advanced age.

Predicting the Need for Renal Replacement Therapy Using a Vascular Occlusion Test and Tissue Oxygen Saturation in Patients in the Early Phase of Multiorgan Dysfunction Syndrome.

BACKGROUND: Acute kidney injury (AKI) is associated with an increased mortality in critically ill patients, especially in patients with multiorgan dysfunction syndrome (MODS). In daily clinical practice, the grading of AKI follows the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In most cases, a relevant delay occurs frequently between the onset of AKI and detectable changes in creatinine levels as well as clinical symptoms. The aim of the present study was to examine whether a near infrared spectroscopy (NIRS)-based, non-invasive ischemia-reperfusion test (vascular occlusion test (VOT)) together with unprovoked (under resting conditions) tissue oxygen saturation (StO2) measurements, contain prognostic information in the early stage of MODS regarding the developing need for renal replacement therapy (RRT). METHODS: Within a period of 18 months, patients at the medical intensive care unit of a tertiary university hospital with newly developed MODS (≤24 h after diagnosis, APACHE II score ≥20) were included in our study. The VOT occlusion slope (OS) and recovery slope (RS) were recorded in addition to unprovoked StO2. StO2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device. The VOT was carried out by inflating a blood pressure cuff on the upper arm. AKI stages were determined by the changes in creatinine levels, urinary output, and/or the need for RRT according to KDIGO. RESULTS: 56 patients with MODS were included in the study (aged 62.5 ± 14.4 years, 40 men and 16 women, APACHE II score 34.5 ± 6.4). Incidences of the different AKI stages were: no AKI, 16.1% (n = 9); AKI stage I, 19.6% (n = 11); AKI stage II, 25% (n = 14); AKI stage III, 39.3% (n = 22). Thus, 39.3% of the patients (n = 22) developed the need for renal replacement therapy (AKI stage III). These patients had a significantly higher mortality over 28 days (RRT, 72% (n = 16/22) vs. no RRT, 44% (n = 15/34); p = 0.03). The mean unprovoked StO2 of all patients at baseline was 81.7 ± 11.1%, and did not differ between patients with or without the need for RRT. Patients with RRT showed significantly weaker negative values of the OS (-9.1 ± 3.7 vs. -11.7 ± 4.1%/min, p = 0.01) and lower values for the RS (1.7 ± 0.9 vs. 2.3 ± 1.6%/s, p = 0.02) compared to non-dialysis patients. Consistent with these results, weaker negative values of the OS were found in higher AKI stages (no AKI, -12.7 ± 4.1%/min; AKI stage I, -11.5 ± 3.0%/min; AKI stage II, -11.1 ± 3.3%/min; AKI stage III, -9.1 ± 3.7%/min; p = 0.021). Unprovoked StO2 did not contain prognostic information regarding the AKI stages. CONCLUSIONS: The weaker negative values of the VOT parameter OS are associated with an increased risk of developing AKI and RRT, and increased mortality in the early phase of MODS, while unprovoked StO2 does not contain prognostic information in that regard.

Influence of inflammation and cardiac hypertrophy on mechanical properties of human pericardium.

Different devices for mechanical circulatory support (MCS) have been developed for the treatment of refractory cardiogenic shock. However, all of them are associated with direct blood contact, the need for anticoagulation and bleeding complications. To overcome these limitations the pericardial sac got into the focus as a promising implantation site for MCS. For this purpose, further knowledge about the mechanical properties of human pericardium is required. In this prospective, monocentric, experimental pilot study 56 samples of human pericardium were extracted postmortem from 13 critically ill patients. After preparation of test specimens uniaxial tensile tests were performed. The primary end points were load at fracture per sample width and strain at fracture. Acute inflammation was assessed by blood levels of C-reactive protein, white blood count and procalcitonin measured at several times during hospital stay. Inflammatory load was estimated by area under the inflammatory curves. Correlation and regression analysis were used to assess the relationship of primary end points to inflammation, comorbidities and postmortem time to preparation. Human pericardium showed a load at fracture per sample width of 1.95 [1.38-2.94] N/mm (median [inter quartile range]) and a strain at fracture of 89.29 [73.84-135.23] %. Markers of acute inflammation and cardiac hypertrophy did not correlate to load or strain at fracture. However, strain at fracture increased with higher body mass index and an increasing number of postmortem days. In contrast, higher patient age was associated with a lower strain at fracture. Inflammation and cardiac hypertrophy did not influence mechanical properties of human pericardium.

