An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

BACKGROUND: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 µg/L) and underwent bone marrow biopsy during their ICU course. RESULTS: Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.

Interdisciplinary perspectives on computed tomography in sepsis: survey among medical doctors at a large university medical center.

OBJECTIVES: This study aims to describe physicians' perspectives on the use of computed tomography (CT) in patients with sepsis. METHODS: In January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed. RESULTS: Physicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria - "signs of decreased vigilance" (89.2%, n = 331/371) and "increased catecholamine demand" (84.7%, n = 314/371) - were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1-6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis. CONCLUSION: Despite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication. KEY POINTS: Despite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties. The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients. Timing of CT reflects the requirements of specific disciplines.

Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

The association between intraoperative hyperglycemia and cerebrovascular markers.

BACKGROUND AND PURPOSE: Hyperglycemia can lead to an increased rate of apoptosis of microglial cells and to damaged neurons. The relation between hyperglycemia and cerebrovascular markers on MRI is unknown. Our aim was to study the association between intraoperative hyperglycemia and cerebrovascular markers. METHODS: In this further analysis of a subgroup investigation of the BIOCOG study, 65 older non-demented patients (median 72 years) were studied who underwent elective surgery of ≥ 60 minutes. Intraoperative blood glucose maximum was determined retrospectively in each patient. In these patients, preoperatively and at 3 months follow-up a MRI scan was performed and white matter hyperintensity (WMH) volume and shape, infarcts, and perfusion parameters were determined. Multivariable logistic regression analyses were performed to determine associations between preoperative cerebrovascular markers and occurrence of intraoperative hyperglycemia. Linear regression analyses were performed to assess the relation between intraoperative hyperglycemia and pre- to postoperative changes in WMH volume. Associations between intraoperative hyperglycemia and postoperative WMH volume at 3 months follow-up were also assessed by linear regression analyses. RESULTS: Eighteen patients showed intraoperative hyperglycemia (glucose maximum ≥ 150 mg/dL). A preoperative more smooth shape of periventricular and confluent WMH was related to the occurrence of intraoperative hyperglycemia [convexity: OR 33.318 (95 % CI (1.002 - 1107.950); p = 0.050]. Other preoperative cerebrovascular markers were not related to the occurrence of intraoperative hyperglycemia. Intraoperative hyperglycemia showed no relation with pre- to postoperative changes in WMH volume nor with postoperative WMH volume at 3 months follow-up. CONCLUSIONS: We found that a preoperative more smooth shape of periventricular and confluent WMH was related to the occurrence of intraoperative hyperglycemia. These findings may suggest that a similar underlying mechanism leads to a certain pattern of vascular brain abnormalities and an increased risk of hyperglycemia.

Treatment and Mortality of Hemophagocytic Lymphohistiocytosis in Adult Critically Ill Patients: A Systematic Review With Pooled Analysis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis is a cytokine release syndrome caused by uncontrolled immune activation resulting in multiple organ failure and death. In this systematic review, we aimed to analyze triggers, various treatment modalities, and mortality in critically ill adult hemophagocytic lymphohistiocytosis patients. DATA SOURCES: MEDLINE database (PubMed) at October 20, 2019. STUDY SELECTION: Studies and case series of patients greater than or equal to 18 years old, of whom at least one had to be diagnosed with hemophagocytic lymphohistiocytosis and admitted to an ICU. DATA EXTRACTION: Source data of studies and case series were summarized and analyzed on an individual basis. Multivariable logistic regression analysis was performed adjusting for age, sex, and trigger groups. Each single treatment agent was entered as a dichotomous variable to determine treatments associated with survival, regardless if given alone or in combination. DATA SYNTHESIS: In total, 661 patients from 65 studies and case series were included. Overall mortality was 57.8%. Infections were the most frequent trigger (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%), unknown triggers (9.4%), and drugs (0.6%). Treatment with IV immunoglobulins was associated with improved survival (odds ratio, 0.548; 95% CI, 0.337-0.891; p = 0.015), while treatment with cyclosporine was associated with increased risk of death (odds ratio, 7.571; 95% CI, 3.702-15.483; p < 0.001). Considering different trigger groups separately, same results occurred only for infection-triggered hemophagocytic lymphohistiocytosis. No information was available on disease severity and other confounding factors. CONCLUSIONS: Mortality of hemophagocytic lymphohistiocytosis in the ICU is high. Most common triggers were infections. Results of survival analyses may be biased by treatment indication and disease severity. Future studies prospectively investigating treatment tailored to critically ill hemophagocytic lymphohistiocytosis patients are highly warranted.

