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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.

ObjectivesPreoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and orthopaedic surgery. However, much less is known about the association between preoperative serum albumin and clinical outcomes after liver surgery. In this study, we sought to determine whether hypoalbuminaemia before partial hepatectomy is associated with a worse postoperative outcome.DesignObservational study.SettingUniversity Medical Centre in Germany.ParticipantsWe analysed 154 patients enrolled in the perioperative PHYsostigmine prophylaxis for liver resection patients at risk for DELIrium and postOperative cognitive dysfunction (PHYDELIO) trial with a preoperative serum albumin assessment. Hypoalbuminaemia was defined as serum albumin Outcome measuresThe outcome parameters of interest were postoperative complications according to Clavien (moderate: I, II; major: ≥III), length of intensive care unit (ICU) stay, length of hospital stay and survival rates 1 year after surgery.ResultsPreoperative hypoalbuminaemia was associated with the occurrence of major postoperative complications (OR 3.051 (95% CI 1.197 to 7.775); p=0.019) after adjusting for age, sex, randomisation, American Society of Anesthesiologists physical status, preoperative diagnosis and Child-Pugh class. Both ICU and hospital lengths of stay were significantly prolonged in patients with preoperative hypoalbuminaemia (OR 2.573 (95% CI 1.015 to 6.524); p=0.047 and OR 1.296 (95% CI 0.254 to 3.009); p=0.012, respectively). One-year survival was comparable between patients with and without hypoalbuminaemia.ConclusionsWe found that low serum albumin before surgery was associated with a worse short-term outcome after partial hepatectomy, which strengthens the prognostic value of serum albumin in the setting of liver surgery.Trial registration numbersISRCTN18978802and EudraCT 2008-007237-47.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome. In adults, secondary HLH is mostly observed. HLH is often triggered by infections, malignancies or autoimmune disorders. However, HLH cases in association with immunotherapies have been described recently. HLH in critically ill patients is often difficult to differentiate from sepsis. Both conditions can also be present at the same time. Early diagnosis and timely initiation of an adequate immunosuppressive therapy are essential for the further course and the prognosis of HLH. Therefore, HLH should represent a differential diagnosis in critically ill patients with persistent fever and additional symptoms (e.g. enlarged spleen, neurologic symptoms) or laboratory parameters (e.g. hyperferritinemia, cytopenia, increased transaminases) compatible with HLH. The diagnosis of HLH is made using the HLH-2004 criteria. The probability of the presence of HLH can be calculated using the HScore. High-dose corticosteroids represent the cornerstone of HLH treatment. Etoposide, immunoglobulins, anakinra or other drugs are added depending on the trigger. The course of HLH is influenced by the time of treatment initiation, the underlying trigger and the response to treatment. Generally, the prognosis of critically ill HLH patients is poor.Bei der hämophagozytischen Lymphohistiozytose (HLH) handelt es sich um ein Hyperinflammationssyndrom bedingt durch aberrant aktivierte Makrophagen und T‑Zellen. Beim Erwachsenen ist in erster Linie die erworbene Form anzutreffen. Häufige Auslöser sind Infektionen, Malignome und Autoimmunerkrankungen. Zuletzt wurden zudem zunehmend Fälle berichtet, in denen das Auftreten im Zusammenhang mit stattgehabten Immuntherapien zu sehen war. Auf der Intensivstation ist die HLH aufgrund des ähnlichen klinischen Erscheinungsbilds oft schwer von der Sepsis abzugrenzen. Zum Teil liegen beide zeitgleich vor. Die frühzeitige Diagnosestellung und Einleitung einer adäquaten immunsuppressiven Therapie ist für den weiteren Verlauf und die Prognose der HLH essenziell. Deshalb muss bei kritisch kranken Patienten mit persistierendem Fieber und entsprechenden Symptomen (z. B. Splenomegalie, neurologische Auffälligkeiten) oder Laborveränderungen (z. B. erhöhter Ferritinwert, Zytopenie von 2 oder 3 Zellreihen, erhöhte Transaminasen) das Vorliegen einer HLH in Betracht gezogen werden. Die Diagnose wird mithilfe der HLH-2004-Kriterien gestellt. Mit dem HScore kann die Wahrscheinlichkeit des Vorliegens einer HLH berechnet werden. Hochdosierte Kortikosteroide stellen den Grundpfeiler der HLH-Therapie dar. Je nach Auslöser werden Etoposid, Immunglobuline, Anakinra oder weitere Medikamente ergänzt. Der Verlauf hängt neben einem frühzeitigen Behandlungsbeginn vom Auslöser sowie dem Ansprechen auf die Therapie ab. Insgesamt ist die Prognose der HLH trotz maximaler intensivmedizinischer Behandlung ungünstig und sie ist mit einer hohen Letalität assoziiert.