Cardiovascular risk factors, living and ageing in Halle: the CARLA study.

The CARLA study (Cardiovascular Disease, Living and Ageing in Halle) is a longitudinal population-based cohort study of the general population of the city of Halle (Saale), Germany. The primary aim of the cohort was to investigate risk factors for cardiovascular diseases based on comprehensive cardiological phenotyping of study participants and was extended to study factors associated with healthy ageing. In total, 1779 probands (812 women and 967 men, aged 45-83 years) were examined at baseline (2002-2005), with a first and second follow-up performed 4 and 8 years later. The response proportion at baseline was 64.1% and the reparticipation proportion for the first and second follow-up was 86% and 77% respectively. Sixty-four percent of the study participants were in retirement while 25% were full- or partially-employed and 11% were unemployed at the time of the baseline examination. The currently running third follow-up focuses on the assessment of physical and mental health, with an intensive 4 h examination program, including measurement of cardiovascular, neurocognitive, balance and gait parameters. The data collected in the CARLA Study resulted in answering various research questions in over 80 publications, of which two thirds were pooled analyses with other similar population-based studies. Due to the extensiveness of information on risk factors, subclinical conditions and evident diseases, the biobanking concept for the biosamples, the cohort representativeness of an elderly population, and the high level of quality assurance, the CARLA cohort offers a unique platform for further research on important indicators for healthy ageing.

[Influence of therapeutic temperature management on the clinical course in patients after in-hospital cardiac arrest : A retrospective analysis]. / Einfluss des therapeutischen Temperaturmanagements auf den klinischen Verlauf bei intrahospital reanimierten Patienten : Eine retrospektive Analyse.

METHODS: Retrospective analysis of all patients with in-hospital cardiac arrest and return of spontaneous circulation (ROSC) in the ICU of the cardiologic department of the University Hospital of Halle (Saale) between 1999 and 2009. RESULTS: During the observation period, 169 patients with in-hospital cardiac arrest and information regarding temperature measurements were treated. Invasive therapeutic temperature management (TTM+) was applied in 64 patients (37.9%), while 105 patients (62.1%) underwent no therapeutic temperature management (TTM-). TTM+ and TTM- showed no relevant differences regarding patient age (TTM+: 67.6 ± 12.6 years; TTM-: 69.8 ± 12.6 years; p = 0.257), comorbidities and the initial rhythm; however, there were more men in the TTM+ group (76.6% vs. 58.1%; p = 0.015). All patients had been intubated. Time until ROSC in TTM+ was significantly longer (25.9 ± 25.8 min vs. 15.0 ± 12.4 min; p < 0.005). TTM+ resulted in a lower 30-day survival and an unfavourable neurologic outcome (Glasgow outcome scale I or II: 75% TTM+ vs. 55.2% TTM-). This negative effect persisted after adjustment for age of the patients, but not after adjustment for age and duration of reanimation (nonadjusted odds ratio for adverse neurologic outcome under TTM+: 0.411 (p = 0.011); odds ratio after adjusting for age: 0.361 (p = 0.09); odds ratio after adjusting for age and duration of the reanimation: 0.505 (p = 0.121)).

Toxic Epidermal Necrolysis Caused by Allopurinol: A Serious but Still Underestimated Adverse Reaction.