Hyperferritinemia in Critically Ill Patients.

OBJECTIVE: Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. DESIGN: Retrospective observational study. SETTING: Adult surgical, anesthesiologic, and medical ICUs of a university hospital. PATIENTS: Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949-0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384-1.665 per log µg/L]; p < 0.001). CONCLUSIONS: This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted.

Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare though often fatal hyperinflammatory syndrome mimicking sepsis in the critically ill. Diagnosis relies on the HLH-2004 criteria and HScore, both of which have been developed in pediatric or adult non-critically ill patients, respectively. Therefore, we aimed to determine the sensitivity and specificity of HLH-2004 criteria and HScore in a cohort of adult critically ill patients. METHODS: In this further analysis of a retrospective observational study, patients ≥ 18 years admitted to at least one adult ICU at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with hyperferritinemia of ≥ 500 µg/L were included. Patients' charts were reviewed for clinically diagnosed or suspected HLH. Receiver operating characteristics (ROC) analysis was performed to determine prediction accuracy. RESULTS: In total, 2623 patients with hyperferritinemia were included, of whom 40 patients had HLH. We found the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity). By adjusting HLH-2004 criteria cutoffs of both hyperferritinemia to 3000 µg/L and fever to 38.2 °C, sensitivity and specificity increased to 97.5% and 96.1%, respectively. Both a higher number of fulfilled HLH-2004 criteria [OR 1.513 (95% CI 1.372-1.667); p <  0.001] and a higher HScore [OR 1.011 (95% CI 1.009-1.013); p <  0.001] were significantly associated with in-hospital mortality. CONCLUSIONS: An HScore cutoff of 168 revealed a sensitivity of 100% and a specificity of 94.1%, thereby providing slightly superior diagnostic accuracy compared to HLH-2004 criteria. Both HLH-2004 criteria and HScore proved to be of good diagnostic accuracy and consequently might be used for HLH diagnosis in critically ill patients. CLINICAL TRIAL REGISTRATION: The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Epidural Anesthesia in Liver Surgery-A Propensity Score-Matched Analysis.

OBJECTIVE: To assess the effects of epidural anesthesia (EA) on patients who underwent liver resection. DESIGN: Secondary analysis of a prospective randomized controlled trial. SETTING: This single-center study was conducted at an academic medical center. METHODS: A subset of 110 1:1 propensity score-matched patients who underwent liver resection with and without EA were analyzed. Outcome measures were pain intensity ≥5 on a numeric rating scale (NRS) at rest and during movement on postoperative days 1-5, analyzed with logistic mixed-effects models, and postoperative complications according to the Clavien-Dindo classification, length of hospital stay (LOS), and one-year survival. One-year survival in the matched cohorts was compared using a frailty model. RESULTS: EA patients were less likely to experience NRS ≥5 at rest (odds ratio = 0.06, 95% confidence interval [CI] = 0.01 to 0.28, P < 0.001). These findings were independent of age, sex, Charlson comorbidity index, baseline NRS, and surgical approach (open vs laparoscopic). The number and severity of postoperative complications and LOS were comparable between groups (P = 0.258, P > 0.999, and P = 0.467, respectively). Reduced mortality rates were seen in the EA group one year after surgery (9.1% vs 30.9%, hazard ratio = 0.32, 95% CI = 0.11 to 0.90, P = 0.031). No EA-related adverse events occurred. Earlier recovery of bowel function was seen in EA patients. CONCLUSIONS: Patients with EA had better postoperative pain control and required fewer systemic opioids. Postoperative complications and LOS did not differ, although one-year survival was significantly improved in patients with EA. EA applied in liver surgery was effective and safe.

Perioperatively Acquired Weakness.