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 0.999, 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.

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 Charite - Universitatsmedizin 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.

Sepsis is one of the oldest and most elusive syndromes in medicine that is still incompletely understood. Biomarkers may help to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This will help to differentiate between systemic inflammation of infectious and noninfectious origin and aid therapeutic decision making, hence improve the prognosis for patients, guide antimicrobial therapy, and foster the development of novel adjunctive sepsis therapies. To reach this goal requires increased systematic investigation that includes twenty-first century scientific approaches and technologies and appropriate clinical evaluation.

Background: Elevated serum ferritin is a common condition in critically ill patients. It is well known that hyperferritinemia constitutes a good biomarker for hemophagocytic lymphohistiocytosis (HLH) in critically ill patients. However, further differential diagnoses of hyperferritinemia in adult critically ill patients remain poorly investigated. We sought to systematically investigate hyperferritinemia in adult critically ill patients without HLH. Methods: In this secondary analysis of a retrospective observational study, patients >= 18 years admitted to at least one adult intensive care unit at Charite-Universitatsmedizin Berlin between January 2006 and August 2018, and with hyperferritinemia of >= 500 mu g/L were included. Patients with HLH were excluded. All patients were categorized into non-sepsis, sepsis, and septic shock. They were also classified into 17 disease groups, based on their ICD-10 codes, and pre-existing immunosuppression was determined. Uni- and multivariable linear regression analyses were performed in all patients. Results: A total of 2583 patients were analyzed. Multivariable linear regression analysis revealed positive associations of maximum SOFA score, sepsis or septic shock, liver disease (except hepatitis), and hematological malignancy with maximum ferritin. T/NK cell lymphoma, acute myeloblastic leukemia, Kaposi's sarcoma, acute or subacute liver failure, and hepatic veno-occlusive disease were positively associated with maximum ferritin in post-hoc multivariable linear regression analysis. Conclusions: Sepsis or septic shock, liver disease (except hepatitis) and hematological malignancy are important differential diagnoses in hyperferritinemic adult critically ill patients without HLH. Together with HLH, they complete the quartet of important differential diagnoses of hyperferritinemia in adult critically ill patients. As these conditions are also related to HLH, it is important to apply HLH-2004 criteria for exclusion of HLH in hyperferritinemic patients. Hyperferritinemic critically ill patients without HLH require quick investigation of differential diagnoses.

Bei der hämophagozytischen Lymphohistiozytose (HLH) handelt es sich um ein Hyperinflammationssyndrom bedingt durch aberrant aktivierte Makrophagen und T‑Zellen. Beim Erwachsenen ist in erster Linie die erworbene Form anzutreffen. Häufige Auslöser sind Infektionen, Malignome und Autoimmunerkrankungen. Zuletzt wurden zudem zunehmend Fälle berichtet, in denen das Auftreten im Zusammenhang mit stattgehabten Immuntherapien zu sehen war. Auf der Intensivstation ist die HLH aufgrund des ähnlichen klinischen Erscheinungsbilds oft schwer von der Sepsis abzugrenzen. Zum Teil liegen beide zeitgleich vor. Die frühzeitige Diagnosestellung und Einleitung einer adäquaten immunsuppressiven Therapie ist für den weiteren Verlauf und die Prognose der HLH essenziell. Deshalb muss bei kritisch kranken Patienten mit persistierendem Fieber und entsprechenden Symptomen (z. B. Splenomegalie, neurologische Auffälligkeiten) oder Laborveränderungen (z. B. erhöhter Ferritinwert, Zytopenie von 2 oder 3 Zellreihen, erhöhte Transaminasen) das Vorliegen einer HLH in Betracht gezogen werden. Die Diagnose wird mithilfe der HLH-2004-Kriterien gestellt. Mit dem HScore kann die Wahrscheinlichkeit des Vorliegens einer HLH berechnet werden. Hochdosierte Kortikosteroide stellen den Grundpfeiler der HLH-Therapie dar. Je nach Auslöser werden Etoposid, Immunglobuline, Anakinra oder weitere Medikamente ergänzt. Der Verlauf hängt neben einem frühzeitigen Behandlungsbeginn vom Auslöser sowie dem Ansprechen auf die Therapie ab. Insgesamt ist die Prognose der HLH trotz maximaler intensivmedizinischer Behandlung ungünstig und sie ist mit einer hohen Letalität assoziiert.