BACKGROUND Allopurinol is the first-line therapy for the treatment of symptomatic hyperuricemia (gout). In clinical practice, there is a tendency to overmedicate asymptomatic patients who have elevated serum urate. Because of this practice, serious and life-threatening reactions such as Stevens-Johnson syndrome (SJS) or the more dramatic toxic epidermal necrolysis (TEN), both frequently caused by uricostatics, may occur. To increase awareness of these complications, we present a case with fulminant TEN caused by allopurinol. CASE REPORT A 75-year-old woman noticed a mildly itching skin rash accompanied by fever, shivering, and weakness approximately 3 weeks after taking newly prescribed allopurinol. The initial clinical examination revealed a generalized maculopapular exanthema. An adverse drug reaction was recognized, and allopurinol was discontinued. Ambulatory supportive therapy using prednisolone and cetirizine was started but failed. The patient developed a progressive exanthema with painful widespread blistering, skin peeling, and mucosal and conjunctival lesions. After recurrent presentations to the Emergency Department, the patient was transferred to our Intensive Care Unit (ICU). The clinical picture confirmed the suspected diagnosis of TEN. Massive fluid replacement, prednisolone, and cyclosporine were used as anti-inflammatory therapy. Polyhexanide and octenidine were applied for local treatment. All treatment measures were guided daily by a multidisciplinary team. After 7 days in the ICU, the patient was transferred to the Dermatology Department and was discharged from the hospital 42 days later. CONCLUSIONS With the prescription of allopurinol, there should be awareness of potentially life-threatening complications such as SJS or TEN. Patients with SJS or TEN should be immediately transferred to an ICU with dermatological expertise and multidisciplinary therapy.

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation-A Retrospective International Multicenter Study.

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. METHODS: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V­V ECMO (PRESERVE) Score, and 30-day survival. RESULTS: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic-AUROC) ranged between 0.548 and 0.605. CONCLUSIONS: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V­V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO.

Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.

BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.

Metabolically Healthy, but Obese Individuals and Associations with Echocardiographic Parameters and Inflammatory Biomarkers: Results from the CARLA Study.

INTRODUCTION: The research on heterogeneity among obese individuals has identified the metabolically healthy, but obese (MHO) phenotype as a distinct group that does not experience the typical cardiovascular-related diseases (CVD). It is unclear if this group differs with regard to preconditions for CVDs. Our aim was to assess differences in echocardiographic parameters and inflammatory biomarkers between MHO and metabolically healthy, normal weight individuals (MHNW). METHODS: The analyses used data from 1412 elderly participants from a German population-based cohort study (CARLA), which collected detailed information on demographic, biochemical, and echocardiographic variables. Participants were subdivided into four groups (MHNW, MHO, MUNW (metabolically unhealthy, normal weight) and MUO (metabolically unhealthy, obese)) based on BMI≥30 kg/m2 (obese or normal weight) and presence of components of the metabolic syndrome. The clinical characteristics of the 4 groups were compared with ANOVA or Chi-Square test, in addition to two linear regression models for 16 echocardiographic parameters. The difference in inflammatory biomarkers (hsCRP, IL-6 and sTNF-RI) between the groups was examined with a multinomial logistic regression model. RESULTS: The MHO individuals were on average 64.2±8.4 years old, with a higher proportion of women (71.6%), low percentage of smokers, larger waist circumference (109.3±10.5 cm vs 89.1±10.8 cm, p<0.0001) and higher odds ratios for hsCRP, IL-6 and sTNF-RI compared to MHNW individuals. Linear regression models revealed greater left atrial (LA) diameter (2.73 (95% CI: 1.35-4.11) mm), LA volume (7.86 (95% CI: 2.88-12.83) mL), and left ventricular mass index (LVMI) (11.82 (95% CI: 4.43-19.22) g/m1.7) in the MHO group compared to the MHNW group. CONCLUSION: The MHO phenotype is associated with echocardiographic markers of cardiac remodeling (LA diameter, volume and LVMI) and higher odds ratios for inflammatory biomarkers.

Prognostic Value of Tissue Oxygen Saturation Using a Vascular Occlusion Test in Patients in the Early Phase of Multiorgan Dysfunction Syndrome.