BACKGROUND: Skeletal muscle failure in critical illness (intensive care unit-acquired weakness) is a well-known complication developing early during intensive care unit stay. However, muscle weakness during the perioperative setting has not yet been investigated. METHODS: We performed a subgroup investigation of a prospective observational trial to investigate perioperative muscle weakness. Eighty-nine patients aged 65 years or older were assessed for handgrip strength preoperatively, on the first postoperative day, at intensive care unit discharge, at hospital discharge, and at 3-month follow-up. Functional status was evaluated perioperatively via Barthel index, instrumental activities of daily living, Timed Up and Go test, and functional independence measure. After exclusion of patients with intensive care unit-acquired weakness or intensive care unit stay of ≥72 hours, 59 patients were included into our analyses. Of these, 14 patients had additional pulmonary function tests preoperatively and on postoperative day 1. Blood glucose was measured intraoperatively every 20 minutes. RESULTS: Handgrip strength significantly decreased after surgery on postoperative day 1 by 16.4% (P < .001). Postoperative pulmonary function significantly decreased by 13.1% for vital capacity (P = .022) and 12.6% for forced expiratory volume in 1 second (P = .001) on postoperative day 1. Handgrip strength remained significantly reduced at hospital discharge (P = .016) and at the 3-month follow-up (P = .012). Perioperative glucose levels showed no statistically significant impact on muscle weakness. Instrumental activities of daily living (P < .001) and functional independence measure (P < .001) were decreased at hospital discharge, while instrumental activities of daily living remained decreased at the 3-month follow-up (P = .026) compared to preoperative assessments. CONCLUSIONS: Perioperatively acquired weakness occurred, indicated by a postoperatively decreased handgrip strength, decreased respiratory muscle function, and impaired functional status, which partly remained up to 3 months.

Risk Factors of Intraoperative Dysglycemia in Elderly Surgical Patients.

BACKGROUNDː Dysglycemia is associated with adverse outcome including increased morbidity and mortality in surgical patients. Acute insulin resistance due to the surgical stress response is seen as a major cause of so-called stress hyperglycemia. However, understanding of factors determining blood glucose (BG) during surgery is limited. Therefore, we investigated risk factors contributing to intraoperative dysglycemia. METHODSː In this subgroup investigation of the BIOCOG study, we analyzed 87 patients of ≥ 65 years with tight intraoperative BG measurement every 20 min during elective surgery. Dysglycemia was defined as at least one intraoperative BG measurement outside the recommended target range of 80-150 mg/dL. Additionally, all postoperative BG measurements in the ICU were obtained. Multivariable logistic regression analysis adjusted for age, sex, American Society of Anesthesiologists (ASA) status, diabetes, type and duration of surgery, minimum Hemoglobin (Hb) and mean intraoperative norepinephrine use was performed to identify risk factors of intraoperative dysglycemia. RESULTSː 46 (52.9%) out of 87 patients developed intraoperative dysglycemia. 31.8% of all intraoperative BG measurements were detected outside the target range. Diabetes [OR 9.263 (95% CI 2.492, 34.433); p=0.001] and duration of surgery [OR 1.005 (1.000, 1.010); p=0.036] were independently associated with the development of intraoperative dysglycemia. Patients who experienced intraoperative dysglycemia had significantly elevated postoperative mean (p<0.001) and maximum BG levels (p=0.001). Length of ICU (p=0.007) as well as hospital stay (p=0.012) were longer in patients with dysglycemia. CONCLUSIONSː Diabetes and duration of surgery were confirmed as independent risk factors for intraoperative dysglycemia, which was associated with adverse outcome. These patients, therefore, might require intensified glycemic control. Increased awareness and management of intraoperative dysglycemia is warranted.

C-reactive protein for risk prediction of post-operative delirium and post-operative neurocognitive disorder.

BACKGROUND: Post-operative delirium (POD) and post-operative neurocognitive disorder (NCD) are frequently seen in the elderly. Development of biomarkers for pre-operative risk prediction is of major relevance. As inflammation present before surgery might predispose to POD and post-operative NCD development, we aim to determine associations between pre-operative C-reactive protein (CRP) and the incidence of POD and post-operative NCD. METHODS: In this observational study, we analyzed 314 patients enrolled in the SuDoCo trial, who had a pre-operative CRP measurement the day before surgery. Primary outcomes were POD assessed according DSM-4 from day 1 until day 7 after surgery and post-operative NCD assessed 3 months after surgery. We conducted multivariable logistic regression analysis adjusted for age, sex, randomization, body mass index, MMSE, ASA status, infection/autoimmune disease/malignoma and types of surgery to determine associations between CRP with POD and post-operative NCD, respectively. RESULTS: Pre-operative CRP was independently associated with POD [OR 1.158 (95% CI 1.040, 1.291); P = .008]. Patients with CRP values ≥5 mg/dL had a 4.8-fold increased POD risk [OR 4.771 (95% CI 1.765, 12.899; P = .002)] compared to patients with lower CRP values. However, no association was seen between pre-operative CRP and post-operative NCD [OR 0.552 (95% CI 0.193, 1.581); P = .269]. CONCLUSIONS: Pre-operative CRP levels were independently associated with POD but not post-operative NCD after three months. Moreover, higher pre-operative CRP levels showed higher risk for POD. This strengthens the role of inflammation in the development of POD. Assessment of CRP before surgery might allow risk stratification of POD. TRIAL REGISTRATION: This study was registered with ISRCTN Register 36437985 on 02 March 2009.