Background Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment. Methods For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charite - Universitatsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis. Results Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (P = 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 μg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771-1.000; sensitivity 93.8%, specificity 78.9%). Conclusions Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring. Trial registration The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Zusammenfassung Die Hämophagozytische Lymphohistiozytose (HLH), in der Literatur auch Hämophagozytosesyndrom oder Makrophagenaktivierungssyndrom im Rahmen einer rheumatologischen Vorerkrankung, wird auf Intensivstationen aufgrund des sepsisähnlichen Krankheitsbildes in über 70 % der Fälle nicht erkannt. Es wird von einem 30-jährigen, zuvor gesunden Patienten berichtet, der nach einer 3‑monatigen Asien- und Südamerikareise mit unklarem Fieber zunächst auf die infektiologische Normalstation der Charité – Universitätsmedizin Berlin aufgenommen und nach 3 Tagen bei respiratorischer Insuffizienz auf die Intensivstation verlegt wurde. Durch die sofortige HLH-Diagnostik mit Initiierung der spezifischen immunsupprimierenden Therapie mittels Dexamethason, Immunglobulinen und Anakinra konnte der Patient nach insgesamt 14-tägigem Krankenhausaufenthalt vollständig genesen in die Häuslichkeit entlassen werden. Es werden weiterhin aktuelle diagnostische und therapeutische Möglichkeiten diskutiert. Ferritin als entscheidender diagnostischer Marker sollte bei jedem Patienten mit unklarem Organversagen bestimmt werden.

ZusammenfassungPatienten mit Multiorganversagen oder Sepsis, die nur unzureichend auf eine antiinfektive Therapie ansprechen oder bei denen keine infektiöse Ursache erkennbar ist, könnten als Ursache das Hyperinflammationssyndrom Hämophagozytische Lymphohistiozytose entwickelt haben. Dieses syndromale Krankheitsbild verläuft klinisch ähnlich der Sepsis und endet aufgrund der verzögerten Diagnosestellung mit irreversiblem Organversagen oft letal, wobei die Erkrankung auch im Rahmen einer Sepsis entstehen kann. Die Kenntnis dieses Syndroms ist für das Überleben der Patienten von herausragender Bedeutung.

Contains fulltext : 235065.pdf (Publisher’s version ) (Closed access) The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

Background Ferritin is the major iron storage protein and an acute phase reactant. Hyperferritinemia is frequently seen in the critically ill where it has been hypothesized that not only underlying conditions but also factors such as transfusions, hemodialysis and extracorporeal life support (ECLS) lead to hyperferritinemia. This study aims to investigate the influence of transfusions, hemodialysis, and ECLS on hyperferritinemia in a multidisciplinary ICU cohort. Methods This is a post-hoc analysis of a retrospective observational study including patients aged ≥ 18 years who were admitted to at least one adult ICU between January 2006 and August 2018 with hyperferritinemia ≥ 500 μg/L and of ≥ 14 days between two ICU ferritin measurements. Patients with hemophagocytic lymphohistiocytosis (HLH) were excluded. To identify the influence of transfusions, hemodialysis, and ECLS on ferritin change, multivariable linear regression analysis with ferritin change between two measurements as dependent variable was performed. Results A total of 268 patients was analyzed. Median duration between measurements was 36 days (22–57). Over all patients, ferritin significantly increased between the first and last measurement (p = 0.006). Multivariable linear regression analysis showed no effect of transfusions, hemodialysis, or ECLS on ferritin change. Changes in aspartate aminotransferase (ASAT) and sequential organ failure assessment (SOFA) score were identified as influencing factors on ferritin change [unstandardized regression coefficient (B) = 2.6; (95% confidence interval (CI) 1.9, 3.3); p < 0.001 and B = 376.5; (95% CI 113.8, 639.1); p = 0.005, respectively]. Using the same model for subgroups of SOFA score, we found SOFA platelet count to be associated with ferritin change [B = 1729.3; (95% CI 466.8, 2991.9); p = 0.007]. No association of ferritin change and in-hospital mortality was seen in multivariable analysis. Conclusions The present study demonstrates that transfusions, hemodialysis, and ECLS had no influence on ferritin increases in critically ill patients. Hyperferritinemia appears to be less the result of iatrogenic influences in the ICU thereby underscoring its unskewed diagnostic value. Trial registration The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

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.