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is a common disease pattern in intensive care units which is associated with an increased mortality. The aim of this study was to investigate whether a near-infrared spectroscopy (NIRS)-based noninvasive ischemia-reperfusion test (vascular occlusion test) using the parameter of tissue oxygen saturation (StO2) contains prognostic information for patients in the early phase of MODS. METHODS: Within a period of 18 months between 2010 and 2012, 56 patients who newly developed MODS (≤24 h after diagnosis, Acute Physiology and Chronic Health Evaluation [APACHE] II score ≥20, subgroups: cardiogenic MODS [cMODS] and septic MODS [sMODS]) were included into the study. The StO2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device, InSpectra Tissue Spectrometer Model 650 (Hutchinson Technology Inc., Hutchinson, MN). The VOT was carried out by inflating a blood pressure cuff on the upper arm 30 mmHg above systolic blood pressure for 5 min. The parameters occlusion slope (OS) and recovery slope (RS) were recorded. RESULTS: Fifteen patients with cMODS and 41 patients with sMODS were included in the study (age: 62.5 ±â€Š14.4 years, 40 men and 16 women, APACHE II score: 34.6 ±â€Š6.4). Twenty-eight-day-mortality was 55.4% (cMODS: 7 out of 15 patients, sMODS: 24 out of 41 patients). The measurement of StO2 while applying the VOT at baseline showed an OS of -11.7 ±â€Š3.7%/min and an RS of 2.2 ±â€Š1.5%/s. Survivors had significantly better values compared with non-survivors at baseline regarding OS (-12.8 ±â€Š3.5%/min vs. -9.8 ±â€Š3.4%/min; P = 0.016) and RS (2.6 ±â€Š1.7%/s vs. 1.6 ±â€Š1.0%/s; P = 0.022). Receiver-operating characteristic (ROC) curves show that the area under the curve (AUC) for OS was found to be significantly related to 28-day mortality (AUC: 0.7; 95% confidence interval [CI]: 0.56-0.85; P = 0.01). However, using both univariate and multivariate binary logistic regression models, RS was significantly associated with increased 28-day mortality (OR [univariate model]: 1.21 [95% CI: 1.1-1.8]; OR [multivariate model]: 1.23 [95% CI: 1.1-1.3]). CONCLUSIONS: Impaired values of the VOT-parameters OS and RS are associated with an increased 28-day mortality in patients in the early phase of MODS.

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

PURPOSE: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). METHODS: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). RESULTS: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58-78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. CONCLUSIONS: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. TRIAL REGISTRATION: NCT01420744.

Optimal course of treatment in acute cardiogenic shock complicating myocardial infarction.

INTRODUCTION: About 5% of patients with myocardial infarction suffer from cardiogenic shock as a complication, with a mortality of ≥30%. Primary percutaneous coronary intervention as soon as possible is the most successful therapeutic approach. Prognosis depends not only on the extent of infarction, but also - and even more - on organ hypoperfusion with consequent development of multiple organ dysfunction syndrome. Areas covered: This review covers diagnostic, monitoring and treatment concepts relevant for caring patients with cardiogenic shock complicating myocardial infarction. All major clinical trials have been selected for review of the recent data. Expert commentary: For optimal care, not only primary percutaneous intervention of the occluded coronary artery is necessary, but also best intensive care medicine avoiding the development of multiple organ dysfunction syndrome and finally death. On contrary, intra-aortic balloon pump - though used for decades - is unable to reduce mortality of patients with cardiogenic shock complicating myocardial infarction.

Reducing Elevated Heart Rates in Patients with Multiple Organ Dysfunction Syndrome with The If (Funny Channel Current) Inhibitor Ivabradine.

INTRODUCTION: A heart rate higher than 90 beats/min indicates an unfavorable prognosis for patients with multiple organ dysfunction syndrome (MODS). We sought to investigate the effect of the pacemaker current (If) inhibitor ivabradine on heart rate, hemodynamics, and disease severity among patients with MODS. PATIENTS AND METHODS: In this prospective, controlled, randomized, open-label, two-arm phase II trial, 70 patients with MODS, a sinus rhythm of at least 90 beats/min, and contraindications to ß-blocker therapy were randomly assigned to receive the standard treatment ± ivabradine (5 mg twice daily) for 96 h via the enteral route. The primary outcome was the percentage of patients with a heart rate reduction of at least 10 beats/min after 96 h. Secondary outcomes included the effect of ivabradine on hemodynamics, disease severity, vasopressor use, mortality, and adverse events. RESULTS: There were no significant differences in the primary outcome between the ivabradine and control groups (P = 0.147). After 96 h, the daily median heart rate was reduced by 7 beats/min in the control group and by 16 beats/min in the ivabradine group (P = 0.014). No differences in secondary outcomes were observed. CONCLUSIONS: The number of critically ill patients with MODS and a sinus rhythm of at least 90 beats/min that experienced a heart rate reduction of at least 10 beats/min after oral ivabradine treatment did not differ significantly between groups. The moderate but significant reduction of heart rate by 7 beats/min did not affect hemodynamics or disease severity.