[Hemophagocytic lymphohistiocytosis in unspecific virus infection]. / Hämophagozytische Lymphohistiozytose bei unspezifischer Virusinfektion.

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome or macrophage activation syndrome within a pre-existing rheumatological disease, remains undiagnosed in over 70% of all cases in intensive care units (ICU) due to the sepsis-like clinical presentation. This report describes the case of a 30-year-old previously healthy male patient who was admitted to the normal infectiology ward of the Charité - Universitätsmedizin Berlin with unclear fever after a 3­month journey around Asian and South America. The patient was transferred to the ICU after 3 days because of respiratory failure. Due to the immediate diagnostics of HLH and initiation of specific immunosuppressive treatment with dexamethasone, immunoglobulins and anakinra, the patient completely recovered and could finally be discharged after a 2­week stay in hospital. Furthermore, the current diagnostic and therapeutic options are discussed. Ferritin is a decisive diagnostic marker that should be determined in every patient with unclear organ failure.

Diabetes, but Not Hypertension and Obesity, Is Associated with Postoperative Cognitive Dysfunction.

BACKGROUND/AIMS: Older people undergoing surgery are at risk of developing postoperative cognitive dysfunction (POCD), but little is known of risk factors predisposing patients to POCD. Our objective was to estimate the risk of POCD associated with exposure to preoperative diabetes, hypertension, and obesity. METHODS: Original data from 3 randomised controlled trials (OCTOPUS, DECS, SuDoCo) were obtained for secondary analysis on diabetes, hypertension, baseline blood pressure, obesity (BMI ≥30 kg/m2), and BMI as risk factors for POCD in multiple logistic regression models. Risk estimates were pooled across the 3 studies. RESULTS: Analyses totalled 1,034 patients. POCD occurred in 5.2% of patients in DECS, in 9.4% in SuDoCo, and in 32.1% of patients in OCTOPUS. After adjustment for age, sex, surgery type, randomisation, obesity, and hypertension, diabetes was associated with a 1.84-fold increased risk of POCD (OR 1.84; 95% CI 1.14, 2.97; p = 0.01). Obesity, BMI, hypertension, and baseline blood pressure were each not associated with POCD in fully adjusted models (all p > 0.05). CONCLUSION: Diabetes, but not obesity or hypertension, is associated with increased POCD risk. Consideration of diabetes status may be helpful for risk assessment of surgical patients.

Innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression.

Background: Postoperative immune suppression, particularly a loss of cell-mediated immunity, is commonly seen after surgery and is associated with worse outcome, i.e. delayed wound healing, infections, sepsis, multiple-organ failure and cancer recurrence. However, the recovery of immune cells focusing on differences between innate and acquired immunity during severe postoperative immunosuppression is not investigated. Methods: In this retrospective randomized controlled trial (RCT) subgroup analysis, 10 postoperatively immune suppressed patients after esophageal or pancreatic resection were analyzed. Innate and acquired immune cells, the expression of human leukocyte antigen-D related on monocytes (mHLA-DR), lipopolysaccharide (LPS)-induced monocytic TNF-α and IL-10 secretion ex vivo, Concanavalin A (Con A)-induced IFN-γ, TNF-α, IL-2, IL-4, IL-5 and IL-10 release were measured preoperatively (od) until day 5 after surgery (pod5). Recovery of immune cells was defined by a significant decrease respectively increase after a significant postoperative alteration. Statistical analyses were performed using nonparametric statistical procedures. Results: Postoperative alterations of innate immune cells recovered on pod2 (eosinophils), pod3 (neutrophils) and pod5 (mHLA-DR, monocytic TNF-α and IL-10 secretion), whereas alterations of acquired immune cells (lymphocytes, T cells, T helper cells, and cytotoxic T cells) did not recover until pod5. Peripheral blood T cells showed an impaired production of the T helper (Th) 1 cytokine IFN-γ upon Con A stimulation on pod1, while Th2 specific cytokine release did not change until pod5.Conclusions: Innate immunity recovered earlier than acquired immunity during severe postoperative immunosuppression. Furthermore, we found a more anti- than pro-inflammatory T cell function on the first day after surgery, while T cell counts decreased.