BACKGROUND: Presurgical cognitive impairment (PreCI) is frequently seen in older age, but the influence on postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) remains unclear. The present study sought to determine the association between PreCI, POD and POCD with special focus to different PreCI domains. METHODS: We analyzed 934 patients with complete baseline neurocognitive assessment. PreCI was determined as cognitive performance of at least two standard deviation (SD) below the mean performance of non-surgical controls. POD was assessed according to the Diagnostic and Statistical Manual of Mental Disorders 4 (DSM-4). POCD at three months follow-up was calculated by the reliable change index (RCI). Associations between PreCI and POD or POCD were assessed using multivariable logistic regression models adjusted for age, sex, randomization, ASA status, type of anesthesia, and type of surgery. RESULTS: PreCI was significantly associated with POD [OR 1.936 (95%CI 1.119 to 3.348); P=0.015] and POCD [OR 3.091 (95%CI 1.287 to 7.426); P=0.012]. Patients with coincident PreCI and POD were significantly more likely to develop POCD [OR 6.131 (95%CI 1.476 to 22.364); P=0.007]. Differentiation between no PreCI, amnestic and non-amnestic PreCI revealed a sole influence of amnestic PreCI on POD and POCD. CONCLUSIONS: Patients ≥ 60 years with PreCI were more likely to develop POD and POCD, respectively. The odds for POCD were highest in patients with PreCI whom also suffered from POD. Amnestic rather than non-amnestic PreCI might play a key role in the development of POD and POCD. These results warrant further pathophysiological investigations and demand preventive strategies.

Background and purpose In hyperglycemic patients, who succumbed to septic shock, an increased rate of apoptosis of microglial cells and damaged neurons of the hippocampus were found. However, the influence of perioperative glucose levels on hippocampal brain structures has not yet been investigated. Methods As part of the ongoing BIOCOG project, a subgroup of N = 65 elderly nondemented patients were analyzed who underwent elective surgery of ≥60 minutes. In these patients, at least one intraoperative blood glucose (BG) measurement was available from the medical charts. Intraoperative glucose maximum was determined in each patient. Preoperatively and at 3 months follow-up, structural neuroimaging was performed with T1-weighted magnetization prepared rapid gradient-echo sequence (MP-Rage) and a dedicated high-resolution hippocampus magnetic resonance imaging (MRI). The MRI scans were analyzed to assess pre- or postoperative volume changes of the hippocampus as a whole and hippocampal subfields. We also assessed changes of frontal lobe volume and cortical thickness. Results Overall, 173 intraoperative BG levels were obtained in 65 patients (median 2 per patient). A total of 18 patients showed intraoperative hyperglycemia (glucose maximum ≥150 mg/dL). Controlling for age and diabetes status, no significant impact of intraoperative hyperglycemia was found on the pre-post volume change of the hippocampus as a whole, hippocampal subfields, frontal lobe, and frontal cortical thickness. Conclusions This study found no effect of intraoperative hyperglycemia on postoperative brain structures and volumes including volumes of hippocampus and hippocampal subfields, frontal lobe, and frontal cortical thickness. Further studies investigating the impact of intraoperatively elevated glucose levels should consider a tighter or even continuous glycemic measurement and the determination of central microglial activation.

Hemophagocytic lymphohistiocytosis in adults (aHLH) is a rare life-threatening hyperinflammatory syndrome caused by excessive activation of macrophages and CD8+ T-cells. Due to the clinical overlap with severe sepsis, aHLH often remains undiagnosed resulting in poor outcome. Here, we present a retrospective study of incidence, clinical findings, and the outcome of aHLH in intensive care units (ICUs).This retrospective analysis was performed at the university hospital Charité - Universitätsmedizin Berlin. We gathered data from 556 out of 46,532 patients admitted to our anesthesiological ICUs between 2006 and 2013, who had at least one plasma ferritin measurement during ICU treatment, and were at least 18 years old. Of these, 244 patients with ferritin at least 500 μg/L and available datasets of at least 4 HLH-2004 criteria were included. HLH-2004 diagnostic criteria and the recently published HScore were used. An aHLH expert team retrospectively reviewed the potential aHLH cases.Seventy-one of the included 244 patients died; 9 out of the 244 patients were retrospectively classified as aHLH of whom 4 patients had died (44.4%). Two of the 9 aHLH patients had been correctly diagnosed and had received specific aHLH treatment. Thus, 7 out of 9 patients (77.8%) remained undetected. ICU patients with at least 1 captured ferritin value and hyperferritinemia showed an aHLH rate of 3.7%, which rises up to 5.6% when only deceased patients are considered. Mortality in this selected cohort is 44.4%.Overall, 7 out of 9 patients (77.8%) suffering from aHLH remained undiagnosed. Awareness of this life-threatening syndrome, especially in ICUs, should be raised. The inclusion of ferritin into the admission lab panel for ICU is warranted.Clinical trial registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016. As this is a retrospective study, trial registration was after final data collection date.

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.

Sepsis is one of the oldest and most elusive syndromes in medicine that is still incompletely understood. Biomarkers may help to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This will help to differentiate between systemic inflammation of infectious and noninfectious origin and aid therapeutic decision making, hence improve the prognosis for patients, guide antimicrobial therapy, and foster the development of novel adjunctive sepsis therapies. To reach this goal requires increased systematic investigation that includes twenty-first century scientific approaches and technologies and appropriate clinical evaluation.

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.

Background Hyperglycemia frequently occurs during major surgery and is associated with adverse postoperative outcomes. This study aimed to investigate the influence of intraoperative hyperglycemia on incidences of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Methods Eighty-seven patients aged ≥65 years undergoing elective surgery were included in this prospective observational subproject of the BioCog study. Blood glucose (BG) levels were measured every 20 minutes intraoperatively. Hyperglycemia was defined as BG levels ≥150 mg·dL-1. Patients were assessed for POD twice daily until postoperative day 7. The occurrence of POCD was determined three months after surgery. Multivariable logistic regression was used to identify associations between hyperglycemia and POD as well as POCD. Secondary endpoints comprised duration of hyperglycemia, maximum glucose level (Glucosemax) and differences between diabetic and non-diabetic patients. Results POD occurred in 41 (47.1%), POCD in five (15.2%) patients. In two separate multivariable logistic regression models, hyperglycemia was significantly associated with POD (OR 3.86 [CI 95% 1.13, 39.49], P=0.044) but not POCD (3.59 [NaN, NaN], P=0.157). Relative duration of hyperglycemia was higher in POD patients compared to patients without POD (20 [0; 71] % versus 0 [0; 55] %, P=0.075), whereas the maximum glucose levels during surgery were similar between the two groups. Considering only non-diabetic patients, relative duration of hyperglycemia (P=0.003) and Glucosemax (P=0.015) were significantly higher in patients with POD. Conclusions Intraoperative hyperglycemia was independently associated with POD but not POCD. Relative duration of hyperglycemia appeared thereby to also play a role. Especially hyperglycemic non-diabetic patients might be at high risk for POD.

Item does not contain fulltext Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.

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.

Model animal; COVID-19; Recerca preclínica Modelo animal; COVID-19; Investigación preclínica Animal model; COVID-19; Pre-clinical research Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

Background Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T‑cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease. Missed or late diagnosis is believed to be a major cause of the high mortality. Objectives To describe the current knowledge on HLH and to raise awareness. Materials and methods Analysis of case reports, current studies, and expert recommendations. Results Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with a clinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. A promising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. Conclusions Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.

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.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.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.

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.

In hyperglycemic patients, who succumbed to septic shock, an increased rate of apoptosis of microglial cells and damaged neurons of the hippocampus were found. However, the influence of perioperative glucose levels on hippocampal brain structures has not yet been investigated.As part of the ongoing BIOCOG project, a subgroup of N = 65 elderly nondemented patients were analyzed who underwent elective surgery of ≥60 minutes. In these patients, at least one intraoperative blood glucose (BG) measurement was available from the medical charts. Intraoperative glucose maximum was determined in each patient. Preoperatively and at 3 months follow-up, structural neuroimaging was performed with T1-weighted magnetization prepared rapid gradient-echo sequence (MP-Rage) and a dedicated high-resolution hippocampus magnetic resonance imaging (MRI). The MRI scans were analyzed to assess pre- or postoperative volume changes of the hippocampus as a whole and hippocampal subfields. We also assessed changes of frontal lobe volume and cortical thickness.Overall, 173 intraoperative BG levels were obtained in 65 patients (median 2 per patient). A total of 18 patients showed intraoperative hyperglycemia (glucose maximum ≥150 mg/dL). Controlling for age and diabetes status, no significant impact of intraoperative hyperglycemia was found on the pre-post volume change of the hippocampus as a whole, hippocampal subfields, frontal lobe, and frontal cortical thickness.This study found no effect of intraoperative hyperglycemia on postoperative brain structures and volumes including volumes of hippocampus and hippocampal subfields, frontal lobe, and frontal cortical thickness. Further studies investigating the impact of intraoperatively elevated glucose levels should consider a tighter or even continuous glycemic measurement and the determination of central microglial activation.