In vivo application of Granulocyte-Macrophage Colony-stimulating Factor enhances postoperative qualitative monocytic function.

BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) can be used as a potent stimulator for immune suppressed patients as defined by a decrease of human leukocyte antigen-D related expression on monocytes (mHLA-DR) after surgery. However, the exact role of GM-CSF on monocytic and T cell function is unclear. METHODS: In this retrospective randomized controlled trial (RCT) subgroup analysis, monocytic respectively T cell function and T cell subspecies of 20 immune suppressed (i.e. mHLA-DR levels below 10,000 monoclonal antibodies (mAb) per cell at the first day after surgery) patients after esophageal or pancreatic resection were analyzed. Each 10 patients received either GM-CSF (250 µg/m²/d) or placebo for a maximum of three consecutive days if mHLA-DR levels remained below 10,000 mAb per cell. mHLA-DR and further parameters of immune function were measured preoperatively (od) until day 5 after surgery (pod5). Statistical analyses were performed using nonparametric statistical procedures. RESULTS: In multivariate analysis, mHLA-DR significantly differed between the groups (p < 0.001). mHLA-DR was increased on pod2 (p < 0.001) and pod3 (p = 0.002) after GM-CSF application. Tumor necrosis factor-α (TNF-α) release of lipopolysaccharide (LPS) stimulated monocytes multivariately significantly differed between the groups (p < 0.008) and was increased in the GM-CSF group on pod2 (p < 0.001) and pod3 (p = 0.046). Th17/regulatory T (Treg) cell ratio was higher after GM-CSF treatment on pod2 (p = 0.041). No differences were seen in lymphocytes and T helper cell (Th)1/Th2 specific cytokine production after T cell stimulation with Concanavalin (Con) A between the groups. CONCLUSIONS: Postoperative application of GM-CSF significantly enhanced qualitative monocytic function by increased mHLA-DR and TNF-α release after LPS stimulation and apparently enhanced Th17/Treg ratio. Clinical trial registered with www.controlled-trials.com (ISRCTN27114642) 05 December 2008.

Peri- and postoperative cognitive and consecutive functional problems of elderly patients.

PURPOSE OF REVIEW: From an elderly patient's perspective, acute and chronic cognitive disturbances are among the most harmful complications that can occur following surgery. For elderly patients, these complications often mean the end of an independent life. This article focuses on this serious aspect, which is increasingly prevalent in our aging society. Cognitive disturbances are associated with severe outcome impairments and increased mortality. This article aims to provide a current overview regarding the diagnosis, pathophysiology, prevention, and treatment of this severe social problem. RECENT FINDINGS: The current knowledge of risk factors, diagnosis, prevention, and treatment of postoperative delirium and postoperative cognitive dysfunction should help to raise awareness and improve the outcome of delirious patients, particularly in the elderly population. SUMMARY: Especially in elderly patients, postoperative delirium constitutes a common, severe complication. Early diagnosis and supportive treatment are essential to improve outcome. To date, no pharmacological treatment strategy was effective, so that further research about the underlying pathophysiology and the development of treatment strategies are urgently required.

Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine.

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.

Circadian rhythm disruption in critically ill patients.

Patients admitted to the intensive care unit (ICU) are in need of continuous organ replacement strategies and specialized care, for example because of neurological dysfunction, cardio-pulmonary instability, liver or kidney failure, trauma, hemorrhagic or septic shock or even preterm birth. The 24-h nursing and care interventions provided to critically ill patients significantly limit resting and/or recovery phases. Consecutively, the patient's endogenous circadian rhythms are misaligned and disrupted, which in turn may interfere with their critical condition. A more thorough understanding of the complex interactions of circadian effectors and tissue-specific molecular clocks could therefore serve as potential means for enhancing personalized treatment in critically ill patients, conceivably restoring their circadian network and thus accelerating their physical and neurocognitive recovery. This review addresses the overarching issue of how circadian rhythms are affected and disturbed in critically ill newborns and adults in the ICU, and whether the conflicting external or environmental cues in the ICU environment further promote disruption and thus severity of illness. We direct special attention to the influence of cell-type specific molecular clocks on with severity of organ dysfunctions such as severity of brain dysfunction, pneumonia- or ventilator-associated lung inflammation, cardiovascular instability, liver and kidney failure, trauma, and septic shock. Finally, we address the potential of circadian rhythm stabilization to enhance and accelerate clinical recovery.