Insa Feinkohl,1,* Gunnar Lachmann,2,* Wolf-Rüdiger Brockhaus,2 Friedrich Borchers,2 Sophie K Piper,3 Thomas H Ottens,4 Hendrik M Nathoe,5 Anne-Mette Sauer,4 Jan M Dieleman,4 Finn M Radtke,6 Diederik van Dijk,7 Tobias Pischon,1,8,9,* Claudia Spies2,* 1Molecular Epidemiology Research Group, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin-Buch, Germany; 2Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 3Institute of Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 4Department of Anesthesiology, University Medical Center Utrecht, Utrecht, the Netherlands; 5Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; 6Department of Anesthesiology, Naestved Hospital, Naestved, Denmark; 7Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; 8Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 9MDC/BIH Biobank, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), and Berlin Institute of Health (BIH), Berlin, Germany *These authors contributed equally to this work Background: Age-related cognitive impairment is rising in prevalence but is not yet fully characterized in terms of its epidemiology. Here, we aimed to elucidate the role of obesity, diabetes and hypertension as candidate risk factors. Methods: Original baseline data from 3 studies (OCTOPUS, DECS, SuDoCo) were obtained for secondary analysis of cross-sectional associations of diabetes, hypertension, blood pressure, obesity (body mass index [BMI] ≥30 kg/m²) and BMI with presence of cognitive impairment in log-binomial regression analyses. Cognitive impairment was defined as scoring more than 2 standard deviations below controls on at least one of 5–11 cognitive tests. Underweight participants (BMI

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.

BACKGROUND: Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality. Postoperative infections are particularly common in the setting of preoperative hyperglycemia; however, the relationship between perioperative glucose levels and the innate immune system remains unclear. METHODS: Immune cells, monocytic respectively T cell function and T cell subspecies of 32 patients after esophageal or pancreatic resection were analyzed preoperatively and on the first day after surgery (pod1). Perioperative blood glucose was measured hourly via arterial blood gas analyses. Groups were classified by maximum perioperative glucose levels

Background. Monocytic human leukocyte antigen D related (mHLA-DR) is essential for antigen-presentation. Downregulation of mHLA-DR emerged as a general biomarker of impaired immunity seen in patients with sepsis and pneumonia and after major surgery. Influencing factors of mHLA-DR such as age, overweight, diabetes, smoking, and gender remain unclear. Methods. We analyzed 20 patients after esophageal or pancreatic resection of a prospective, randomized, placebo-controlled, double-blind trial (placebo group). mHLA-DR was determined from day of surgery (od) until postoperative day (pod) 5. Statistical analyses were performed using multivariate generalized estimating equation analyses (GEE), nonparametric multivariate analysis of longitudinal data, and univariate post hoc nonparametric Mann–Whitney tests. Results. In GEE, smoking and gender were confirmed as significant influencing factors over time. Univariate analyses of mHLA-DR between smokers and nonsmokers showed lower preoperative levels (p=0.010) and a trend towards lower levels on pod5 (p=0.056) in smokers. Lower mHLA-DR was seen in men on pod3 (p=0.038) and on pod5 (p=0.026). Overweight patients (BMI > 25 kg/m2) had lower levels of mHLA-DR on pod3 (p=0.039) and pod4 (p=0.047). Conclusion. Smoking is an important influencing factor on pre- and postoperative immune function while postoperative immune function was influenced by gender and overweight. Clinical trial registered with ISRCTN27114642.

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.

Purpose Surgical patients are at high risk for developing infectious complications and postoperative delirium. Prolonged infections and delirium result in worse outcome. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and influenza vaccination are known to increase HLA-DR on monocytes and improve immune reactivity. This study aimed to investigate whether GM-CSF or vaccination reverses monocyte deactivation. Secondary aims were whether it decreases infection and delirium days after esophageal or pancreatic resection over time. Methods In this prospective, randomized, placebo-controlled, double-blind, double dummy trial setting on an interdisciplinary ICU of a university hospital 61 patients with immunosuppression (monocytic HLA-DR [mHLA-DR]